СЕЛЕКТИВНЫЕ ИНГИБИТОРЫ ГЛИКОЗИДАЗЫ И ИХ ПРИМЕНЕНИЕ

Изобретение относится к соединениям, представленным формулами (1), (2) или (3), или их фармацевтически приемлемой соли. Изобретение также относится к фармацевтической композиции, включающей в качестве активного ингредиента соединение, представленное формулами (1), (2) или (3), обладающей ингибирующей активностью в отношении O-GlcNAcase, или его фармацевтически приемлемую соль и фармацевтически приемлемый носитель. Соединения или их фармацевтически приемлемая соль предназначены для лечения Альцгеймера, болезни Паркинсона или прогрессирующего супрануклеарного паралича (PSP) у пациента человека, нуждающегося в этом. Технический результат – соединения, являющиеся селективными ингибиторами гликозидазы. 12 н. и 33 з.п. ф-лы, 6 табл., 33 пр.(1),(2),(3).

ТЕРАПЕВТИЧЕСКИЕ ПОЛИПЕПТИДЫ, ИХ ГОМОЛОГИ, ИХ ФРАГМЕНТЫ И ИХ ПРИМЕНЕНИЕ ДЛЯ МОДУЛЯЦИИ АГРЕГАЦИИ, ОПОСРЕДОВАННОЙ ТРОМБОЦИТАМИ

Настоящее изобретение относится к биотехнологии. Описаны полипептиды, включающие в себя, по меньшей мере, одно однодоменное антитело, направленное против vWF, А1 домена vWF, А1 домена активированного vWF, A3 домена vWF, gplb и/или коллагена. Представлены способы получения названных полипептидов, способы покрытия используемых в медицинской практике устройств (например, для РСТА, эндопротезирования) названными полипептидами. Изобретение позволяет получать полипептиды, предназначенные для лечения состояний, требующих модуляции опосредованной тромбоцитами агрегации. 18 н. и 22 з.п. ф-лы, 30 ил., 32 табл.

АНТИТЕЛО ПРОТИВ РЕЦЕПТОРА IL-6

Изобретение относится к области биохимии, в частности к вариантам антител против рецептора IL-6, вариабельные области тяжелой и легкой цепи которых модифицированы путем введения аминокислотных замен. Раскрыта фармацевтическая композиция для лечения заболеваний, ассоциированных с IL-6, содержащая указанный вариант антитела. Изобретение позволяет эффективно лечить заболевания, ассоциированные с IL-6. 4 н. и 4 з.п. ф-лы, 48 ил., 16 табл, 20 пр.

СЕЛЕКТИВНЫЕ ИНГИБИТОРЫ ГЛИКОЗИДАЗЫ И ИХ ПРИМЕНЕНИЕ

Изобретение относится к соединению формулы (I) или его фармацевтически приемлемой соли, где Rи Rнезависимо представляют собой Н или F; Rпредставляет собой ORи Rпредставляет собой Н, или Rпредставляет собой Н и Rпредставляет собой OR; каждый из Rпредставляет собой Н; Rпредставляет собой Н или OR; Rвыбирают из группы, состоящей из Н и C-алкила; Rвыбирают из группы, состоящей из C-алкила, необязательно замещенного 1-3 атомами фтора; и каждый Rнезависимо выбирают из группы, состоящей из Н, C-алкила, или две группы Rсвязаны вместе с атомом азота, к которому они присоединены, с образованием 4-членного кольца, содержащего 3 атома углерода. Соединения формулы (I) предназначены для изготовления лекарственного средства или фармацевтической композиции, обладающих ингибирующей активностью в отношении гликопротеин 2-ацетамидо-2-деокси-β-D-глюкопиранозидазы (O-GlcNAcase). Также изобретение относится к способу селективного ингибирования гликопротеин 2-ацетамидо-2-деокси-β-D-глюкопиранозидазы (O-GlcNAcase ...

ИЗГОТОВЛЕНИЕ АКТИВНЫХ ВЫСОКОФОСФОРИЛИРОВАННЫХ ЛИЗОСОМАЛЬНЫХ ФЕРМЕНТОВ СУЛЬФАТАЗ ЧЕЛОВЕКА И ИХ ПРИМЕНЕНИЕ

Изобретение относится к области биотехнологии. Представлен очищенный препарат рекомбинантного фермента N-ацетилгалактозамин-6-сульфатаза (GALNS) человека, где указанный фермент включает аминокислотную последовательность, по меньшей мере, на 95% идентичную аминокислотам 27-522 SEQ ID NO:4, пригодный для лечения субъекта, страдающего лизосомальной болезнью накопления, которая ассоциирована с GALNS, где: (a) указанный препарат фермента GALNS имеет чистоту, по меньшей мере, приблизительно 95% при определении окрашиванием кумасси синим при SDS-PAGE в невосстанавливающих условиях; и (b) остаток цистеина в положении 79, по меньшей мере, приблизительно в 50% молекул фермента GALNS в указанном препарате фермента GALNS преобразован в C-формилглицин (FGly); где указанный фермент GALNS является гликозилированным N-связанным гликозилированием по остаткам аспарагина в положениях 204 и 423, где, по меньшей мере, приблизительно 50% олигоманнозных цепей, присоединенных к остатку аспарагина в положении 204 ...

РЕГУЛЯТОРЫ ММР-9 И ИХ ПРИМЕНЕНИЕ

Изобретение относится к медицине и касается способа идентификации агента для лечения рака и воспалительных заболеваний, заключающегося в определении способности агента взаимодействовать с OG-доменом ММР-9, где упомянутый агент является предполагаемым понижающим регулятором коллагенолитической активности ММР, и определении способности указанного агента понижающе регулировать коллагенолитическую активность ММР-9. Изобретение обеспечивает снижение коллагенолитической активности ММР-9. 2 н. и 8 з.п. ф-лы, 7 пр., 7 ил., 2 табл.

МЕТОД АНАЛИЗА СПОСОБНОСТИ СОЕДИНЕНИЙ ИЛИ СРЕДСТВ СНИЖАТЬ АКТИВНОСТЬ МИКРОСОМАЛЬНОЙ ПРОСТАГЛАНДИН-E-СИНТАЗЫ ИЛИ ГЕМАТОПОЭТИЧЕСКОЙ ПРОСТАГЛАНДИН-D-СИНТАЗЫ

... 1. Способ определения способности соединения или средства снижать активность простагландин-синтазы, выбранной из группы, состоящей из микросомальной простагландин-Е-синтазы (mPGES) и гематопоэтической простагландин-D-синтазы (hPGDS), в реакции с субстратом с образованием конечного простагландина, включающий следующие стадии: (a) перемешивание простагландин-синтазы с субстратом, кофактором и соединением или средством; (б) инкубирование смеси, полученной на стадии (a), с останавливающим раствором, который содержит средство, препятствующее спонтанному превращению субстрата в конечный простагландин; (в) инкубирование смеси, полученной на стадии (б), с детектирующим реагентом, содержащим конечный простагландин, помеченный флуоресцентной меткой, и антитело, для которого конечный простагландин является иммуногеном; (г) облучение смеси, полученной на стадии (в), и контрольной смеси плоскополяризованным светом с длиной волны возбуждения флуоресцентной метки и измерение поляризации флуоресценции ...

СПОСОБЫ И КОМПОЗИЦИИ ДЛЯ ПОВЫШЕНИЯ ЭФФЕКТИВНОСТИ АНТИТЕЛ ДЛЯ ЛЕЧЕБНЫХ ЦЕЛЕЙ С ИСПОЛЬЗОВАНИЕМ СОЕДИНЕНИЙ, ПОТЕНЦИИРУЮЩИХ NK-КЛЕТКИ

... 1. Способ лечения заболевания у субъекта-человека, нуждающегося в этом, включающий a) введение указанному субъекту соединения, блокирующего ингибирующий рецептор или стимулирующего активирующий рецептор N-клетки, и b) введение указанному субъекту антител для лечебных целей, которые могут связываться CD16. 2. Способ по п.1, где указанные антитела для лечебных целей содержат Fc-участок человеческого IgGI или IgG3. 3. Способ по п.1 или 2, где указанное соединение представляет собой антитело или содержит его антигенсвязывающий фрагмент, 4. Способ по п.1, где указанные антитела для лечебных целей являются моноклональными антителами или содержат их антигенсвязывающие фрагменты. 5. Способ по п.1, где указанные антитела для лечебных целей не конъюгированы с радиоактивной или токсичной группой. 6. Способ по п.1, где указанное соединение ингибирует ингибирующий рецептор N-клетки. 7. Способ по п.1, где указанное соединение стимулирует активирующий рецептор N-клетки. 8. Способ по п.1, где указанное ...

ПРОИЗВОДНЫЕ АЗАИНДОЛА В КАЧЕСТВЕ ИНГИБИТОРОВ ПРОТЕИНКИНАЗ

ОБНАРУЖЕНИЕ АНТИГЕНА-МИШЕНИ, ФЕНОТИПИЧЕСКИЙ СКРИНИНГ И ЕГО ПРИМЕНЕНИЕ ДЛЯ ИДЕНТИФИКАЦИИ СПЕЦИФИЧНЫХ ЭПИТОПОВ-МИШЕНЕЙ КЛЕТОК-МИШЕНЕЙ

ВЕЩЕСТВА ДЛЯ ПРОФИЛАКТИКИ И ЛЕЧЕНИЯ ПАНКРЕАТИТА

... 1. Способ определения веществ-кандидатов в качестве профилактических и терапевтических агентов при панкреатите, включающий: ! определение активности связывания (pKis) тестируемого вещества с рецепторами 5-НТ2А и 5-НТ2В; и ! определение тестируемого вещества как вещества-кандидата в качестве профилактического и терапевтического агента при панкреатите, если активность связывания с 5-НТ2А рецептором, по меньшей мере, на 1,0 больше активности связывания с 5-НТ2В рецептором. ! 2. Способ по п.1, дополнительно включающий определение активности связывания тестируемого вещества с рецептором 5-HT2C и определение тестируемого вещества как профилактического и терапевтического агента при панкреатите, если активность связывания с рецептором 5-НТ2А, по меньшей мере, на 1,0 больше активности связывания с рецептором 5-НТ2В и рецептором 5-НТ2С. ! 3. Фармацевтическая композиция для профилактики и лечения панкреатита, включающая в качестве действующего вещества антагонист рецептора 5-НТ2А, где активность связывания ...

СПОСОБЫ ИДЕНТИФИКАЦИИ МОДУЛЯТОРОВ GPR92

СПОСОБЫ ИДЕНТИФИКАЦИИ, ИЗОЛЯЦИИ И ПРИМЕНЕНИЯ РЕЦЕПТОРОВ ПАХУЧИХ ВЕЩЕСТВ И АРОМАТОВ

ОТЛИЧНЫЕ ОТ ЧЕЛОВЕКА ЖИВОТНЫЕ С ГУМАНИЗИРОВАННЫМ ГЕНОМ СИГНАЛЬНОГО РЕГУЛЯТОРНОГО БЕЛКА

СПОСОБ И СОЕДИНЕНИЯ ДЛЯ ИНГИБИРОВАНИЯ ОТТОРЖЕНИЯ ТРАНСПЛАНТАТА

... 1. Способ ингибирования отторжения трансплантата у млекопитающего, нуждающегося в таком ингибировании, включающий введение терапевтически эффективного количества антитела млекопитающему, при этом указанное антитело взаимодействует с внеклеточным доменом «экспрессирующегося в селезенке» полипептида (SPEX), ингибируя посредством этого указанное отторжение трансплантата. 2. Способ по п.1, отличающийся тем, что указанный трансплантат выбран из группы, включающей аллогенный трансплантат, трансплантат кожи, трансплантат ткани, трансплантат органа, трансплантат костного мозга. 3. Способ по п.1, дополнительно включающий введение дополнительного ингибитора отторжения трансплантата. 4. Способ по п.3, отличающийся тем, что дополнительный ингибитор отторжения трансплантата включает циклоспорин, рапамицин, FK506, кортикостероид или антитело, которое взаимодействует с рецептором интерлейкина (ИЛ)-2. 5. Способ по п.1, отличающийся тем, что указанное антитело включает моноклональное антитело или его связывающий ...

ЧАСТИЧНЫЕ КОНСТРУКТЫ МНС И СПОСОБЫ ИХ ПРИМЕНЕНИЯ

... 1. Выделенный полипептид, содержащий:α1 домен главного комплекса гистосовместимости (МНС) класса II, где полипептид не включает α2, β1 или β2 домен МНС класса II; иличасть α1 домена МНС класса II, где часть α1 домена МНС класса II способна связываться с CD74 или снижать экспрессию или активность CD74.2. Выделенный полипептид по п. 1, гдеα1 домен содержит α1 домен МНС класса II человека,α1 домен содержит домен DR-α1, DQ-α1, DP-α1, DM-α1 или DO-α1,α1 домен содержит аминокислотные остатки 1-75 зрелой α-цепи МНС класса II или по меньшей мере ее 5 последовательных аминокислот,α1 домен содержит α1 домен α-цепи, содержащей аминокислотную последовательность, представленную любой из SEQ ID NO: 1-49, и/иличасть α1 домена МНС класса II содержит аминокислотные остатки 38-58 зрелой DR-α-цепи или ее часть, или область, гомологичную DPα или DQα.3. Выделенный полипептид по п. 1, дополнительно содержащий антигенную детерминанту, гдеантигенная детерминанта ковалентно связана с α1 доменом, где ковалентная ...

VERBINDUNGEN ZUR BEHANDLUNG VON ERKRANKUNGEN,DIE MIT DES VASCULOGENESE UND/ODER ANGIOGENESE IN VERBUNDEN STEHEN.

VERFAHREN ZUR ERHÖHUNG DER BIOVERFÜGBARKEIT ORALER ARZNEIMITTEL

VERWENDUNG VON PROTEIN-KINASE-N-BETA

HOCHDURCHSATZ-SCREENING

ERWEITERTER "TETHERING" ANSATZ ZUM SCHNELLEN AUFFINDEN VON LIGANDEN

CLAUDIN POLYPEPTIDE

Methods

G Proteins

Method of changing a globular protein structure into a fibrillar protein structure.

The method comprising the steps of providing a globular protein, forming a solution containing the globular protein, adding a detergent to the solution containing the globular protein, and applying the solution to a molecular sizing column with a pore size of at least 70 kDa. The column is preferably selected from a SuperdexRTM200 or a HW555, and the detergent is preferably selected from SDS or Zwittergent 3-14. The globular protein is preferably selected from albumin, fibronectin or recombinant capsid proteins VP1, VP2, or VP3 of the foot and mouth disease virus, or precursor or chimeric proteins thereof. The proteins may have a use in medicine, particularly in the treatment of cancer, or they may be used as vaccine adjuvants.

Screening Systems Utilizing RTP801

RTP801 represents a unique gene target for hypoxia-inducible factor 1 (HIF-I). Down regulation of the mTOR pathway activity by hypoxia requires de novo mRNA synthesis and correlates with increased expression of RTP801. The present invention relates to screening systems utilizing RTP801 and/or RTP801 interactors and/or RTP801 biological activity, to drag candidates identified by such screening systems, and to the use of such drug candidates in the treatment of various disorders.

Diagnostic and prognostic compounds and method

Proteins

G Proteins

The invention provides a mutant of a parent heterotrimeric G protein alpha (Gα) subunit, which mutant (i) lacks at least one helix of the helical domain of the parent Gα subunit; (ii) is capable of binding to a GPCR in the absence of a heterotrimeric G protein beta (Gβ) subunit and a heterotrimeric G protein gamma (Gγ) subunit; and (iii) has an amino acid sequence that contains one or more mutations compared to the amino acid sequence of the parent heterotrimeric Gα subunit, which mutations are selected from a deletion, a substitution and an insertion.

Screening Systems Utilizing RTP801

Methods for identification

G Proteins

High throuoghput screen

COMPOSITIONS AND METHODS FOR ALTERING SECOND MESSENGER SIGNALING

Novel antibiotic preparation method and platform system based on same

Viral drug susceptibility testing

A method of testing phenotypic drug susceptibility in an enveloped virus-infected mammalian individual by testing on an enzyme packaged into an enveloped virus, such as HIV, recovered from a biological sample, such as blood or plasma, from said individual is described. The method comprises the steps of a) adding an enzyme inactivating agent to the sample for inactivating polymerase activity other than that present in the envelope virion, b) removing the enzyme inactivating agent, enzyme activity blocking antibodies, endogenous enzyme activity inhibitors and antiviral drugs, c) lysing the virus particle to release the enzyme, d) recovering the concentrated purified viral enzyme, such as a HIV reverse transcriptase (RT), resulting from c) and determining the drug sensitivity profile of the individual from the recovered enzyme by using sensitive enzyme assays. The drug sensitivity profile may be used for selecting drug treatment therapy. A commercial package is included.

Polypeptides comprising gax protein domains, involved in repressing transcription and or interacting with other proteins corresponding nucleic acids andtheir use.

The invention concerns polynucleotides comprising gax domains involved in the biological activity of gax. In particular it may concern domains involved in the interaction of gax with other molecules or dommains responsible for a biological activity. The invention also concerns the chimerical molecules comprising a functional domain of gax. It further concerns the use of gax for repressing the expression of genes, and the use of compounds inhibiting the interaction of gax with certain cell partners for modulating the activity of gax. It also concerns a method for screening and/or identifying cell partners of gax.

Viral drug susceptibility testing.

Triazole compounds useful in therapy.

COMPOSITIONS AND METHODS FOR ALTERING SECOND MESSENGER SIGNALING

Novel antibiotic preparation method and platform system based on same

Viral drug susceptibility testing.

Polypeptides including/understanding of the fields of the protein gax implied in the repression of transcription and/or interacting with aoutres nucleic acid proteins correspondents and their uses

Triazole compounds useful in therapy.

Viral drug susceptibility testing.

Viral drug susceptibility testing.

Novel antibiotic preparation method and platform system based on same

COMPOSITIONS AND METHODS FOR ALTERING SECOND MESSENGER SIGNALING

Triazole compounds useful in therapy.

WITH PHÄNOTYPI MEDICINE RESISTANCE TRANSKRIPTASE CORRELATED MUTATION PROFILES IN HIV-1-REVERSE

PROCEDURE FOR THE IDENTIFICATION INTERNALIZING REDUCED BY TRANSMEMBRANREZEPTORAGONISTEN WITH

SCREENING PROCEDURE FOR SUBSTANCES FOR THE TREATMENT OF DIABETES

NEW SCREENING TEST FOR ANTI-MALARIA MEANS

CLEANED ACTIVE HCV NS2/3 PROTEASE

IDENTIFICATION OF ONE, IN WHICH POLYCYTHEMIA VERA IMPLIED, JAK2 MUTANTE

PROCEDURE FOR THE IDENTIFICATION OF MODULATORS OF THE HUMAN OREXIN-2-REZEPTORS

MIXTURE OF AT LEAST TWO FUSION PROTEINS AS WELL AS YOUR PRODUCTION AND USE

NEW AGGRECANASE

NEW KCNQ POLYPEPTIDE AND THEIR USE WITH THE DIAGNOSIS OF MENTAL DISORDERS

USE FROM EPH RECEPTOR INHIBITORS TO THE TREATMENT OF NEURODEGENERATIVE DISEASES

PROCEDURES IN CONNECTION WITH ABNORMAL PHOSPHATE METABOLISM ASSOCIATED ILLNESSES

PHARMACEUTICALS AND PROCEDURES FOR THE HYPOXIA TREATMENT AND SCREENING PROCEDURE FOR IT

EMPLOYMENT OF THE CYTOCHROM P450-ENZYMS CYP2WI AS GOAL MOLECULE FOR ACTIVE SUBSTANCES WITH THE CANCER THERAPY

NEW PROCEDURE FOR CREATING PROTEIN KINASE INHIBITORS

SPECIAL PROTEIN OF THE PANKREATI BETA CELLS OF THE LONG HANS ISLANDS AND ITS APPLICATIONS

DIAGNOSIS AND TREATMENT OF ATHEROSKLEROSE

PROCEDURE FOR THE IDENTIFICATION OF TFF2 ADJUSTMENT AGENTIEN

NEW TEST TO SCREENING OF ANTIPSYCHOTIKA

CHOLESTERIN IMITATING PYRENSONDEN

UPS AS THE BETA CATENIN PATH MODIFYING SUBSTANCES AND OPERATING TECHNIQUE

NEW LIGAND G-PROTEIN-CONJUGATING OF A RECEPTOR PROTEIN AND A USE OF IT

FGFR AGONISTE

SCREENINGVERFAHREN FOR PEPTIDE, THE CONNECTION OF PP1C TO THE PROTEINS BCL-2, BCL-XL AND BCL-W RESTRAINING

STABILIZATION OF STRUCTURALLY UNEINDEUTIGER HELIX FOR THE PREVENTION OF AMYLOIDBILDUNG

N-Ä3-FLUORO-4 (Ä6 (METHYLOXY) - 7-Ä (3-MORPHOLIN-4 YLPROPYL) OXYÜQUINOLIN-4-YLÜOXY) PHENYLÜ N' (4FLUOROPHENYL) CYCLOPROPANE-1,1-DICARBOXAMID FOR the TREATMENT OF CANCER

PROCEDURE FOR THE SCREENEN OF CONNECTIONS, WHICH THE GPI BIO-SYNTHESIS OF MALARIA PARASITE RESTRAINING

TEST PROCEDURE FOR THE RECOGNITION FROM ACTIVE SUBSTANCES TO THE MODIFICATION OF THE ACTIVITY OF NAPE PLD OR ABH4

PROCEDURE FOR THE DETECTION OF MODULATORS THE ASPARAGINYLHYDROXYLASE

SELECTION AND ISOLATION OF LIVING CELLS USING RNA BINDING PROBES

AUTOCIMMUNE ILLNESSES AND NADPH OXIDASE DEFECTS

PROCEDURE AND DEVICE FOR THE MEASUREMENT OF THE ACTIVATION OF NEUTROPHILEN CELLS

Screening compound as cognitive enhancer of 3-aminopropyl-butyl-phosphinic acid type, comprises e.g. administering screening- and inactivate-compound to mice, performing Morris-water-maze-test, isolating hippocampal, and identifying

Screening compounds for their potency as cognitive enhancers of 3-aminopropyl-butyl-phosphinic acid (SGS742) type comprises: administering the compounds to a first group of mice; administering inactivate compound to a second group of mice; performing Morris-water-maze-tests on the mice groups; isolating the hippocampal from mice groups and extracting the protein from it to obtain a hippocampal-protein extract of the mice groups; determining the levels of e.g. (1) L-lactate dehydrogenase chain and (11) aconitate hydratase, in the protein extract; and identifying the compound. Method of screening compounds for their potency as cognitive enhancers of 3-aminopropyl-butyl-phosphinic acid (SGS742) type; comprises administering the screening compounds to a first group of mice; administering inactivate compound to a second group of mice; performing a Morris-water-maze-tests on the first and second mice group; isolating the hippocampal from the first and second mice group and extracting the protein ...

HGFR BINDUNGSORT WITH HIGH AFFINITY AND PROCEDURE FOR THE IDENTIFICATION OF ANTAGONISTS OF THE SAME

PROCEDURE FOR THE PROOF OF A TO A NUKLEÄREN RECEPTOR BOUND SUBSTANCE

HOCHDURCHSATZ SCREENING

PROCEDURE FOR THE IDENTIFICATION OF CONNECTIONS, THE NEURAL ACTIVITY MODULATING

PHARMAKOPHORE RECOMBINATION FOR the IDENTIFICATION OF ßLEADß VERBINDUNGEN OF SMALL MOLECULE MEDICINES

INTERMEDIATE CONNECTIONS OF ADVANCED GLYKOSYLIERUNG FINAL PRODUCTS AND POST OFFICE AMADORI INHIBITOR

USE OF BETA KETOACYL COA SYNTHASE ONES FOR FINDING HERBICIDES

PROCEDURE FOR THE IDENTIFICATION INTERNALIZING REDUCED BY TRANSMEMBRANREZEPTORAGONISTEN WITH

PROCEDURE FOR THE IDENTIFICATION INTERNALIZING REDUCED BY TRANSMEMBRANREZEPTORAGONISTEN WITH

PROCEDURE FOR THE IDENTIFICATION INTERNALIZING REDUCED BY TRANSMEMBRANREZEPTORAGONISTEN WITH

PROCEDURE FOR THE IDENTIFICATION INTERNALIZING REDUCED BY TRANSMEMBRANREZEPTORAGONISTEN WITH

PROCEDURE FOR THE IDENTIFICATION INTERNALIZING REDUCED BY TRANSMEMBRANREZEPTORAGONISTEN WITH

PROCEDURE FOR THE IDENTIFICATION INTERNALIZING REDUCED BY TRANSMEMBRANREZEPTORAGONISTEN WITH

Mek mutations conferring resistance to mek inhibitors

The present invention relates to methods, compositions and kits concerning resistance to treatment with an anti-cancer agent, specifically an inhibitor of MEK. In particular embodiments, the invention concerns mutations in a MEK sequence that confer resistance to a MEK inhibitor. Identification of such mutations in a MEK sequence allows the identification and design of second-generation MEK inhibitors. Methods and kits for detecting the presence of a mutant MEK sequence in a sample are also provided.

Estrogen receptors and methods of use

The present invention provides isolated polypeptides having an amino acid sequence having at least 70% identity to SEQ ID NO:20, wherein the polypeptide has ER-α36 activity. The invention further provides methods for identifying agents that bind to such polypeptides, methods for detecting such polypeptides, and methods for altering the activity of such polypeptides. Also provided are antibodies that specifically bind to an amino acid sequence depicted at SEQ ID NO:1, or an immunogenic fragment thereof, and methods for making and using such antibodies.

Fluorescence resonance energy transfer assays for sarco/endoplasmic reticulum calcium atpase and phospholamban

Provided herein are methods for identifying molecules capable of modulating SERCA, the SERCA-PLB complex or the microenvironment of the complex. An exemplary assay provided herein is fluorescence resonance energy transfer (FRET). Also provided herein are FRET assays that are optimized for high-throughput screening (HTS) for identifying small molecules that modulate SERCA or the SERCA-PLB complex. Further provided are kits for carrying out said methods for identifying molecules.

Compositions and methods for treating or preventing inflammatory bowel disease and colon cancer

The invention provides compositions and methods for useful for the diagnosis of inflammatory bowel disease, ETBF-induced colitis, colonic hyperplasia and/or colon carcinogenesis in a subject in biological samples (e.g., stool, urine, blood, serum, tissue). The invention further provides compositions and methods for the treatment or prevention of colitis, colon cancer, or inflammatory bowel disease (e.g., Crohn's disease).

Identification of a jak2 mutation involved in vaquez polyglobulia

The present invention concerns the V617F variant of the protein-tyrosine kinase JAK2, said variant being responsible for Vaquez Polyglobulia. The invention also relates to a first intention diagnostic method for erythrocytosis and thrombocytosis allowing their association with myeloproliferative disorders, or to the detection of the JAK2 V617F variant in myeloproliferative disorders allowing their reclassification in a new nosological group.

Pharmaceutical composition containing nuclear factor involved in proliferation and differentiation of central neuronal cells

With an aim to provide a novel factor inducing proliferation of neural stem cells and differentiation of these cells into nerve cells, a pharmaceutical composition comprising 1) CRBN, 2) a nucleic acid encoding CRBN, or 3) a stem cell or a neural progenitor cell in which CRBN is expressed, a method including administering the pharmaceutical composition to a non-human animal and inducing proliferation of neural stem cells or neural progenitor cells of the non-human animal and differentiation of these cells into nerve cells, and a method for screening for a therapeutic drug for a disease of cerebral cortex or a surgical injury of cerebral cortex, using CRBN, are provided.

Antibodies and Methods of Use Thereof

The disclosure relates to protease-binding agent specific for a protease. The agent may be an antibody capable of specifically binding and inhibiting a protease, such as a P1-Arg-specific protease. The disclosure also provides methods of producing, and compositions comprising the subject agent. Methods and kits related to the protease-binding agent find use in protection against, detection, diagnosing, treating cancer and infections due to pathogens containing active proteases.

Fatty acid binding proteins as drug targets for endocannabinoids

The invention provides a method of modulating the level of an endocannabinoid in a subject in need thereof comprising administering an effective amount of an agent that inhibits the interaction of the endocannabinoid with an intracellular fatty acid binding protein (FABP). The invention also provides a method of identifying an agent for modulating the level of an endo cannabinoid in a subject comprising testing the agent for its ability to modulate binding of the endocannabinoid with an intracellular FABP. The invention also provides a method of identifying an agent for modulating the level of an endocannabinoid in a subject comprising testing the agent for its ability to modulate expression of an intracellular FABP. The invention also provides a method of identifying an agent for treatment of a neurological disorder comprising testing the agent for its ability to modulate the interaction of an endocannabinoid with an intracellular FABP. The invention also relates to modulation of levels of fatty acid amides for treatment or amelioration of diseases or disorders by modulating binding of the fatty acid amides to fatty acid binding proteins. In one embodiment, the fatty acid binding protein is one or more of FABP3, FABP5, and FABP7. In one embodiment, the level of an endocannabinoid is modulated.

Spinal muscular atrophy (sma) treatment via targeting of smn2 splice site inhibitory sequences

The present invention is directed to methods and compositions capable of blocking the inhibitory effect of a newly-identified intronic inhibitory sequence element, named ISS-N1 (for “intronic splicing silencer”), located in the SMN2 gene. The compositions and methods of the instant invention include oligonucleotide reagents (e.g., oligoribonucleotides) that effectively target the SMN2 ISS-N1 site in the SMN2 pre-mRNA, thereby modulating the splicing of SMN2 pre-mRNA to include exon 7 in the processed transcript. The ISS-N1 blocking agents of the invention cause elevated expression of SMN protein, thus compensating for the loss of SMN protein expression commonly observed in subjects with spinal muscular atrophy (SMA).

Further use of protein kinase n beta

The present invention is related to use of protein kinase N beta or a fragment or derivative thereof as a downstream target of the PI 3-kinase pathway, preferably as a downstream drug target of the PI 3-kinase pathway.

Modulation of Synaptic Maintenance

C1q is shown to be expressed in neurons, where it acts as a signal for synapse elimination. Methods are provided for protecting or treating an individual suffering from adverse effects of synapse loss. These findings have broad implications for a variety of clinical conditions, including Alzheimer's disease.

Assay for pcsk9 inhibitors

The present invention provides methods for identifying modulators of PCSK9, for example, using a variety of assay formats. Inhibitors of PCSK9 can be used for example, to treat diseases such as hyperlipidemia and related disorders.

Compositions and Methods for Treatment of Eye Disorders

The present invention provides compounds and methods for the treatment of LFA-1 mediated diseases. In particular, LFA-1 antagonists are described herein and these antagonists are used in the treatment of LFA-1 mediated diseases. One aspect of the invention provides for diagnosis of an LFA-1 mediated disease and administration of a LFA-1 antagonist, after the patient is diagnosed with a LFA-1 mediated disease. In some embodiments, the LFA-1 mediated diseases treated are dry eye disorders. Also provided herein are methods for identifying compounds which are LFA-1 antagonists.

Compositions and Methods for Identifying Agents Which Modulate PTEN Function and PI-3 Kinase Pathways

Methods are provided for the identification, biochemical characterization and therapeutic use of agents which impact PTEN, p53, PI-kinase and AKT mediated cellular signaling.

Small molecules that covalently modify transthyretin

A family of covalent kinetic stabilizer compounds that selectively and covalently react with the prominent plasma protein transthyretin in preference to more than 4000 other human plasma proteins is disclosed. A contemplated compound corresponds in structure to Formula I, below, where the various substituents are defined within, and reacts chemoselectively with one or two of four Lys-15 ε-amino groups within the transthyretin tetramer. The crystal structure confirms the binding orientation of the compound substructure and the conjugating amide bond. A covalent transthyretin kinetic stabilizer exhibits superior amyloid inhibition potency, compared to a non-covalent counterpart, and inhibits cytotoxicity associated with amyloidogenesis.

Inhibitors of Atypical Protein Kinase C and Their Use in Treating Hedgehog Pathway-Dependent Cancers

Methods and compositions are provided for modulating Hedgehog (Hh) pathway signaling in a cell. Aspects of the methods include methods for inhibiting Hh pathway-promoted cancer proliferation and/or metastasis that is promoted by Hh pathway signaling, methods for treating cancers promoted by Hh pathway signaling, and methods for screening candidate agents for the ability to treat a cancer promoted by Hh pathway signaling. In addition, reagents and kits thereof that find use in practicing the subject methods are provided.

Dynamic Monitoring of Activation of Receptor Tyrosine Kinase (RTK) in Living Cells Using Real-Time Microelectronic Cell Sensing Technology

Methods for identifying a compound capable of interacting with a Receptor Tyrosine Kinase (RTK) including providing a device capable of measuring cell-substrate impedance, adding test cells expressing a RTK to the device, measuring first impedances, adding a compound to at least one compound well and adding a vehicle control at least one control well, measuring second impedances of the compound well and the control well, determining the change in the impedance for the compound well and the one control well, comparing the change in impedance between the compound well and the control well, and identifying the compound interacts with the RTK if the comparison demonstrates a significant difference between the change in impedance.

Compound capable of binding to naturally occurring denatured protein, and method for screening for the compound

Screening for low molecular weight compounds that regulate protein-protein interactions of a large number of proteins, including transcription factors, that have disordered sequences has been performed, but it has been almost impossible to obtain low molecular weight compounds having sufficient activity. The present inventors found that, regarding screening for a protein that regulates an interaction between an intrinsically disordered protein and a partner protein, carrying out screening while focusing on an disordered sequence, and selecting a candidate compound from peptidomimetic compounds that have a peptidomimetic backbone and have a peptide side chain or a side chain similar thereto enable a compound that regulates the activity of an intrinsically disordered protein to be efficiently selected, and the present inventors accomplished the present invention.

Method for screening ameliorants of dry skin caused by atopic dermatitis using bleomycin hydrolase activity as indicator

The present invention provides a method for screening and evaluating ameliorants of dry skin caused by atopic dermatitis, comprising: evaluating a candidate drug as being an ameliorant of dry skin caused by atopic dermatitis in the case the candidate drug significantly increases expression and/or activity of bleomycin hydrolase in comparison with a control drug.

Therapeutic Applications Targeting SARM1

The present disclosure provides methods for reducing axonal and/or synaptic degradation in neurons by modulating sterile α/Armadillo/Toll-Interleukin receptor homology domain protein (SARM) activity and/or expression.

Stimulation of the synthesis of the activity of an isoform of lysyl oxidase-like loxl for stimulating the formation of elastic fibers

The invention relates to the stimulation of the synthesis and of the activity of an isoform of lysyl oxidase, and more particularly of the LOXL (lysyl oxidase-like) isoform. The invention relates notably to a method of identifying an active principle which stimulates the formation of elastic fibers. The aim of the invention is mainly to provide such a method of identification so as to provide compositions which enable stimulating the formation of elastic fibers.

Compositions and Methods for Enhancing Proteasome Activity

Proteinopathies result from the proteasome not acting efficiently enough to eliminate harmful proteins and prevent the formation of the pathogenic aggregates. As described herein, inhibition of proteasome-associated deubiquitinase Usp 14 results in increased proteasome efficiency. The present invention therefore provides novel compositions and methods for inhibition of Usp14, enhancement of proteasome activity and treatment of proteinopathies.

Detection and treatment of lrp4-associated neurotransmission disorders

The present invention includes methods for the detection of neurotransmission or developmental disorders, including, but not limited to, myasthenia gravis that is seronegative for autoantibodies to the acetylcholine receptor (AChR) and/or muscle specific tyrosine kinase (MuSK), the method including detecting autoantibodies that bind to LRP4, or an epitope thereof. Also included are methods for the treatment of an individual suffering from a neurotransmission disorder, the method including detecting in a bodily fluid of the individual autoantibodies that bind to LRP4, or an epitope thereof, and administering to the patient an effective amount an immunosuppressant and/or another appropriate therapeutic modality. Also included are antibodies that bind to autoantibodies to LRP4 and kits for the detection of neurotransmission or developmental disorders.

Indentifying antifungal agents that inhibit iaa or a yap family

The present invention relates to methods of screening for antifungal agents by identifying agents that bind to or otherwise inhibit indole-3-acetic acid (IAA) or that bind to or otherwise inhibit the expression or activity of a protein within the Yap family or a gene encoding a protein within the Yap family.

Compositions and methods to treat bone related disorders

The present invention relates to the use of modulators of the sclerostin: sclerostin-binding-partner interaction for the treatment, amelioration, and diagnosis of sclerostin-related disorders, e.g., osteoporosis and sclerosteosis, and sclerostin-related disorders, e.g., cancers and cardiovascular disorders. The invention also relates to the use of sclerostin-binding-partner mimetics for the treatment, amelioration, and diagnosis of sclerostin-related disorders. Assays for the identification of modulators of the sclerostin: sclerostin-binding-partner interaction, as well as the resulting signaling, are also provided.

Light-Activated Cation Channel and Uses Thereof

The present invention provides compositions and methods for light-activated cation channel proteins and their uses within cell membranes and subcellular regions. The invention provides for proteins, nucleic acids, vectors and methods for genetically targeted expression of light-activated cation channels to specific cells or defined cell populations. In particular the invention provides millisecond-timescale temporal control of cation channels using moderate light intensities in cells, cell lines, transgenic animals, and humans. The invention provides for optically generating electrical spikes in nerve cells and other excitable cells useful for driving neuronal networks, drug screening, and therapy.

Polypeptides that bind membrane proteins

Polypeptides which bind to the helical transmembrane region of membrane proteins are disclosed, as are methods for the design of polypeptides that bind to the transmembrane region of membrane proteins. Also provided are methods for the use of the disclosed polypeptides in various applications, as well as products made through the practice of the instant methods.

Use of molecular markers for the preclinical profiling of inhibitors of enzymes having histone deacetylase activity

The present invention relates to the use of molecular markers and related signaling mechanisms for the preclinical and clinical profiling of inhibitors of enzymes having histone deacetylase activity. The invention also relates to the use of such markers as diagnostic and/or prognostic tools for the treatment of tumor patients with such inhibitors.

Phosphodiesterase activity and regulation of phosphodiesterase 1b-mediated signaling in brain

The present invention provides methods and compositions for modulating the activity of phosphodiesterase 1B (PDE1B) in intracellular signaling pathways, including but not limited to, dopamine D1 intracellular signaling pathways. The invention also provides methods and compositions for modulating the activities of intracellular signaling molecules, including, but not limited to, DARPP-32 and GluR1 AMPA receptor, via modulation of PDE1B. The invention also provides pharmaceutical compositions and methods of screening for compounds that modulate PDE1B activity. The invention also provides methods of treating or ameliorating the symptoms of a disorder, including but not limited to a PDE1B-related disorder or a dopamine D1 receptor intracellular signaling pathway disorder, by administering a modulator of PDE1B, preferably, but not limited to, an inhibitor of PDE1B or an agent that decreases the production of PDE1B.

Compositions and methods comprising histidyl-trna synthetase splice variants having non-canonical biological activities

Isolated histidyl-tRNA synthetase splice variant polynucleotides and polypeptides having non-canonical biological activities are provided, as well as compositions and methods related thereto.

Activators of SGK-1 for Use as Cardioprotective Agents

Compositions for activating SGK-1 are provided. SGK-1 activators can be identified by the methods of screening provided herein. The SGK-1 activators can be used in the disclosed methods of reducing cell death and methods of treating ischemic-reperfusion injury. The ischemic-reperfusion injury can be due to a variety of complications resulting in blood loss to tissue and then the re-establishment of blood flow to the tissue.

Engineered conformationally-stabilized proteins

Provided herein are conformationally stabilized ubiquitin proteins and methods for using the same to identify agents that bind to the stabilized ubiquitin protein or that bind to a protein that interacts with or processes the stabilized form of the ubiquitin protein. Also provided herein are methods for screening for conformationally stabilized proteins having increased binding affinity to a binding partner in comparison to the binding affinity of the wildtype form of the protein to the binding partner.

Compstatin and analogs thereof for eye disorders

The present invention features the use of compstatin and complement inhibiting analogs thereof for treating and/or preventing age related macular degeneration and other conditions involving macular degeneration, choroidal neovascularization, and/or retinal neovascularization. The invention also provides compositions comprising compstatin or a complement inhibiting analog thereof and a second therapeutic agent. The invention also provides compositions comprising compstatin or a complement inhibiting analog thereof and a gel-forming material, e.g., soluble collagen, and methods of administering the compositions.

Inhibitors of Human EZH2 and Methods of Use Thereof

The invention relates to determining the presence of an EZH2 gene mutation in a sample from a subject and inhibition of wild-type and certain mutant forms of human histone methyltransferase EZH2, the catalytic subunit of the PRC2 complex which catalyzes the mono-through tri-methylation of lysine 27 on histone H3 (H3-K27). In one embodiment the inhibition is selective for the mutant form of the EZH2, such that trimethylation of H3-K27, which is associated with certain cancers, is inhibited. The methods can be used to treat cancers including follicular lymphoma and diffuse large B-cell lymphoma (DLBCL). Also provided are methods for identifying small molecule selective inhibitors of the mutant forms of EZH2 and also methods for determining responsiveness to an EZH2 inhibitor in a subject.

Methods and Compositions for Producing Active Vitamin K-Dependent Proteins

The present invention provides methods and compositions for the production of vitamin K dependent proteins.

Transglutaminase-2 inhibitors and uses thereof

The present invention refers to a method of treating a disease or disorder associated with the expression of at least one transgluaminase-2 and a method of identifying a candidate transglutaminase-2 inhibitor.

Pyrazolopyridine and pyrazolopyrimidine derivatives as melanocortin-4 receptor modulators

Disclosed herein is a compound of Formula I: wherein X, R 1 , R 2 , and R 3 are as defend herein, or a pharmaceutically acceptable salt thereof to allow the drug to penetrate the cell membrane; or a prodrug, or the compound is labeled with a detectable label or an affinity tag thereof. Also disclosed is a pharmaceutical composition, a method of treating a disorder mediated by melanocortin-4 receptors, and a method of treating obesity using the compounds described.

SMALL MOLECULE ANTAGONISTS OF DUSP5 AND METHODS OF USE

The present invention is directed to compounds that specifically target DUSP5 and act as antagonists of that enzyme. Such compounds are useful in the treatment of various conditions including, but not limited to vascular anomalies, cancer, and macular degeneration. 1. A pharmaceutical composition comprising a compound , or a pharmaceutically acceptable salt , solvate , or hydrate thereof , and a pharmaceutically acceptable carrier , wherein the compound comprises two negatively charged sulfonate groups or bioisosteric sulfonate analog groups tethered by a core scaffold of biphenyl or a planar analog of biphenyl , and wherein the core scaffold separates the negatively charged groups at a distance of about 6 to about 8 Angstroms.2. The composition of claim 1 , wherein the core scaffold comprises one or more of fluorene claim 1 , biphenyl claim 1 , carbazole claim 1 , dibenzofuran claim 1 , calixarene claim 1 , and naphthalene.4. The composition of claim 1 , wherein the negatively charged sulfonate groups or bioisosteric sulfonate analog groups are separated by a distance of about 7 angstroms.5. The composition of claim 1 , wherein the bioisosteric sulfonate analog groups are selected from the group consisting of sulfonamide claim 1 , tetrazole claim 1 , and carboxylic acid.6. The composition according to claim 1 , wherein said compound is a dual specificity phosphatase-5 (DUSP5) inhibitor.7. A medicament for treating claim 1 , preventing claim 1 , or alleviating a vascular anomaly comprising at least one compound as defined in in an effective amount to antagonize DUSP5.8. A method of treating claim 1 , preventing claim 1 , or alleviating a vascular anomaly comprising administering to a subject in need thereof a therapeutically effective amount of a compound or composition defined in wherein the compound antagonizes dual specificity phosphatase-5 (DUSP5).9. The method of claim 7 , wherein the vascular anomaly is associated with a Serine to Proline mutation at amino ...

COMPOUND AND METHOD FOR THE TREATMENT AND DIAGNOSIS OF NEURODEGENERATIVE CONDITIONS

A reagent selected from cholestenoic acid or an inhibitor of an enzyme in the cholestenoic acid biosynthetic or metabolic pathway for use in the treatment of neurodegenerative conditions. In particular, the reagent is a cholestenoic acid of a particular form, such as 3β,7α-dihydroxycholest-5-en-26-oic (3β,7α-diHCA), not previously associated with neural tissue or CSF. Pharmaceutical compositions, methods of treatment or prevention of neurodegenerative conditions as well as diagnostic methods and novel biomarkers form further aspects of the invention. 1. A method for the treatment of neurodegenerative conditions , comprising administering to a patient in need thereof an effective amount of a reagent chosen from a cholestenoic acid , a cholestenoic acid precursor , an inhibitor of an enzyme in the cholestenoic acid biosynthetic or metabolic pathway , or a pharmaceutically acceptable salt thereof.2. The method of wherein the reagent is a cholestenoic acid or a pharmaceutically acceptable salt thereof.3. The method of wherein the reagent comprises 3β claim 1 ,7α-dihydroxycholest-5-en-26-oic (3β claim 1 ,7α-diHCA).4. The method of wherein the reagent is an inhibitor of an epimerase that converts 3β claim 1 ,7α-dihydroxycholest-5-en-26-oic (3β claim 1 ,7α-diHCA) to 3β claim 1 ,7β-dihydroxycholest-5-en-26-oic (3β claim 1 ,7β-diHCA).57-. (canceled)8. A pharmaceutical or veterinary composition comprising a cholestenoic acid claim 1 , a cholestenoic acid precursor or inhibitor of an enzyme in the cholestenoic acid biosynthetic or metabolic pathway claim 1 , or a pharmaceutically acceptable salt for use in the treatment of neurodegenerative conditions.9. A method of treatment or prevention of neurodegenerative conditions which method comprises modifying the amount of specific cholestenoic acids in an individual.10. The method of wherein the amount of 3β claim 9 ,7α-dihydroxycholest-5-en-26-oic (3β claim 9 ,7α-diHCA) is increased claim 9 , and/or the amount of 3β claim 9 ,7β- ...

INHIBITORS OF HEMOPOIETIC CELL KINASE (P-59-HCK) AND THEIR USE IN THE TREATMENT OF INFLUENZA INFECTION

The present invention relates inter alia to the treatment or prevention of influenza virus infection (including subtypes influenza A virus, influenza B virus, avian strain H5N1, A/H1N1, H3N2 and/or pandemic influenza) using compounds which inhibit the activity of p59-HCK and to a method of screening for a candidate drug substance intended to prevent or treat influenza virus infection in a subject, said method comprising identifying a test substance capable of inhibiting p59-HCK activity. 117-. (canceled)19. The method of claim 18 , wherein the influenza infection is secondary to at least one of the following conditions:I. pregnancyII. chemotherapy;III. complications arising from infection by influenza virus (A, B and C strains); orIV. chronic disease.20. The method of claim 18 , wherein the compound is administered in combination with one or more anti-viral drugs.21. The method of claim 20 , wherein the anti-viral drug is selected from the group consisting of zanamrivir claim 20 , oseltamivir claim 20 , laninamivir claim 20 , peramivir claim 20 , ribavirin and exogenous interferons.22. A compound capable of inhibiting hemopoietic cell kinase (p59-HCK) activity wherein the compound is not N-(4-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido) naphthalen-lyloxy)pyridin-2-yl)-2-methoxyacetamide or a pharmaceutically acceptable salt or solvate thereof.23. The compound of claim 22 , wherein the compound is a molecule that suppresses the expression of p59-HCK.24. The compound of claim 23 , wherein the molecule is an RNAi molecule or microRNA (miRNA) molecule.25. A method of screening for a candidate drug substance intended to prevent or treat influenza virus infection (A claim 23 , B and C strains) in a subject which comprises identifying a test substance capable of inhibiting p59-HCK activity by measuring the effects of said test substance on p59-HCK activity.26. A method of screening according to comprising:a. contacting p59-HICK with a test substance in the ...

Tailored cyclodepsipeptides as potent non-covalent serine protease inhibitors

The present invention pertains to an improved chemical synthesis method for Ahp-cyclodepsipeptides which allows straight forward and easy synthesis of tailor-made Ahp-cyclodepsipeptides. The invention further provides Ahp-cyclodepsipeptides for use as HTRA protease inhibitors and their medical use.

G protein-coupled receptor screening systems

Disclosed herein is a G protein-coupled receptor (GPCR) assay platform comprised of two complementary systems that equate dynamic intermolecular interactions between a receptor and transducer with more complex stimulus-response cascades in living cells. In the disclosed in vitro ADSoRB method, the forced dissociation of transducers like G protein heterotrimers from receptors alters receptor conformations and ligand interactions to simulate pathway activation in a cell. In the disclosed TRUPATH method, measuring the extent of engineered G protein heterotrimer complex dissociation provides single transducer resolution in a cell.

NOVEL PEPTIDES AND COMBINATION OF PEPTIDES FOR USE IN IMMUNOTHERAPY AGAINST EPITHELIAL OVARIAN CANCER AND OTHER CANCERS

The present invention relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated T-cell peptide epitopes, alone or in combination with other tumor-associated peptides that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules. 1. A method of eliciting an immune response in a patient who has cancer , comprising administering to said patient a composition comprising a population of activated T cells that kill cancer cells in the patient that present a peptide , wherein said peptide consists of the amino acid sequence of SEQ ID NO: 130 , 1 , 122 , 128 , 2 , 86 , 98 , 119 , 147 , 3-81 , 83 , 85 , 87-97 , 99-118 , 120 , 121 , 123-127 , 129 , 131-146 , or 148-549 , wherein said cancer is selected from the group consisting of ovarian cancer , non-small cell lung cancer , small cell lung cancer , kidney cancer , brain cancer , colon or rectum cancer , stomach cancer , liver cancer , pancreatic cancer , prostate cancer , leukemia , breast cancer , Merkel cell carcinoma , melanoma , esophageal cancer , urinary bladder cancer , uterine cancer , gallbladder cancer , and bile duct cancer.2. The method of claim 1 , wherein the T cells are autologous to the patient.3. The method of claim 1 , wherein the T cells are obtained from a healthy donor.4. The method of claim 1 , wherein the T cells are derived from tumor infiltrating lymphocytes or peripheral blood mononuclear cells.5. The method of claim 1 , further comprising expanding T cells in vitro.6. The method of claim 1 , wherein the peptide is in ...

Novel peptides and combination of peptides for use in immunotherapy against epithelial ovarian cancer and other cancers

The present invention relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated T-cell peptide epitopes, alone or in combination with other tumor-associated peptides that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules.

New target for diabetes treatment and prevention

The present invention relates to the identification of ALMS1 as the missing player involved in the regulation of the insulin-mediated glucose uptake through GLUT4 sorting vesicles, and to the down-regulation of ALMS1 by αPKC. Accordingly, the present invention relates to a molecule capable of preventing the binding of αPKC on ALMS1 for use for treating or preventing diabetes, in particular type 2 diabetes. In addition, the present invention relates to a method for identifying molecule capable of preventing the binding of αPKC on ALMS1.

TRIAZOLE DERIVATIVES AND THEIR USE AS PDE4 ACTIVATORS

Compounds of Formula (I), which are activators of long form cyclic nucleotide phosphodiesterase-4 (PDE4) enzymes, are provided. Methods and uses of these compounds for the treatment or prevention of disorders requiring a reduction of second messenger responses mediated by cyclic 3′,5′-adenosine monophosphate (cAMP) are also described. 112-. (canceled)14. (canceled)16. (canceled)17. The method of wherein the excessive intracellular cyclic AMP signalling is caused by:a. excessive hormone levels produced by an adenoma;b. a gain-of-function gene mutation in a G-protein coupled receptor (GPCR);{'sub': 's', 'c. an activating mutation in the GNAS1 gene, which encodes the α-subunit of the G-protein G; or'}d. a bacterial toxin.18. The method of claim 15 , wherein the disease is cancer.19. The method of claim 18 , wherein the cancer is prostate cancer.20. The method of claim 15 , wherein the disease is:a. pituitary adenoma, Cushing's disease, polycystic kidney disease or polycystic liver disease;b. hyperthyroidism, Jansens's metaphyseal chondrodysplasia, hyperparathyroidism, or familial male-limited precocious puberty;c. McCune-Albright syndrome;d. cholera, whooping cough, anthrax, or tuberculosis;e. HIV, AIDS, or Common Variable Immunodeficiency (CVID);f. melanoma, pancreatic cancer, leukaemia, prostate cancer, adrenocortical tumours, testicular cancer, primary pigmented nodular adrenocortical diseases (PPNAD),or Carney Complex;g. autosomal dominant polycystic kidney disease (ADPKD) or autosomal recessive polycystic kidney disease (ARPKD);h. maturity onset diabetes of young type 5 (MODY5); ori. cardiac hypertrophy.21. The method of claim 20 , wherein the disease is:a. autosomal dominant polycystic kidney disease (ADPKD); orb. autosomal recessive polycystic kidney disease (ARPKD).23. (canceled)24. The method of claim 22 , wherein the disease or disorder is mediated by excessive intracellular cyclic AMP signalling.25. (canceled)26. The method of claim 24 , wherein the abnormal ...

LABELED GLUTAMINASE PROTEINS, ISOLATED GLUTAMINASE PROTEIN MUTANTS, METHODS OF USE, AND KIT

The present invention relates to a labeled glutaminase (GLS) protein comprising a GLS protein and a fluorescent reporter group attached to the GLS protein, wherein the fluorescent reporter group is attached to the GLS protein within the glutaminase domain pfam04960 of GLS. The present invention also relates to isolated glutaminase protein mutants. Also disclosed is a method of screening for compounds that allosterically bind to a glutaminase protein. The present invention also relates to a method of identifying compounds that inhibit or stabilize tetramer formation of glutaminase protein. The present invention further relates to a screening kit for compounds that inhibit or stabilize tetramer formation. 1. A labeled glutaminase (GLS) protein comprising:a GLS protein anda fluorescent reporter group attached to the GLS protein, wherein the fluorescent reporter group is attached to the GLS protein within the glutaminase domain pfam04960 of GLS.2. The labeled GLS protein according to claim 1 , wherein the GLS protein is a wild type protein.3. The labeled GLS protein according to claim 1 , wherein the GLS protein is a GLS isoform selected from the group consisting of glutaminase C (GAC) and KGA.4. The labeled GLS protein according to claim 1 , wherein the GLS protein is GLS isoform GAC claim 1 , having an amino acid sequence selected from the group consisting of SEQ ID NO:1 and SEQ ID NO:3.5. The labeled GLS protein according to claim 1 , wherein the GLS protein is GLS isoform KGA claim 1 , having an amino acid sequence selected from the group consisting of SEQ ID NO:5 and SEQ ID NO:7.6. The labeled GLS protein according to claim 1 , wherein the GLS protein is a mutated GLS protein.7. The labeled GLS protein according to claim 6 , wherein the mutated GLS protein has an amino acid sequence selected from the group consisting of SEQ ID NO:9 claim 6 , SEQ ID NO:10 claim 6 , SEQ ID NO:11 claim 6 , and SEQ ID NO:12.8. The labeled GLS protein according to claim 6 , wherein the ...

Inhibitors of thioredoxin-interacting protein (TXNIP) for therapy

Described is a compound capable of reducing or inhibiting (a) the biological activity of thioredoxin-interacting protein (TXNIP) or (b) the expression of the gene encoding TXNIP for treating a condition where improving the resistance towards oxidative stress has a beneficial effect, e.g., for improving female fertiliy or extending healthy lifespan. 19-. (canceled)10. A method of improving female fertility in a subject comprising administering a compound capable of reducing or inhibiting: (a) a biological activity of thioredoxin-interacting protein (TXNIP) or (b) an expression of a gene encoding TXNIP , wherein said compound is:(i) an antisense oligonucleotide or a small hairpin RNA (shRNA) that reduces or inhibits the expression of the gene encoding TXNIP, or(ii) an antibody directed against TXNIP or a fragment thereof that reduces or inhibits the biological activity of TXNIP, or(iii) an inactive TXNIP or nucleic acid sequences encoding an inactive TXNIP.11. A method for identifying a compound that improves female fertility by reducing or inhibiting a biological activity of TXNIP or an expression of a gene encoding TXNIP , comprising the steps of:(a) incubating a candidate compound with a test system comprising TXNIP or the gene encoding TXNIP; and 'wherein an inhibition or loss of the biological activity of TXNIP is indicative that the candidate compound improves female fertility.', '(b) assaying the biological activity of TXNIP;'}12. The method of claim 11 , wherein the inhibition or loss of the biological activity of TXNIP is determined by comparison to a test system without said candidate compound. This application is a Continuation of U.S. patent application Ser. No. 14/364,250, filed Jun. 10 2014, which is a U.S. National Phase Application under 35 U.S.C. §371 of International Patent Application No. PCT/EP2013/001143, filed Apr. 17, 2013, and claims the priority of European Patent Application No. 12002914.5, filed Apr. 25, 2012, all of which are incorporated ...

MULTI-VALENT HEPATITIS B VIRUS ANTIGEN BINDING MOLECULES AND USES THEREOF

This disclosure provides a multimeric hepatitis B virus (HBV) protein binding molecule, e.g., a dimeric IgA or a pentameric or hexameric IgM binding molecule, comprising at least two bivalent binding units, or variants or fragments thereof, each comprising at least two antibody heavy chain constant regions or fragments thereof, wherein each heavy chain constant region or fragment thereof is associated with an HBV antigen binding domain. The disclosure also provides compositions comprising the multimeric binding molecules, polynucleotides encoding the multimeric binding molecules, and methods to make and use the multimeric binding molecules. 1. A multimeric binding molecule comprising at least two IgA bivalent binding units , or variants or fragments thereof and a J-chain or fragment or variant thereof;wherein each IgA binding unit comprises at least two IgA antibody heavy chain constant regions or fragments thereof, each associated with an antigen binding domain;wherein the antigen binding domains specifically bind to a hepatitis B virus (HBV) antigen expressed on the surface of infectious viral particles, on the surface of HBV infected cells, or a combination thereof, andwherein the binding molecule is more potent than a reference IgG antibody comprising the antigen binding domain that specifically binds to the HBV antigen.23-. (canceled)4. The binding molecule of claim 1 , further comprising a secretory component claim 1 , or fragment or variant thereof.5. The binding molecule of claim 1 , wherein the IgA heavy chain constant regions or fragments thereof each comprise a Cα3-tp domain claim 1 , and further comprise a Cα1 domain claim 1 , Cα2 domain claim 1 , or Cα1 domain and a Cα2 domain.6. (canceled)7. The binding molecule of claim 1 , wherein the IgA heavy chain constant regions are human IgA constant regions.8. The binding molecule of claim 1 , wherein each binding unit comprises two IgA heavy chains each comprising a heavy chain variable region (VH) situated ...

DIFFERENTIATION INTO BROWN ADIPOCYTES

The technology described herein is directed to methods and compositions relating to the differentiation and activity of brown adipocytes, and the therapeutic uses thereof. 1. A method for promoting the differentiation of cells into brown adipocytes comprising;a) contacting a population of cells with at least one agent that increases the level or activity of PPARγ2 and C/EBPβ; andb) culturing the cells under conditions favorable for differentiation into brown adipocytes;wherein the method does not comprise contacting the cells with an agent which increases the level of PRDM16.2. The method of claim 1 , wherein the agent that increases the level or activity of PPARγ2 and C/EBPβ comprises a polynucleotide comprising a gene sequence that encodes a PPARγ2 and/or a C/EBPβ polypeptide.3. The method of claim 1 , wherein the agent that increases the level or activity of PPARγ2 and C/EBPβ comprises a PPARγ2 polypeptide and/or C/EBPβ polypeptide.4. The method of claim 1 , wherein the agent that increases the level or activity of PPARγ2 and C/EBPβ comprises a small molecule that increases the level or activity of PPARγ2 or C/EBPβ.5. The method of claim 3 , wherein the small molecule is a selected from the group consisting of:a thiazolidinedione or a glitazar.6. The method of claim 1 , wherein the cells are selected from the group consisting of:non-neuronal somatic cells, differentiated non-neuronal cells, fibroblasts, adipose-derived cells, adipose-derived stromal vascular cells, and stem or progenitor cells.7. The method of claim 6 , wherein the stem cells or progenitor cells are chosen from the group consisting of:induced pluripotent stem cells, adipose-derived stem cells, adipose-derived mesenchymal stem cells, adipose progenitor cells, embryonic stem cells, and mesenchymal stem cells.8. The method of claim 1 , wherein said cells are initially provided by inducing a population of pluripotent stem cells to differentiate to a mesenchymal stem cell phenotype.9. The method of ...

METHOD TO IDENTIFY COMPOUNDS ABLE TO BIND TO THE ROSSMANN FOLD OF C-TERMINAL-BINDING PROTEINS, IDENTIFIED COMPOUNDS AND MEDICAL USES THEREOF

The invention refers to a method for identifying an anti-tumoral and/or anti-proliferative and/or an inhibitor of the fission machinery involved in mitotic Golgi partitioning and/or a molecule modulator of CtBP corepressor activity by testing their affinity binding for the Rossmann fold of C-terminal-binding proteins (CtBPs); to said identified molecules and to the use thereof as anti-proliferative and/or anti tumoral agents. 1. A method for identifying a molecule acting as an anti-tumoral and/or an anti-proliferative and/or an inhibitor of the fission machinery involved in mitotic Golgi partitioning and/or a modulator of C-terminal-binding proteins (CtBPs) corepressor activity , comprising the steps of:assaying candidate molecules for their affinity binding for the Rossmann fold of C-terminal-binding proteins (CtBPs);selecting molecules having an high affinity binding for the Rossmann fold of C-terminal-binding proteins (CtBPs);testing such high affinity binding molecules for their capacity of inhibiting proliferation and/or inducing an apoptotic response in a cell system.2. The method according to wherein the candidate molecules are previously selected from a database through virtual docking on the C-terminal-binding proteins (CtBPs).3. The method according to wherein the Rossmann fold belongs to the CtBP1-S/BARS (BARS) protein (BARS GenBank accession No. AF067795.4. The method according to wherein the molecule is anti-tumoral against a solid tumor.5. The method according to wherein the cell system used for testing expresses high levels of CD38.6. A method of treatment of a tumor claim 1 , comprising administering to a subject in need thereof an effective amount of a molecule selected from the group consisting of:a) a BFA-ADPR conjugate, said conjugate being formed by ADP-ribosyl cyclase activity, orb) an inhibitor of binding to BARS of the BFA-ADPR conjugate and/or of NAD/NADH and/or of Acyl CoAs, with the proviso that said inhibitor is not gossypol.7. The method ...

MOLECULAR TARGETS AND COMPOUNDS, AND METHODS TO IDENTIFY THE SAME, USEFUL IN THE TREATMENT OF DISEASES ASSOCIATED WITH EPITHELIAL MESENCHYMAL TRANSITION

The present invention relates to methods and assays for identifying agents useful in the treatment of diseases associated with epithelial mesenchymal transition (EMT), in particular fibrotic diseases and cancer. The invention provides polypeptide and nucleic acid TARGETs, siRNA sequences based on these TARGETs and antibodies against the TARGETs. The invention is further related to pharmaceutical composition comprising siRNA sequences based on the TARGETs and antibodies against the TARGETs for use in the treatment of diseases associated with epithelial mesenchymal transition, in particular fibrotic disease and cancer. The invention further provides in vitro methods for inhibition of epithelial mesenchymal transition. 1. A method for identifying a compound useful for the treatment of a disease associated with epithelial mesenchymal transition , said method comprising:a) contacting a test compound with a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 21-22, 18-20 and 23-34, functional fragments and derivatives thereof, or with a cell expressing said polypeptide;b) determining a binding affinity of the test compound to said polypeptide, or measuring expression, amount or an activity of said polypeptide;c) contacting the test compound with a population of epithelial cells;d) measuring a property related to epithelial mesenchymal transition; ande) identifying a compound capable of capable of inhibiting of epithelial mesenchymal transition and demonstrating binding affinity to said polypeptide or reducing or inhibiting the expression, amount or an activity of said polypeptide.2. (canceled)3. (canceled)4. A method for identifying a compound inhibiting epithelial mesenchymal transition (EMT) , said method comprising:a) contacting a test compound with a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 21-22, 18-20 and 23-34, functional fragments and functional derivatives thereof ...

METHOD FOR INHIBITING THE SWAP-70 PROTEIN

The invention relates to the field of biomedical and pharmacological research, in particular in the field of immunology, allergies, cancers, bone diseases and autoimmune diseases. 1. Method for identifying a substance which inhibits the activity of SWAP-70 , wherein the method comprises the following: (a) a test substance with', '(b) SWAP-70,, '(i) contacting(ii) detecting the degree of dimerisation of SWAP-70,(iii) selecting a test substance which inhibits the dimerisation of SWAP-70.2. Method according to claim 1 , characterised in that differently labelled SWAP-70 molecules are used as SWAP-70 in step (i).3. Method according to either or claim 1 , characterised in that SWAP-70 molecules labelled with fluorescent markers are used in step (i).4. Method according to any of to claim 1 , characterised in that a FRET-based assay is performed in step (ii).5. Method according to claim 1 , characterised in that step (ii) is carried out by means of a method selected from surface plasmon resonance claim 1 , fluorescence correlation spectroscopy claim 1 , chromatography or using a quartz microbalance.6. Method according to any of to claim 1 , characterised in that the interaction of the differently labelled SWAP-70 molecules is measured in vitro or in situ.7. Use of a substance obtained by a method according to any of to for the treatment of allergies claim 1 , IgE-dependent autoimmune diseases claim 1 , cancer and/or osteoporosis.8. Test kit for identifying a substance which inhibits the activity of SWAP-70 claim 1 , comprising:a.) differently labelled SWAP-70 molecules, and/orb.) surface-bound SWAP-70, as well as soluble SWAP-70.9. Use of a test kit according to for identifying a substance which inhibits the activity of SWAP-70.11. Use of a dimerisation domain according to for identifying a substance which inhibits the activity of SWAP-70 claim 8 , in particular in a method according to any one of to .12. Use of a dimerisation domain according to as a target for inhibiting ...

FELINE BITTER TASTE RECEPTORS AND METHODS

A family of novel feline bitter taste receptors, referred to as feline TAS2R (fTAS2R), are disclosed herein. Isolated polynucleotides encoding the novel feline bitter taste receptors and chimeric polypeptides are also disclosed, as are expression vectors and host cells for expression of the novel feline bitter taste receptors. Methods of identifying compounds that bind to the novel feline bitter taste receptors and modulate their activity are disclosed. 1. A polypeptide comprisingthe amino acid sequence of SEQ ID NO:2, oran amino acid sequence having at least 95% homology to the sequence of SEQ ID NO:2;wherein the polypeptide is covalently bound to a label, a solid support, or a lipid monolayer.2. The polypeptide of comprising the amino acid sequence of SEQ ID NO:2.3. The polypeptide of comprising an amino acid sequence having at least 95% homology to SEQ ID NO:2.4. The polypeptide of claim 1 , wherein the polypeptide is covalently bound to a lipid monolayer.5. The polypeptide of claim 1 , wherein the polypeptide is covalently bound to a label.6. The polypeptide of claim 5 , wherein the label is a heterologous polypeptide sequence.7. The polypeptide of claim 6 , wherein the heterologous polypeptide sequence is a membrane targeting sequence or a peptide tag sequence.8. The polypeptide of claim 5 , wherein the label is a radiolabel claim 5 , a fluorescence label claim 5 , a chemiluminescent label claim 5 , an enzymic label claim 5 , or an immunogenic label.9. The polypeptide of claim 1 , wherein the polypeptide is covalently bound to a solid support.10. A chimeric polypeptide comprising at least one extracellular domain of SEQ ID NO:2 covalently linked to a heterologous polypeptide sequence claim 1 , wherein the extracellular domain comprises amino acids 1 claim 1 , 68-84; 146-179; or 249-257 of SEQ ID NO:2.11. A chimeric polypeptide comprising at least one intracellular domain of SEQ ID NO:2 covalently linked to a heterologous polypeptide sequence claim 1 , wherein ...

Surface plasmon resonance approach to monitor protein-ligand interactions

The present invention provides assays utilizing SPR to detect protein-ligand interactions as well as compositions utilized is such assays.

METHOD OF IDENTIFYING AGENTS THAT AFFECT MATURATION, SURVIVAL AND MYELINATION

The present invention discloses a method of identifying agents that affect maturation and survival of oligodendrocytes or myelination of neuronal cells using ex-vivo differentiated embryonic stem cells. 130.-. (canceled)31. A method of making enriched oligodendrocyte precursor cells (OPCs) , comprising:(a) culturing human embryonic stem cells (hES) in a medium comprising retinoic acid and Epidermal Growth Factor (EGF), thereby generating neurospheres;(b) contacting the neurospheres with an adherent substrate comprising an extracellular matrix;(c) following step (b), dissociating the neurospheres;(d) culturing the dissociated neurospheres in a medium comprising EGF and basic Fibroblast Growth Factor (bFGF);(e) following step (d), culturing the dissociated neurospheres in a medium lacking growth factors, thereby generating ex vivo differentiated neural cells;(f) selecting the ex vivo differentiated neural cells to be O4-positive or CD140-positive;(g) expanding, freezing, and thawing the selected neural cells in a medium comprising EGF and bFGF;(h) after thawing, culturing the selected neural cells for at least one day in a medium lacking growth factors; thereby making the enriched OPCs.32. The method of claim 31 , wherein the OPCs further express Hes5.33. The method of claim 31 , wherein the hES in step (a) are aggregated.34. The method of claim 31 , wherein the medium of step (a) further comprises noggin.35. The method of claim 31 , wherein the medium of step (e) comprises noggin.36. The method of claim 31 , wherein the selecting of step (f) is performed by magnetic sorting (MACS) or fluorescence activated cell sorting (FACS).37. A method of quantifying an effect of an agent on myelination of OPCs or on maturation or survival of oligodendrocytes claim 31 , or a combination thereof claim 31 , comprising:{'claim-ref': {'@idref': 'CLM-00031', 'claim 31'}, '(a) making enriched OPCs according to ;'}(b) following step (a), contacting the enriched OPCs with the agent; and,( ...

MOLECULAR PROFILING OF TUMORS

Provided herein are methods and systems of molecular profiling of diseases, such as cancer. In some embodiments, the molecular profiling can be used to identify treatments for a disease, such as treatments that were not initially identified as a treatment for the disease or not expected to be a treatment for a particular disease. 1. A system for generating a report identifying at least one therapeutic agent for an individual with a cancer comprising:a. at least one device configured to assay a plurality of molecular targets in a biological sample from the individual to determine molecular profile test values for each of the plurality of molecular targets, wherein the molecular targets comprise ERBB2, PTEN, TOP2A, TOPO1 and TS; and i. a reference value for each of the plurality of molecular targets; and', 'ii. a listing of therapeutic agents with efficacy linked to a biological state of at least one member of the plurality of molecular targets;, 'b. at least one computer database comprisingc. a computer-readable program code comprising instructions to input the molecular profile test values and to compare each molecular profile test value with a corresponding reference value in (b)(i) to identify a biological state for each member of the plurality of molecular targets;d. a computer-readable program code comprising instructions to identify at least one therapeutic agent from the listing of therapeutic agents in (b)(ii), wherein the biological state identified in (c) for at least one member of the plurality of molecular targets provides an indication of likely benefit of the at least one therapeutic agent for treating the cancer; ande. a computer-readable program code comprising instructions to generate a report that comprises a listing of the at least one therapeutic agent identified in (d) and the biological state of each molecular target with efficacy linked thereto.2. The system of claim 1 , wherein the molecular profile test values are input into the system from a ...

INTEGRATED COMPOUND DISCOVERY SYSTEMS AND METHODS

Methods, systems, devices and apparatus for use in screening and/or selecting a library of nucleic acid molecules and/or nucleic acid tagged or encoded molecules for binding to or interaction with a target molecule or substance (e.g., for use in new compound or drug discovery) are described. In some embodiments the device comprises: (a) a spatially addressable array, said array comprising a plurality of separate and discrete locations thereon; (b) a plurality of different oligomers operably connected to said spatially addressable array at different ones of said separate and discrete locations; (c) a tag sequence which is complementary to, and is hybridized to, each of said oligomers; and (d) a candidate chemical operably connected to each of said tag sequences, wherein each of said discrete locations is a unique identifier for its corresponding oligomer; and wherein said tag sequence is a unique identifier for its connected candidate chemical. 1. A device comprising:(a) a spatially addressable array, said array comprising a plurality of separate and discrete locations thereon;(b) a plurality of different oligomers operably connected to said spatially addressable array at different ones of said separate and discrete locations;(c) a tag sequence which is complementary to, and is hybridized to, each of said oligomers; and(d) a candidate chemical operably connected to each of said tag sequences,wherein each of said discrete locations is a unique identifier for its corresponding oligomer;and wherein said tag sequence is a unique identifier for its connected candidate chemical.2. The device of claim 1 , wherein said spatially addressable array is a field-effect transistor array claim 1 , an electrochemical array or an optical array.3. The device of claim 1 , wherein said oligomers and said tag sequences are nucleic acids.4. The device of claim 1 , wherein said candidate chemicals are selected from the group consisting of small molecules claim 1 , peptides claim 1 , ...

THERAPEUTIC AGENT FOR AUTOIMMUNE DISEASES OR ALLERGY, AND METHOD FOR SCREENING FOR THE THERAPEUTIC AGENT

Disclosed is a therapeutic agent for treating a cellular immune disease, comprising as an active ingredient a substance that inhibits binding between Sema3A and a Neuropilin-1/Plexin-A1 heteroreceptor. The substance includes, for example, a Sema3A neutralizing antibody, a Neuropilin-1 neutralizing antibody, or a soluble Neuropilin-1 or derivative thereof. Also disclosed is a method for screening a therapeutic agent for treating a cellular immune disease utilizing a signal generated by the interactions of Neuropilin-1, Plexin-A1 and Sema3A as a marker. 1. A method for suppressing migration of dendritic cells to regional lymph nodes , the method comprising inhibiting binding between Sema3A and a Neuropilin-1/Plexin-A1 heteroreceptor expressed in dendritic cells by an inhibitor.2. The method of claim 1 , wherein the inhibitor is a Sema3A neutralizing antibody.3. The method of claim 2 , wherein the Sema3A neutralizing antibody binds to a peptide comprising the amino acid sequence of from amino acid 363 to amino acid 381 of SEQ ID No: 1.4. The method of claim 3 , wherein the amino acid sequence of the peptide is NYQWVPYQGRVPYPRPGTC (SEQ ID No. 12).5. The method of claim 1 , wherein the inhibitor is a Neuropilin-1 neutralizing antibody.6. The method of claim 5 , wherein the Neuropilin-1 neutralizing antibody binds to a peptide comprising the amino acid sequence of from amino acid 265 to amino acid 857 of SEQ ID No: 2.7. The method of claim 1 , wherein the inhibitor is a neutralizing antibody that is a polyclonal antibody.8. The method of claim 1 , wherein the inhibitor is a neutralizing antibody that is a monoclonal antibody.9. The method of claim 1 , wherein the inhibitor is a soluble Neuropilin-1.10. The method of claim 9 , wherein the soluble Neuropilin-1 comprises a polypeptide selected from the group consisting of:(1) a polypeptide comprising the amino acid sequence of from amino acid 23 to amino acid 589 of SEQ ID NO: 2,(2) a polypeptide comprising the amino acid ...

METHOD

The present invention relates generally methods and kits for detecting binding interactions, in particular protein-protein interactions, and particularly to high throughput methods for labelling, analysing, detecting and measuring protein-protein interactions. 1. A method of determining a binding interaction between a binding agent and a target comprisinga) contacting a binding agent library with a target to allow formation of binding agent/target complex, wherein each member of said binding agent library is associated with a unique nucleotide sequence and wherein said target is associated with a unique nucleotide sequence;b) isolating said binding agent/target complexes into compartments so that there is a single binding/agent complex in one compartment;c) linking the unique nucleotide sequence(s) associated with the binding agent and target in the binding agent/target complex to form a linked nucleotide sequence, wherein isolation of the isolated binding agent/target complexes is maintained during the linking step;d) identifying the binding agent(s) present in the complex from the linked nucleotide sequence; ande) using the linked nucleotide sequence correlating the unique nucleotide sequence of each member of said binding agent library with the binding characteristics of said member.2. The method as claimed in wherein said binding agent library comprises an antibody library.3. The method of wherein said antibody library comprises an antibody display library or a library of antibodies wherein each antibody is labelled with said unique nucleotide sequence.4. (canceled)5. The method of wherein said target comprises a protein.6. The method of wherein said target comprises a protein display library claim 1 , herein each member of said library is associated with a unique nucleotide sequence.7. (canceled)8. The method of claim 5 , wherein said protein is within a protein mixture or an enriched protein mixture.9. (canceled)10. The method of claim 8 , wherein said protein ...

MARKER SEQUENCES FOR DIAGNOSING AND STRATIFYING SYSTEMIC SCLEROSIS PATIENTS

The present invention relates to methods for identifying markers for systemic sclerosis (also scleroderma; SSc) and to the markers identified with the aid of this method, which can differentiate between SSc and other autoimmune diseases on the one hand and between different SSc subgroups on the other hand. The invention also relates to panels, diagnostic devices and test kits which comprise these markers, and to the use and application thereof, for example for the diagnosis, prognosis and therapy control of SSc. The invention also relates to methods for screening and for validating active substances for use in SSc. 115-. (canceled)16. A fusion protein for detecting systemic sclerosis (SSc) , comprising a peptide sequence selected independently of one another from any one of SEQ ID NOs: 1-10 , 13 , 15-18 and at least one protein tag bound to the peptide sequence.17. The fusion protein of claim 16 , wherein the peptide sequence has a length of no more than 25 amino acids.18. The fusion protein of claim 16 , wherein the peptide sequence has a length of no more than 15 amino acids.19. The fusion protein of claim 16 , wherein the tag is selected from c-myc claim 16 , His tag claim 16 , Arg tag claim 16 , FLAG claim 16 , alkaline phosphatase claim 16 , V5 tag claim 16 , T7 tag or Strep tag claim 16 , HAT tag claim 16 , NusA claim 16 , S tag claim 16 , SBP tag claim 16 , thioredoxin claim 16 , and DsbA.20. The fusion protein of claim 16 , wherein the fusion protein has one or more additional domains selected from a cellulose-binding domain claim 16 , green fluorescent protein claim 16 , maltose-binding protein claim 16 , calmodulin-binding protein claim 16 , glutathione S-transferase and lacZ.21. The fusion protein of claim 16 , wherein the peptide sequence is a binding region.22. The fusion protein of claim 16 , wherein the peptide sequence is an epitope.23. The fusion protein of claim 16 , wherein the fusion protein binds to autoantibodies that are present during the ...

PEPTIDIC INHIBITOR OF SIGNAL TRANSMISSION FROM G-ALPHA-S TO G-ALPHA-I-COUPLED RECEPTOR CASCADES

The present invention relates to novel peptidic inhibitors of signal transmission from Gαs- to Gαi-coupled receptor cascades and methods for their use. 1. A PKA RII-derived peptide consisting of 12 to 17 amino acids , wherein the PKA RII-derived peptide comprises the amino acid sequence DSFXIXE (SEQ ID No. 1) or XXXXXDSFXIXEXXX (SEQ ID No. 4) , and wherein X is any amino acid.2. The peptide according to claim 1 , comprising the amino acid sequence DSFFIVE (SEQ ID No. 2) or XXXXXDSFFIVEXXX (SEQ ID No. 5) claim 1 , wherein X is any amino acid.3. The peptide according to claim 1 , comprising the amino acid sequence DSFYIIE (SEQ ID No. 3) or XXXXXDSFYIIEXXX (SEQ ID No. 6) claim 1 , wherein X is any amino acid.4. The peptide according to claim 1 , which is QGDSADSFFIVESGE (SEQ ID No. 7) or QGASADSFFIVESGE (SEQ ID No. 8).5. The peptide according to claim 1 , which is fused to another peptide or protein.6. The peptide according to claim 1 , which is labelled.7. (canceled)8. A method for treating cancer in a subject in need thereof claim 1 , the method comprising administering to the subject the peptide according to .9. A method for treating a hormone-related disease or heart failure in a subject in need thereof claim 1 , the method comprising administering to the subject the peptide according to10. (canceled)11. A pharmaceutical composition comprising the peptide according to and a pharmaceutically acceptable carrier.12. The pharmaceutical composition of claim 11 , comprising a further pharmaceutically active agent.13. A method for screening candidate drugs claim 11 , the method comprising:{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, 'a) providing a peptide structure comprising peptide according to and at least one candidate drug,'}b) bringing the compounds of step a) in physical contact with each other under binding conditions andc) analysing the binding of the at least one candidate drug to the peptide structure.14. The method of claim 13 , wherein in step a) a cAMP ...

Compositions and Methods for Culturing Spirochetes

The present invention relates to methods for culturing spirochetes, in particular . The present invention also provides methods of identifying spirochetes present in a biological sample. The present invention further provides methods of diagnosing diseases cause by a spirochete infection, such as Lyme disease, syphilis, and multiple sclerosis. The present invention further provides methods for identifying spirochete susceptibilities to antimicrobials and antimicrobial compositions and cocktails. The present invention also provides methods for treating subjects suspected of having a spirochete infection. 130-. (canceled)31. A composition for culturing spirochetes comprising a spirochete-supporting medium , serum , a reducing agent , and an antibiotic.32. An in vitro method of culturing a spirochete comprising:{'b': '1', '(1) inoculating a composition according to claim with the spirochete to generate a short-term culture; and'}(2) incubating the short-term culture in a short-term culture vessel for about 4-6 days.33. A method of identifying a spirochete in a subject comprising:{'b': '2', '(1) culturing the spirochete by the method of claim ; and'}(2) identifying the spirochete in an identification assay.34. A method of diagnosing a spirochete infection in a subject comprising:{'b': '2', '(1) culturing the spirochete by the method according to claim , wherein the spirochete is obtained from a sample from a subject possibly suffering from a spirochete infection; and'}(2) detecting the spirochete in a detection assay,wherein detection of the spirochete indicates that the subject is suffering from a spirochete infection.35. A method of identifying the antibiotic sensitivity of a spirochete comprising:{'b': '1', '(1) inoculating a spirochete culture medium in a culture vessel with a spirochete, wherein the spirochete culture medium is a composition according to claim ;'}(2) incubating the inoculated medium for about 4-6 days;(3) transferring the cultured spirochetes into ...

Contemporaneous, heterogeneously-oriented, multi-targeted therapeutic modification and/or modulation of disease by administration of sulfur-containing, amino acid-specific small molecules

The present invention discloses and claims novel pharmaceutical compositions, methods, and kits used for the contemporaneous, heterogeneously-oriented, multi-targeted therapeutic modification and/or modulation of cellular metabolic anomalies or other undesirable physiological conditions, including cancer, where the normal cellular biochemical function and/or the expression levels of various proteins/enzymes (i.e., the target molecules) are abnormal and must be modified and/or modulated in order to treat these metabolic anomalies or other undesirable physiological conditions, including cancer. The aforementioned target molecules, by way of non-limiting example, include: anaplastic lymphoma kinase (ALK), mesenchymal epithelial transition (MET) kinase, the receptor tyrosine kinase (ROS1), epidermal growth factor receptor (EGFR), peroxiredoxin (Prx), excision repair cross-complementing protein 1 (ERCC1), insulin growth factor 1 receptor (IGF1R), ribonucleotide reductase (RNR), tubulin, farnesyltransferase, and various other classes of proteins/enzymes. Additionally, the present invention discloses and claims methods and kits for (a) the selection of subjects for treatment; (b) the determination of the most effective medicinal agent(s) to be administered in combination with the administration of the sulfur-containing, amino acid-specific small molecules of the present invention; (c) the dosage of the medicinal agent(s) to be administered; (d) the determination of the length and/or number of treatment cycles; (e) the adjustment of the specific medicinal agent(s) used and the dosage administered during treatment; and/or (f) ascertaining the potential treatment responsiveness of the specific disease to the medicinal agents (s) selected for administration to a subject suffering from one or more types of: (i) cancer or (ii) metabolic anomalies or other undesirable physiological conditions by quantitatively determining the level of the abnormal biochemical activity and/or ...

Immunomodulatory compounds

The present invention is based on the finding that in addition to interfering with or blocking, preventing and/or inhibiting the interaction between a pathogen and, for example, a sialic acid containing cell surface receptor, certain sialic acid binding molecules have immunomodulatory properties. The invention provides methods and uses which exploit sialic acid binding molecules in the treatment and/or prevention of disease by modulation and/or priming of the host immune response.

METHODS OF TREATING CANCER

A method of treating cancer is disclosed. The method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising an agent which induces a dissociation of the 26S proteasomal complex into a 20S component and a 19S component to thereby inhibit 26S proteasomal activity, wherein the pharmaceutical agent is devoid of a chemotherapeutic agent. 1. A method of treating a disease for which inhibiting a proteasome is advantageous , the method comprising administering to the subject a therapeutically effective amount of an agent which down-regulates an expression and/or activity of a subunit of the 19S regulatory particle of the proteasome 26S subunit , non-ATPase , said subunit being selected from the group consisting of Psmd1 , Psmd2 , Psmd3 , Psmd4 , Psmd7 , Psmd8 , Psmd11 and Psmd12 , thereby treating the disease.2. A method of treating a disease for which inhibiting a proteasome is advantageous , the method comprising administering to the subject a therapeutically effective amount of a polynucleotide agent which down-regulates an expression of a subunit of the 19S regulatory particle of the proteasome 26S subunit , with the proviso that said subunit is not Psmd14 , thereby treating the disease.3. A method of treating ovarian or breast cancer , the method comprising administering to the subject a therapeutically effective amount of an agent which down-regulates an expression and/or activity of a subunit of the 19S regulatory particle of the proteasome 26S subunit , non-ATPase , said subunit being selected from the group consisting of Psmd1 , Psmd2 , Psmd3 , Psmd4 , Psmd7 , Psmd8 , Psmd11 and Psmd12 , thereby treating the disease.4. The method of claim 1 , wherein the disease is selected from the group consisting cancer claim 1 , an inflammatory disease and a neurodegenerative disease.5. The method of claim 4 , wherein said cancer comprises breast cancer or ovarian cancer.6. The method of claim 1 , wherein the agent ...

Pharmaceuticals and methods for treating hypoxia and screening methods therefor

Light-generating fusion proteins having a ligand binding site and a light-generating polypeptide moiety and their use as diagnostics, in drug screening and discovery, and as therapeutics, are disclosed. The light-generating fusion protein has a feature where the bioluminescence of the polypeptide moiety changes upon binding of a ligand at the ligand binding site. The ligand may be, for example, an enzyme present in an environment only under certain conditions, e.g., ubiquitin ligase in a hypoxic state, such that the light-generating fusion protein is “turned on” only under such conditions.

Screening Method

Provided is a high-throughput coupled enzyme method of screening for a tryptophan-2,3-dioxygenase (TDO) inhibitor compound and/or an indoleamine-2,3-dioxygenase (IDO) inhibitor compound, which method comprises: (a) reacting tryptophan with isolated IDO and/or isolated TDO in the presence of a test compound to form N-formylkynurenine; (b) reacting N-formylkynurenine from step (a) with isolated kynurenine formamidase to form kynurenine; and (c) detecting the kynurenine produced in step (b) and determining whether the test compound is a TDO and/or an IDO inhibitor compound or not from the presence or absence or quantity of the detected kynurenine, wherein step (a) is conducted in the presence of a reducing system suitable for converting IDO and/or TDO from the Fe to the Fe state, and which does not prevent the formation of kynurenine in step (c). 2. A method according to claim 1 , wherein the reducing system comprises a reducing agent and an electron transport agent.3. A method according to claim 2 , wherein the reducing agent is selected from ascorbic acid claim 2 , TCEP and/or dithionite.4. A method according to claim 2 , wherein the electron transport agent comprises methylene blue.5. A method according to claim 1 , wherein the detection of kynurenine is carried out by direct absorbance or by fluorescence.6. A method according to claim 5 , wherein the absorbance wavelength is from 480-500 nm.78-. (canceled)9. A method according to claim 1 , wherein step (c) comprises a step of measuring the presence or absence or quantity of kynurenine by reacting the product of step (b) with Ehrlich's reagent and measuring the fluorescence intensity of the product.10. A method according to claim 1 , wherein the tryptophan comprises L-tryptophan.11. A method according to claim 1 , wherein the IDO comprises human IDO.12. A method according to claim 1 , wherein the IDO comprises recombinant IDO.13. A method according to claim 1 , wherein the TDO comprises human TDO.14. A method ...

IN-SILICO BASED TECHNIQUES IN THE IDENTIFICATION OF POTENT ß-GLUCORONIDASE INHIBITORS

The invention relates to a method of identifying inhibitors against target receptor β-glucoronidase. Three compounds were found to be completely non-cytotoxic while, the remaining compounds showed moderate cytotoxicity. 1. (canceled)2. (canceled)3. A β-glucuronidase enzyme inhibitor selected from a group of compounds consisting of 3-(bis(5-bromo-1H-indol-3-ypmethyl)benzene-1 ,2-diol; (E)-((2 ,S ,3R ,4R ,5S ,6R)-3 ,4 ,5-trihydroxy-6-(5-hydroxy-2-(4-hydroxyphenyl)-4-oxo-4H-chromen-7-yloxy)tetrahydro-2H-pyran-2-yl)methyl 3-(4-hydroxyphenyl)acrylate; 5-(2-{[3 ,4-dimethoxyphenyl]methylidene)amino}-4-hydroxy-1 ,1-dioxo-2H-1 ,2-benzothiazine-3-yl)-2 ,4-dihydro-3H-1 ,2 ,4-triazole-3-thione; 5-(2-[{2 ,3 ,4-trimethoxyphenyl)methylidene]amino}-4-hydroxy-1 ,1-dioxido-2H-1 ,2-benzothiazine-3-yl)-2 ,4-dihydro-3H-1 ,2 ,4-triazole-3-thione; 5-(2-[{4-N-N′-dimethylaminophenyl)methylidene]amino}-4-hydroxy-1 ,1-dioxido-2H-1 ,2-benzothiazine-3-yl)-2 ,4-dihydro-3H-1-1 ,2 ,4-triazole-3-thione; 1-((5-(methyldyneammonio)-1H-indol-3-yl)-4-phenylpiperazin-1-ium; and 5-(4-Hydroxy-2-{[(E)-(2-hydroxy-3-methoxyphenyl)methylidene]amino}-1 ,1-dioxido-2H-1 ,2-benzothiazin-3-yl)-2 ,4-dihydro-3H-1 ,2 ,4-triazole-3-thione.4. The β-glucuronidase enzyme inhibitor of claim 1 , wherein said β-glucuronidase enzyme inhibitor is used to treat breast claim 1 , colon and prostate cancer. β-Glucoronidase is an important glycosidase enzyme which catalyzes the hydrolysis of complex carbohydrates into simplest monomeric units. Its over-expression relates with, several type of cancers, including breast, colon and prostate cancer. To treat these disorders the available drug brands on the market are silymyrin, and its derivatives. Some other drugs such as Nialamide, Isocarboxazid, and Phenelzine have also been reported to inhibit GUS activity. However, camptothecin, a plant alkaloid, its derivatives hycamptin and camptosar have been reported to have been granted approval for clinical use, but cause severe side effects ...

MONOCLONAL ANTIBODY FOR DETECTING EXOSOMES

A monoclonal antibody for detecting or capturing an exosome, selected from the group consisting of a monoclonal antibody or antibody fragments thereof that recognize amino acid numbers 113 to 195 of the amino acid sequence as shown in SEQ ID NO: 1, a monoclonal antibody or antibody fragments thereof that recognize amino acid numbers 104 to 202 of the amino acid sequence as shown in SEQ ID NO: 2, a monoclonal antibody or antibody fragments thereof that recognize amino acid numbers 36 to 54 of the amino acid sequence as shown in SEQ ID NO: 3, and a monoclonal antibody or antibody fragments thereof that recognize amino acid numbers 113 to 201 of the amino acid sequence as shown in SEQ ID NO: 3, each capable of detecting or capturing an exosome. The monoclonal antibody for detecting an exosome of the present invention is capable of detecting CD9, CD63 or CD81 on the exosome in a living body with an excellent sensitivity and specificity. 1. A monoclonal antibody for detecting or capturing an exosome , selected from the group consisting of a monoclonal antibody or antibody fragments thereof that recognize amino acid numbers 113 to 195 of the amino acid sequence as shown in SEQ ID NO: 1 , a monoclonal antibody or antibody fragments thereof that recognize amino acid numbers 104 to 202 of the amino acid sequence as shown in SEQ ID NO: 2 , a monoclonal antibody or antibody fragments thereof that recognize amino acid numbers 36 to 54 of the amino acid sequence as shown in SEQ ID NO: 3 , and a monoclonal antibody or antibody fragments thereof that recognize amino acid numbers 113 to 201 of the amino acid sequence as shown in SEQ ID NO: 3 , each capable of detecting or capturing an exosome.2. A monoclonal antibody for detecting or capturing an exosome selected from the group consisting of:a monoclonal antibody (CD9-12A12 antibody) produced by a hybridoma deposited under Accession Number FERM ABP-11519 or fragments thereof which are monoclonal antibody fragments that recognize ...

CRYSTAL STRUCTURE OF THE NanR AND ManNAc-6P COMPLEX, AND USES THEREOF

The present invention relates to a three-dimensional structure of a complex explored by crystallization of the complex of NanR which is a key pathogenic regulatory protein of and ManNA6P which is a NanR regulator. Further, the present invention relates to a modified NanR protein, a polynucleotide encoding the protein, a vector including the polynucleotide, and a transformant including the vector. Furthermore, the present invention relates to a method for screening a substance regulating interaction between NanR and the transcriptional control region of nan operon which is a gene cluster regulated by NanR, or a substance regulating interaction between NanR and ManNAc-6P, by designing three-dimensional structure of the complex, and to an antibacterial composition including the screened substance. 1. A method for crystallizing a complex of NanR protein and ManNAc-6P , comprising(a) mixing NanR protein having an amino acid sequence of SEQ ID NO. 1 with N-acetylmannosamine 6-phosphate (ManNAc-6P); and(b) crystallizing the mixture of step (a).2. The method according to claim 1 , wherein the step (a) is carried out by mixing NanR protein and ManNAc-6P in a molar ratio of 1:10 to 1:200.3. The method according to claim 1 , wherein the step (b) is carried out in a solution comprising 1 to 20% MME-PEG 2000 claim 1 , 0.01 to 1 M ammonium sulfate claim 1 , 0.01 to 2 M sodium formate claim 1 , 0.5 to 6% low molecular polyglutamic acid (PGA-LM) claim 1 , and 0.01 to 1 M sodium acetate.4. The method according to claim 1 , wherein in the step (b) claim 1 , the mixture is incubated on ice for 1 to 24 hours.5. The method according to claim 1 , wherein the NanR protein is a SeMet-NanR protein having selenomethionine instead of methionine constituting the protein.6. A crystal of NanR protein and ManNAc-6P complex which has a space group of P321 and a unit-cell dimension of a=109.21 claim 1 , b=109.21 and c=82.47 claim 1 , α=β=90° and γ=120° claim 1 , wherein the NanR protein has an ...

Novel Screening Methods

The present invention includes a luciferase-based high-throughput screening assay that identifies compounds that are inhibitors of cellular metabolism. This assay is applicable to all bacterial and eukaryotic membranes. 2. The method of claim 1 , wherein the level of luminescence in the first mixture is less than about 70% of the level of luminescence in the second mixture.3. The method of claim 1 , wherein the test compound inhibits or disrupts the activity of at least one enzyme in the oxidative phosphorylation pathway in the cell.4. The method of claim 1 , wherein the test compound inhibits or disrupts the proton motive force (H gradient) altering the electrochemical gradient across the cellular membrane affecting the proton concentration across the membrane.5. The method of claim 1 , wherein the test compound inhibits or disrupts the difference in electric potential across the cellular membrane.6. The method of claim 1 , wherein the cell is eukaryotic.7. The method of claim 6 , wherein the eukaryotic cell is mammalian.8. The method of claim 1 , wherein the cell is bacterial.9. The method of claim 8 , wherein the bacterium is Gram positive.10Staphylococcus aureus, Mycobacterium smegmatis, Bacillus thuringiensis, Enterococcus. The method of claim 9 , wherein the Gram positive bacterium is selected from the group consisting of claim 9 , and combinations thereof.11. The method of claim 8 , wherein the bacterium is Gram negative.12Acinetobacter baumannii, Pseudomonas aeruginosa, Yersinia enterocolitica, Escherichia coli, Klebsiella pneumonia. The method of claim 11 , wherein the Gram negative bacterium is selected from the group consisting of claim 11 , and combinations thereof.13. The method of claim 1 , wherein the luciferase is added at the beginning of the assay.14. The method of claim 1 , wherein the assay is carried out over a period of time of two hours or less.15. The method of claim 1 , wherein the volume of assay reactions ranges from about 5 μL to about 20 ...

MU OPIOID RECEPTOR AGONIST ANALOGS OF THE ENDOMORPHINS

The invention relates to cyclic peptide agonists that bind to the mu (morphine) opioid receptor and their use in the treatment of acute and/or chronic pain. Embodiments of the invention are directed to cyclic pentapeptide and hexapeptide analogs of endomorphin that have (i) a carboxy-terminal extension with an amidated hydrophilic amino acid and (ii) a substitution in amino acid position 2, and in some embodiments, a 2′,6′-dimethyltyrosine (Dmt) residue in place of the N-terminal tyrosine residue a position 1. These peptide analogs exhibit increased solubility compared to similar tetrapeptide analogs while maintaining favorable or improved therapeutic ratios of analgesia to side effects. 2. The peptide of claim 1 , wherein:{'sub': 1', '4, '(i) Xis selected from the group consisting of D-Lys, D-Orn, D-Dpr, and D-Dab; and Xis selected from the group consisting of D-Asp, D-Glu, Asp, and Glu; or'}{'sub': 1', '4, '(ii) Xis selected from the group consisting of D-Asp and D-Glu; and Xis selected from the group consisting of Lys, Orn, Dpr, and Dab.'}3. The peptide of claim 1 , wherein:{'sub': '2', 'Xis selected from the group consisting of Trp, Phe, and N-alkyl-Phe, wherein the alkyl group of N-alkyl-Phe comprises 1 to about 6 carbon atoms; and'}{'sub': 3', '2, 'Xis selected from the group consisting of Phe, D-Phe, and p-Y-Phe, wherein Y is NO, F, Cl, or Br.'}4. The peptide of claim 3 , wherein Xis N-methyl-Phe.5. The peptide of claim 3 , wherein Xis p-Cl-Phe.6. The peptide of claim 1 , wherein R is H and Xis NH.7. The peptide of claim 1 , wherein R is H and Xis Ala-NH claim 1 , Arg-NH claim 1 , Asn-NH claim 1 , Asp-NH claim 1 , Cys-NH claim 1 , Glu-NH claim 1 , Gln-NH claim 1 , Gly-NH claim 1 , His-NH claim 1 , Ile-NH claim 1 , Leu-NH claim 1 , Met-NH claim 1 , Orn-NH claim 1 , Phe-NH claim 1 , Pro-NH claim 1 , Ser-NH claim 1 , Thr-NH claim 1 , Trp-NH claim 1 , Tyr-NHor Val-NH.8. The peptide of claim 1 , wherein the alkyl group is a methyl claim 1 , ethyl claim 1 , propyl ...

CELL PENETRATING PEPTIDES WHICH BIND IRF5

The present invention comprises cell penetrating peptides that bind to interferon regulatory factor IRF5 and disrupt the IRF5 homo-dimerization and/or attenuate downstream signaling, and a method for screening peptides that inhibit IRF5. Generally, the cell penetrating peptides of the invention bind human interferon regulatory factor IRF5 (CPP-IRF5). 1. A cell-penetrating peptide which binds interferon regulatory factor IRF5 (CPP-IRF5) , wherein the peptide comprises an amino acid sequence of 20 to 40 amino acids and wherein said amino acid sequence further comprises , in part , an amino acid sequence motif selected from the group consisting of: I isisoleucine,', 'L is leucine,', 'S is serine,', 'P is proline,', 'K is lysine, and', 'x is independently selected from any amino acid; or, 'a) I-x-L-x-I-S-x-P-x-x-K (SEQ ID NO: 30), wherein'} Y is tyrosine,', 'R1 is an amino acid selected from the group of tryptophan (W) or alanine (A),', 'R2 is an amino acid selected from the group consisting of leucine (L) or threonine (T),', 'R3 is an amino acid selected from the group consisting of leucine (L), alanine (A), aspartic acid (D), phenylalanine (F), or tyrosine (Y),', 'R8 is leucine (L),', 'R4 is an amino acid selected from the group consisting of leucine (L), glycine (G) or threonine (T),', 'R5 is an amino acid selected from the group consisting of phenylalanine (F), leucine (L) or methionine (M), and', 'R9 is valine (V) or leucine (L); or, 'b) Y-R1-R2-R3-R8-R4-R5-R9 (SEQ ID NO: 31), wherein'} K is lysine,', 'D is aspartic acid,', 'R6 is an amino acid selected from the group consisting of leucine or aspartic acid,', 'M is methionine,', 'R7 is selected from the group consisting of Glutamine-Tryptophan (Q-W) and arginine-phenylalanine (R-F), and', 'F is phenylalanine;, 'c) K-D-R6-M-V-R7-F-K-D (SEQ ID NO: 2), wherein'}or a pharmaceutically acceptable salt thereof.2. The CPP-IRF5 peptide according to claim 1 , wherein the peptide comprises an amino acid sequence of 20 to 40 ...

ANTI-VASOHIBIN 2 ANTIBODY

An anti-Vasohibin-2 antibody, a genetically recombinant anti-Vasohibin-2 antibody, or a fragment thereof, which recognizes amino acid numbers 269 to 288 of the amino acid sequence shown in SEQ ID NO: 2. The anti-Vasohibin-2 antibody of the present invention recognizes a Vasohibin-2 protein with an excellent specificity, and can inhibits an action of promoting angiogenesis owned by the Vasohibin-2 protein, so that the pharmaceutical composition containing the anti-Vasohibin-2 antibody is suitably used in the treatment of a disease requiring inhibition of angiogenesis such as cancer, and the like. 1. An anti-Vasohibin-2 antibody or a fragment thereof , which recognizes amino acid numbers 269 to 288 of the amino acid sequence shown in SEQ ID NO: 2.2. The antibody or a fragment thereof according to claim 1 , which is a monoclonal antibody.3. The antibody or a fragment thereof according to claim 2 , produced by a hybridoma shown by the accession number NITE BP-1474.4. A genetically recombinant anti-Vasohibin-2 antibody or a fragment thereof claim 2 , which recognizes amino acid numbers 269 to 288 of the amino acid sequence shown in SEQ ID NO: 2.5. A hybridoma that produces an anti-Vasohibin-2 monoclonal antibody recognizing amino acid numbers 269 to 288 of the amino acid sequence shown in SEQ ID NO: 2.6. The hybridoma according to claim 5 , which is shown by the accession number NITE BP-1474.7. An angiogenesis inhibitor comprising the antibody or a fragment thereof as defined in .8. A pharmaceutical composition comprising the antibody or a fragment thereof as defined in .9. A pharmaceutical composition for treatment of a disease requiring inhibition of angiogenesis claim 7 , comprising the angiogenesis inhibitor as defined in .10. The pharmaceutical composition for treatment according to claim 9 , wherein the disease requiring inhibition of angiogenesis is cancer.11. A method for assessing pharmacological efficacy of an anti-angiogenesis agent claim 9 , comprising:{' ...

Membrane Transporter NaPi2b (SCL34A2) Epitope for Antibody Therapy, Antibodies Directed Thereto, and Target for Cancer Therapy

The present invention relates generally to the membrane transporter NaPi2b (SLC34A2) as a target for therapy, including immunotherapy, and particularly cancer therapy. The SLC34A2 epitope peptide encompassing amino acids 312-340 of SLC34A2 has been identified as an ovarian cancer epitope using the monoclonal antibody MX35. The invention also relates to the use of SLC34A2 and particularly SLC34A2 peptides in generating antibodies which have anti-tumor or anti-cancer activity or in stimulating an immunological response. The invention further relates to antibodies specifically directed against NaPi2b (SLC34A2) and the SLC34A2 peptide(s), including veneered, chimeric, single chain and humanized antibodies. Methods for generating an immune response and for treatment of tumors and cancer are also provided. Assays for screening and identifying compounds directed against SLC34A2, including the SLC34A2 epitope peptide, and additional antibodies are provided. 1. An isolated antibody which specifically binds the extracellular region of SLC34A2 and which recognizes amino acids 312-340 of SLC34A2.2. (canceled)3. The antibody of wherein said antibody was raised to or selected by binding to any of SEQ ID NOS: 1-8.4. (canceled)5. The antibody of having a heavy chain and a light chain wherein the heavy chain variable region comprises the CDRs as set out in or highly homologous to SEQ ID NOs: 26-28 and the light chain variable region comprises the CDRs as set out in or highly homologous to SEQ ID NO: 31-33.6. (canceled)7. The antibody of having a heavy chain and a light chain wherein the heavy chain variable region is selected from or is highly homologous to SEQ ID NO: 25 claim 1 , 37 claim 1 , 38 and 40 and the light chain variable region is selected from or is highly homologous to SEQ ID NO: 30 claim 1 , 35 claim 1 , 39 and 41.8. (canceled)9. The isolated antibody of which is fully human claim 1 , humanized or chimerized.10. (canceled)11. (canceled)12. (canceled)13. The antibody ...

MEANS AND METHODS FOR ASSESSING KIDNEY TOXICITY

The present invention pertains to the field of diagnostics for kidney toxicity and toxicological assessments for risk stratification of chemical compounds. Specifically, it relates to a method for diagnosing kidney toxicity. It also relates to a method for determining whether a compound is capable of inducing such kidney toxicity in a subject and to a method of identifying a drug for treating kidney toxicity. Furthermore, the present invention relates to a device and a kit for diagnosing kidney toxicity. 120-. (canceled)21. A method for diagnosing kidney toxicity comprising:(a) determining the amount of at least one biomarker selected from any one of Tables 1a, 1b, 1c, 1d, 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d, 4a, 4b, 4c, 4d, 5a, 5b, 6a, 6b, 7a, 7b, 8a, 8b, 11a or 11b in a test sample of a subject suspected to suffer from kidney toxicity, and(b) comparing the amounts determined in step (a) to a reference, whereby kidney toxicity is to be diagnosed.22. The method of claim 21 , wherein said subject has been brought into contact with a compound suspected to be capable of inducing kidney toxicity.23. The method of claim 22 , wherein said compound is at least one compound selected from the group consisting of: Amphotericin B claim 22 , Beta-ionone claim 22 , Caffeine claim 22 , Captopril claim 22 , Carboplatin claim 22 , Cyclosporin A claim 22 , Dichlorprop-p claim 22 , Dipyrone claim 22 , Ethylbenzene claim 22 , Furosemide claim 22 , Hexachlorobutadiene claim 22 , Hydroquinone claim 22 , Lisinopril claim 22 , Lithocholic acid claim 22 , MCPA claim 22 , Mecoprop-p claim 22 , Penicillamine claim 22 , Pentachlorophenol claim 22 , Probenecid claim 22 , Ramipril claim 22 , Theobromine claim 22 , Theophylline claim 22 , Tobramycin s.c. claim 22 , Tricresyl phosphate claim 22 , 1 claim 22 ,1 claim 22 ,2 claim 22 ,2-tetrachloroethane claim 22 , 2 claim 22 ,2 claim 22 ,4-trimethylpentane claim 22 , D-Limonene and Decalin.24. The method of claim 21 , wherein said reference is derived ...

Alpha1 proteinase inhibitor peptides methods and use

The invention is directed to the use of peptides that can bind and block the interaction of α1 proteinase inhibitor (αPI) and one or more molecules, for example antibodies to HIV-1 envelope proteins. The invention features methods of activating αPI in a cell, methods of treating or preventing a disease or disorder in a subject, for example HIV-1 or AIDS. The invention also features pharmaceutical compositions comprising one or more peptides that block the interaction of α1 αPI and one or more molecules. Also included in the invention are kits. 175.-. (canceled)76. A method for increasing the number of circulating CD4+ lymphocytes in an HIV-1-infected human subject comprising administering to a subject in need of such treatment a pharmaceutical composition comprising an amount of an active α1 Protease Inhibitor (α1 PI) effective to increase the number of circulating CD4+ lymphocytes in said subject , wherein said subject has less than 500 circulating CD4+ lymphocytes per μl and is receiving antiretroviral therapy.77. The method of wherein said subject has less than 500 copies of HIV-1 RNA per ml.78. The method of wherein said patient is receiving antiretroviral therapy.79. A method for determining the number of CD4+ lymphocytes in the blood of an HIV-1 infected human subject comprising the steps of:determining the amount of active α1 PI in the serum of the human subject by assaying for α1 PI activity;wherein the number of CD4+ lymphocytes in the subject's serum is proportional to the amount of active α1 PI present in said subject's serum and said subject has less than 500 HIV-1 RNA copies/ml; andadministering a composition comprising an amount of active α1 PI effective to increase the number of CD4+ lymphocytes in said subject's serum.80. The method of wherein the activity of active α1 PI is determined by an assay method for α1 PI selected from the group consisting of elastase inhibition claim 79 , induction of receptor co-capping and cell motility claim 79 , ...

Benzodiazepine compounds with anti-flavivirus activity

The present invention describes a unique antiviral screen system. The assay is based on quantitatively monitoring viral activation of host cell beta-interferon (IFN-β) gene expression in a HEK293-derived reporter cell line expressing a firefly luciferase gene under the control of a human IFN-β promoter. Unlike the traditional high throughput antiviral assays that measure either the reduction of viral components/yields or cytopathic effect, the readout of the reporter assay in the present invention is the virus-induced host cellular innate immune response. Hence, the assay allows for identification of compounds that inhibit virus infection. In addition, because induction of IFN is one of the most common attributes of viruses, the assay is applicable to all the viruses that are able to infect the reporter cell line and induce IFN-β expression. Compounds that interfere with viral mediated activation of the interferon pathway in a primary screen, can be further screened with virus-specific assay to confirm their antiviral activity. 1. An antiviral screening system comprising quantifying viral activation of IFN-β gene expression in a host cell having a reporter gene.2. The method of where quantifying is determined from a correlation between output of the reporter gene in a reporter assay and a virus-induced innate immune response from the host cell.3. The method of wherein the innate immune response is due to an increase in viral replication.4. The method of wherein the host cell line is HEK293 having the reporter gene.5. The method of wherein the reporter gene is a firefly luciferase gene under the control of a human IFN-β promoter.6. The method of further adding compounds suspected of inhibiting virus infection wherein said compounds interfere with viral-mediated activation of an interferon pathway.7. The method of further testing with a virus-specific assay as a secondary screening to confirm antiviral activity.8. The method of wherein the viral activation is from ...

INHIBITION OF THE GLYCINE CLEAVAGE SYSTEM FOR TREATMENT OF CANCER

In some aspects, methods of inhibiting survival or proliferation of a tumor cell are provided, the methods comprising inhibiting the glycine cleavage system (GCS) of the tumor cell. In some aspects, methods of treating a subject in need of treatment for a tumor, the method comprising inhibiting the GCS in the tumor. In some embodiments, the methods comprise contacting a tumor cell or tumor with a GCS inhibitor. In some embodiments, the tumor cell or tumor has elevated expression of serine hydroxymethyltransferase 2 (SH1VIT2). In some aspects, methods of identifying a tumor cell or tumor that is sensitive to inhibiting the GCS are provided, the methods comprising determining whether the tumor cell or tumor overexpresses SHMT2. In some aspects, methods of identifying a candidate anti-cancer agent are provided, the methods comprising identifying or modifying a GCS inhibitor. 1. A method of inhibiting proliferation or survival of a tumor cell , the method comprising contacting the cell with an inhibitor of the glycine cleavage system (GCS).2. The method of claim 1 , wherein the tumor cell overexpresses serine hydroxymethyltransferase 2 (SHMT2) as compared with a control cell.3. The method of claim 1 , wherein the tumor cell is a brain tumor cell claim 1 , bladder tumor cell claim 1 , breast tumor cell claim 1 , cervical tumor cell claim 1 , colorectal tumor cell claim 1 , embryonal tumor cell claim 1 , gastric tumor cell claim 1 , germ cell tumor cell claim 1 , head and neck tumor cell claim 1 , hematologic tumor cell claim 1 , kidney tumor cell claim 1 , melanoma cell claim 1 , mesothelial tumor cell claim 1 , ovarian tumor cell claim 1 , yolk sac tumor cell claim 1 , or sarcoma cell.4. The method of claim 1 , wherein the tumor cell is a glioblastoma multiforme (GBM) cell.5. The method of claim 1 , wherein the tumor cell is a tumor stem cell.6. The method of claim 1 , wherein the tumor cell is a human tumor cell.7. The method of claim 1 , wherein the GCS inhibitor ...

METHOD OF SCREENING A DRUG SUCH AS INSULIN SECRETAGOGUE

The screening method of the present invention is useful for screening drugs such as insulin secretagogues having an insulin secretagogue activity with minimized side effects (hypoglycemia induction, etc.). The transformant in which a polynucleotide encoding the fusion protein used for the screening method is introduced, the screening kit comprising the transformant, etc. are also useful for screening excellent drugs. 141.-. (canceled)42. A polynucleotide encoding a fusion protein of preproinsulin and a luciferase ,{'i': 'Gaussia', 'wherein the luciferase is luciferase, and'}{'i': 'Gaussia', 'wherein luciferase is a protein is selected from the group consisting of (a) through (c) below(a) a protein comprising the amino acid sequence of SEQ ID NO: 8;(b) a protein consisting of an amino acid sequence comprising deletion, substitution, insertion and/or addition of 1-10 amino acid residues in the amino acid sequence of SEQ ID NO: 8, and having substantially the same activity as a protein consisting of the amino acid sequence of SEQ ID NO: 8; and(c) a protein consisting of an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 8, and having substantially the same activity as a protein consisting of the amino acid sequence of SEQ ID NO: 8; andwherein the preproinsulin consists of a signal peptide of preproinsulin and the polypeptide is selected from the group consisting of (i) through (k) below:(i) a polypeptide consisting of the amino acid sequence of SEQ ID NO: 4;(j) a polypeptide comprising a polypeptide consisting of an amino acid sequence comprising deletion, substitution, insertion and/or addition of 1-10 amino acid residues in the amino acid sequence of SEQ ID NO: 4, and having substantially the same activity as the polypeptide consisting of the amino acid sequence of SEQ ID NO: 4; and(k) a polypeptide comprising a polypeptide consisting of an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID ...

ASSAY FOR POLYPEPTIDE AGGREGATION USING MICRODROPLETS

A method for detecting the presence of aggregatory seeds of a polypeptide in a sample is provided. The method may be used for identifying a subject at risk of a conformational disease caused by the aggregation of a polypeptide or for diagnosing, assessing or monitoring a conformational disease caused by the aggregation of a polypeptide in a subject. The invention also relates to methods for preparing products free from aggregatory seeds of a polypeptide and methods for the measurement of the effect of a test substance on the aggregation of a polypeptide. 1. A method for detecting the presence of aggregatory seeds of a polypeptide in a sample , comprising:(i) contacting the sample with monomers of the polypeptide;(ii) separating the sample into a plurality of microdroplets;(iii) incubating the microdroplets under conditions suitable for aggregation of the polypeptide; and(iv) determining the subsequent formation of aggregates of the polypeptide in the microdroplets,wherein the formation of aggregates of the polypeptide in a microdroplet indicates the presence of one or more aggregatory seeds in the sample.2. A method for identifying a subject at risk of a conformational disease caused by the aggregation of a polypeptide or for diagnosing , assessing or monitoring a conformational disease caused by the aggregation of a polypeptide in a subject ,comprising detecting the presence of aggregatory seeds of the polypeptide in a sample obtained from the subject, wherein the detecting comprises:(i) contacting the sample with monomers of the polypeptide;(ii) separating the sample into a plurality of microdroplets;(iii) incubating the microdroplets under conditions suitable for aggregation of the polypeptide; and(iv) determining the subsequent formation of aggregates of the polypeptide in the micro droplets,wherein the formation of aggregates of the polypeptide in a microdroplet indicates the presence of one or more aggregatory seeds in the sample, and the presence of ...

METHOD OF SCREENING A DRUG SUCH AS INSULIN SECRETAGOGUE

The screening method of the present invention is useful for screening drugs such as insulin secretagogues having an insulin secretagogue activity with minimized side effects (hypoglycemia induction, etc.). The transformant in which a polynucleotide encoding the fusion protein used for the screening method is introduced, the screening kit comprising the transformant, etc. are also useful for screening excellent drugs. 141-. (canceled)42. A polynucleotide encoding a fusion protein of preproinsulin and a luciferase ,{'i': 'Gaussia', 'wherein the luciferase is luciferase, and'}{'i': 'Gaussia', 'wherein luciferase is a protein selected from the group consisting of (a) through (c) below(a) a protein comprising the amino acid sequence of SEQ ID NO: 8;(b) a protein consisting of an amino acid sequence comprising deletion, substitution, insertion and/or addition of 1-10 amino acid residues in the amino acid sequence of SEQ ID NO: 8, and having substantially the same activity as a protein consisting of the amino acid sequence of SEQ ID NO: 8; and(c) a protein consisting of an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 8, and having substantially the same activity as a protein consisting of the amino acid sequence of SEQ ID NO: 8; andwherein the preproinsulin consists of a signal peptide of preproinsulin and the polypeptide selected from the group consisting of (i) through (k) below:(i) a polypeptide consisting of the amino acid sequence of SEQ ID NO: 4;(j) a polypeptide comprising a polypeptide consisting of an amino acid sequence comprising deletion, substitution, insertion and/or addition of 1-10 amino acid residues in the amino acid sequence of SEQ ID NO: 4, and having substantially the same activity as the polypeptide consisting of the amino acid sequence of SEQ ID NO: 4; and(k) a polypeptide comprising a polypeptide consisting of an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 4, ...

POTENCY TEST FOR VACCINE FORMULATIONS

The invention relates to certain methods for the determination of an antigen content of a first antigen in a mixture comprising two or more antigens. The invention also relates to a potency test for an antigen in a combination vaccine. The method allows the determination of the antigen content in a mixture additionally comprising antibodies that are capable of binding with the antigen. 1. A method for the determination of an antigen content of a first antigen in a mixture of at least a composition comprising the first antigen and a composition comprising (i) a second antigen and (ii) antibodies that are capable of binding with the first antigen , the method comprising the steps of:a) dissociating antigen-antibody complexes in the mixture, formed between the first antigen and the antibodies; andb) determining the antigen content of the first antigen by means of an immunoassay.2Mycoplasma hyopneumoniae. The method of claim 1 , wherein the first antigen is a porcine circovirus type 2 (PCV-2) antigen and the second antigen is a antigen.3. The method of claim 1 , wherein the immunoassay is an ELISA (enzyme linked immunosorbant assay).4. The method of claim 1 , wherein the mixture is a ready-to-use vaccine formulation.5. The method of claim 1 , wherein the mixture is incubated with an acid solution to dissociate the antigen-antibody complexes.6. The method of claim 5 , wherein the acid solution is a citric acid solution.7. The method of claim 5 , wherein the mixture is incubated with the acid solution for at least 8 hours.8. The method of claim 5 , wherein the mixture is incubated at a ratio (v/v) between the acid solution and the mixture of at least 25 claim 5 , preferably 25-75 claim 5 , more preferably 25-50.9. The method of claim 5 , wherein the acid solution has a pH of 1.0-3.0.10Mycoplasma hyopneumoniaeM. hyo. A method for the determination of an antigen content of a porcine circovirus type 2 (PCV-2) antigen in a mixture of at least a composition comprising the PCV- ...

DIAGNOSIS AND TREATMENT FOR RESPIRATORY TRACT DISEASES

The invention provides methods and compositions for the diagnosis, prognosis and treatment of respiratory tract diseases. Specifically, the invention provides diagnosis, prognosis and treatment of respiratory infections using bitter and sweet taste signal transduction pathways. In one aspect, the invention relates to a method for treating a respiratory infection by administering a composition to the respiratory tract of a subject in an amount capable of activating bitter taste signaling and/or inhibiting sweet taste signaling. The composition comprises at least a bitter receptor agonist and, optionally, a pharmaceutically acceptable carrier for delivering the composition to the respiratory tract. In another aspect, the invention relates to a composition for treatment of a respiratory infection. Such composition comprises at least a bitter receptor agonist and, optionally, a pharmaceutically acceptable carrier for delivering the composition to the respiratory tract. 1. A method for treating a respiratory infection in a subject , the method comprising:administering a composition to the respiratory tract of the subject, wherein the composition comprises an agent capable of activating a bitter taste signal pathway or inhibiting a sweet taste signal pathway in the subject, thereby treating the respiratory infection in the subject.2. The method of claim 1 , wherein the composition comprises at least one bitter taste receptor agonist.3. The method of claim 2 , wherein said at least one bitter taste receptor agonist is selected from the group consisting of denatonium benzoate and absinthin.4. The method of claim 1 , wherein said composition comprises at least one sweet taste receptor antagonist.5. The method of claim 4 , wherein said at least one sweet taste receptor antagonist is selected from the group consisting of lactisole claim 4 , a gymnemic acid claim 4 , ziziphin and hodulcine.6. The method of claim 1 , wherein said composition comprises a combination of at least ...

FURO [3, 2-B] PYRR0L-3-0NES AS CATHESPIN S INHIBITORS

A first aspect of the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, complex or pro-drug thereof,

Lipopeptides for Use in Treating Liver Diseases and Cardiovascular Diseases

The present invention relates to lipopeptide-based compounds for use in the diagnosis, prevention and/or treatment of a liver disease or condition, preferably liver involved metabolic diseases, as well as in the control or modification of the cholesterol level or cholesterol uptake and, thus, diagnosis, prevention and/or treatment of a cardiovascular disease. The present invention furthermore relates to an in vitro or in vivo assay or method for testing or measuring the NTCP-mediated transport of test compound(s). The present invention furthermore relates to a method for the diagnosis, prevention and/or treatment of a liver disease or condition, comprising administering a therapeutically effective amount of a lipopeptide-based compound to a patient. The present invention furthermore relates to a method for the diagnosis, prevention and/or treatment of a cardiovascular disease.

DEVICE AND METHOD FOR BACTERIAL CULTURE AND ASSAY

The present invention provides a simple culture device that is designed for manufacture and use in areas of limited resources. The device is useful for cell culture in such environments with limited resources because cells grow in paper just as they do in a culture dish. Also provided is a binding assay that employs an activatable dormant bacteriophage carrying a reporter gene to qualitatively or quantitatively detect the presence of a substance of interest in a sample. 1. A portable culture device comprising:a) a first culture strip comprising at least one culture region within a first strip of fluid impermeable material having an adhesive on its inner surface;b) a second culture strip comprising at least one culture region within a second strip of fluid impermeable material having an adhesive on its inner surface, wherein each of the at least one culture regions of the second culture strip corresponds to one of the at least one culture regions of first culture strip to form a culture region pair,wherein each culture region comprises an inner layer of porous hydrophilic material and at least one culture region in each culture region pair comprises an outer layer of a gas permeable membrane, andwherein the device is moveable between an open condition and a closed condition in which the first and second culture strips are releasably adhered via the inner adhesive surfaces such that the culture regions in each culture pair are aligned and the outer gas permeable membrane or gas permeable membranes are exposed to the environment to permit gas flow to the interior of the device.2. The device of claim 1 , wherein at least one of the culture regions comprises an adsorbent pad layered on the side of the porous hydrophilic material opposite the interior of the device.3. The device of claim 2 , wherein a dialysis membrane is layered between the adsorbent pad and the porous hydrophilic material.4. The device of claim 1 , wherein the first culture strip is connected to the ...

PERSONALIZED MEDICINE FOR THE PREDICTION OF THERAPY TARGETING THE HEDGEHOG PATHWAY

Methods and composition for tumor therapy, especially esophageal adenocarcinoma (EAC), are described. For example, in certain aspects methods for determining Hedgehog and mTOR signaling pathway status to select patients for administering a combination therapy of Hedgehog and mTOR signaling inhibitors are described. Furthermore, the invention provides compositions that involve testing kits for determining signaling status. 1. A composition for use in treating a cancer or a gastrointestinal tract disease in a subject , wherein the subject has been determined to have elevated S6K phosphorylation or Gli1 phosphorylation relative to a first reference level and elevated Gli1 expression or Gli1 nuclear localization relative to a second reference level , said composition comprising an SMO inhibitor and a mTOR inhibitor.2. A composition for use in treating a cancer or a gastrointestinal tract disease in a subject , wherein the subject has been determined to have elevated S6K phosphorylation or Gli1 phosphorylation relative to first reference level but not elevated Gli1 expression or Gli1 nuclear localization relative to a second reference level , said composition comprising a mTOR inhibitor and not comprising a SMO inhibitor.3. A composition for use in treating a cancer or a gastrointestinal tract disease in a subject , wherein the subject has been determined to have an elevated Gli1 expression or nuclear localization relative to first reference level but not an elevated S6K phosphorylation or Gli1 phosphorylation relative to a second reference level , said composition comprising a SMO inhibitor and not comprising a mTOR inhibitor.4. A method of treating a subject having a cancer or a gastrointestinal tract disease , comprising:a) selecting a subject having a cancer or a gastrointestinal tract disease, and who has been determined to have elevated S6K phosphorylation or Gli1 phosphorylation relative to a first reference level and elevated Gli1 expression or Gli1 nuclear ...

Identification of antitumor compounds using placenta

Provided herein are methods of evaluating potential antitumor compounds, and thereby identifying antitumor compounds, using placenta or a portion thereof and tumor cells, and compositions for accomplishing the same. In one embodiment, provided herein is a method of determining whether a potential antitumor compound is effective against a plurality of tumor cells, comprising introducing a plurality of tumor cells to, e.g., into or onto, a mammalian placenta or portion thereof; contacting said plurality of tumor cells for a period of time with said antitumor compound; and determining whether said antitumor compound is effective against said tumor cells, wherein said antitumor compound is effective against said tumor cells if said antitumor compound over said period of time reduces the number of said tumor cells or reduces the growth rate of said tumor cells.

METHODS FOR DETECTING LP-PLA2 ACTIVITY AND INHIBITION OF LP-PLA2 ACTIVITY

This invention relates to methods for determining the activity of Lp-PLA2 in at least one sample from an animal. The invention also relates to methods for determining the inhibition of Lp-PLA2 activity in samples from animals that are administered an Lp-PLA2 inhibitor. 1. A colorimetric or fluorometric method of determining the percentage of inhibition of Lp-PLA2 activity , the method comprising:colorimetrically or fluorometrically detecting Lp-PLA2 activity from a first blood sample that is taken from the subject at a first time and diluted less than 33 times;colorimetrically or fluorometrically detecting Lp-PLA2 activity from a second blood sample that is taken from the subject at a second time one hour or more after the first time and diluted less than 33 times; anddetecting greater than 30% inhibition of Lp-PLA2 activity between the first and second blood samples by comparing the activity of the Lp-PLA2 between the first and second blood samples, indicating that the subject has taken a drug that inhibits Lp-PLA2.2. The method of claim 1 , further comprising preparing a solution comprising a substrate for Lp-PLA2 having a colorimetric or fluorometric detectable moiety.3. The method of claim 1 , wherein the second blood sample is taken after the subject has been administered a drug that inhibits Lp-PLA2.4. The method of claim 1 , wherein detecting greater than 30% inhibition of Lp-PLA2 activity comprises detecting greater than 90% inhibition of Lp-PLA2 between the first and second blood samples5. The method of claim 1 , wherein detecting greater than 30% inhibition of Lp-PLA2 activity comprises detecting 85-95% inhibition of Lp-PLA2 between the first and second blood samples.6. The method of claim 1 , wherein the first and second blood samples comprise blood plasma or blood serum samples.7. The method of claim 1 , wherein colorimetrically or fluorometrically detecting Lp-PLA2 activity from the first and second blood samples comprises detecting Lp-PLA2 activity ...

Cancer stem cells

Cancer stem cell populations characterized by expression of CD44 hi , ABCG2, β-catenin, CD117, CD133, ALDH, VLA-2, CD166, CD201, IGFR, and/or EGF1R, and methods of isolating and using the same.

Pharmaceutical composition for preventing or treating fabry disease, containing tsp1 protein inhibitor as active ingredient

The present invention relates to a pharmaceutical composition for preventing or treating Fabry disease, containing a TSP1 protein inhibitor as an active ingredient. Particularly, in vascular endothelial cells produced by knocking out a TSP1 gene in induced pluripotent stem cells derived from a Fabry disease patient, of the present invention, the recovery of cell morphology, a decrease in the expression of a TSP1 gene, a decrease in the expression levels of a TSP1 protein and a phosphorylated-SMAD protein, which are anti-angiogenic factors, and an increase in the expression levels of a KDR protein and an eNOS protein, which are angiogenic factors, have been confirmed, and thus a TSP1 gene expression inhibitor or a TSP1 protein activity inhibitor can be effectively used in the treatment of Fabry disease.

Methods to Protect Against and Treat Multiple Sclerosis

The invention provides epsilon toxin (ETX) produced by type B or type D as a causative toxin for human multiple sclerosis (MS). The invention further identifies ETX binding receptor MAL for ETX mediated cell death and other toxin-logical activities in MS. Methods and compositions to prevent humans from multiple sclerosis (MS) and/or treating MS by directly or indirectly interfering with epsilon toxin (ETX), its binding receptor (e.g., MAL), or ETX-receptor interactions so as to inhibit or suppress downstream ETX mediated receptor signaling activities are provided. Also provided are various methods to detect, diagnose, monitor, assess multiple sclerosis (MS) by determining an expression level of ETX gene or its encoding protein in human patient suspected for and/or at risk for multiple sclerosis (MS).

NOVEL BT TOXIN RECEPTORS AND METHODS OF USE

The disclosure relates to Bt toxin resistance management. One embodiment relates to the isolation and characterization of polynucleotides and polypeptides corresponding to novel Bt toxin receptors. The polynucleotides and polypeptides are useful in identifying or designing novel Bt toxin receptor ligands including novel insecticidal toxins. 1. A heterologous polynucleotide comprising:a) the nucleotide sequence set forth in SEQ ID NO: 1, 3, 5, 7, or 9;b) a nucleotide sequence encoding the amino acid sequence set forth in SEQ ID NO: 2, 4, 6, 8, or 10;c) a nucleotide sequence having at least about 90% sequence identity to the nucleotide sequence set forth in SEQ ID NO: 1, 3, 5, 7, or 9, wherein said nucleotide sequence having at least about 90% sequence identity to the nucleotide sequence set forth in SEQ ID NO: 1, 3, 5, 7, or 9 encodes a polypeptide having Bt toxin binding activity;d) a nucleotide sequence that hybridizes to the complement of the nucleotide sequence set forth in SEQ ID NO: 1, 3, 5, 7, or 9 under stringent conditions, wherein said nucleotide sequence that hybridizes to the complement of the nucleotide sequence set forth in SEQ ID NO: 1, 3, 5, 7, or 9 under stringent conditions encodes a polypeptide having Bt toxin binding activity; ore) a nucleotide sequence complementary to at least one nucleotide sequence set forth in a), b), c), and d).2. The heterologous polynucleotide of claim 1 , wherein said heterologous polynucleotide comprises a nucleotide sequence encoding a polypeptide having Cry toxin binding activity.3. The heterologous polynucleotide of claim 2 , wherein said heterologous polynucleotide comprises a nucleotide sequence encoding a polypeptide having Cry2A binding activity.4. A heterologous polypeptide having the amino acid sequence comprising:a) the amino acid sequence set forth in SEQ ID NO: 2, 4, 6, 8, or 10; or b) a variant of the amino acid sequence set forth in SEQ ID NO: 2, 4, 6, 8, or 10, wherein said sequence variant has Bt toxin ...

Methods of Screening for Activation Deaminase Inhibitors Through Nuclear Import Inhibitors

The present invention provides methods for obtaining specific and non-toxic inhibitors of AID nuclear import. The methods comprise a primary screen and a counter screen to identify a pool of AID specific nuclear import inhibitors that do not have off-target of toxic effects. AID specific nuclear import inhibitors identified by the screens of the invention prevent nuclear entry, limit the access of AID to genomic DNA, and inhibit AID mutagenic activity. Preparations, including pharmaceutical preparations, comprising specific nuclear import inhibitors, used for example, to inhibit cancer progression, are also encompassed in the invention. 1. A method of screening a library of compounds to provide a pool of specific and non-toxic nuclear import inhibitors for Activity-induced Deaminase (AID) , said method comprising:a) conducting a primary screen to evaluate an on-target effect of at least one compound from the library for the ability to inhibit nuclear import of AID, wherein the primary screen comprises administering the at least one compound from the library and a nuclear export inhibitor to a cell modified to comprise AID tagged with a detectable label;b) conducting a counter screen to evaluate an off-target effect of the at least one compound from the library for the ability to alter the cellular localization of a non-AID protein, wherein the counter screen comprises administering the at least one compound from the library and the nuclear export inhibitor to a cell modified to comprise the non-AID protein tagged with a detectable label, wherein the non-AID protein is selected from the group consisting of histone H1 (H1), APOBEC1 Complementation Factor (ACF), heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), and transaldoase 1 (TALDO-1);c) selecting a compound from the library that exhibits the ability to inhibit nuclear import of AID and does not substantially alter the cellular localization of the protein that is not AID, thereby providing a pool of specific ...

Modulation of breast cancer growth by modulation of xbp1 activity

Described herein is a previously unknown function of XBP1 in triple-negative breast cancer (TNBC). It is shown that XBP1 is preferentially spliced and activated in TNBC, and that deletion of XBP1 significantly blocks triple negative breast tumor growth. Strikingly, XBP1 is required for the self-renewal of breast tumor initiating cells (TICs). Genome-wide mapping of the XBP1 transcriptional regulatory network identified a fundamental role for XBP1 in regulating the response to hypoxia via the transcription factor hypoxia-inducible factor 1a (HIF1a). Importantly, activation of this pathway appears to carry prognostic implications, as expression of the XBP1-dependent signature is associated with shorter survival times in human TNBC.

Methods and compositions for the detection of functional clostridium difficile toxins

Methods and compositions for the identification of functional C. difficile toxin, as among other things identifying individuals infected with toxigenic C. difficile and therefore in need of therapy. In specific embodiments, the methods and compositions provide colorimetric assays for cleavage activity of C. difficile toxin.

Anti-cd43 antibody and use thereof for cancer treatment

Provided is an antibody for treating a cancer, more specifically, an anti-CD43 antibody binding to an extracellular domain of CD43, compositions for treating a cancer or inhibiting a cancer stem cell comprising the antibody as an active ingredient, and methods for screening an agent of inhibiting a cancer stem cell.

METHODS FOR MODULATING CYCLIC NUCLEOTIDE-MEDIATED SIGNALING IN CARDIAC MYOCYTES AND COMPOSITIONS

The invention provides a polypeptide possessing anti-hypertrophic activity in a cardiac myocyte, wherein the polypeptide is a mutant variant derived from wild-type PDE3A1 protein and wherein the wild-type PDE3A1 protein has the amino acid sequence given in SEQ ID NO:1 at amino acid position 146 to 1141. 155.-. (canceled)56. A method for preventing , inhibiting or reversing myocardial hypertrophy comprising administering a vector having a nucleic acid molecule encoding an isolated or purified polypeptide possessing anti-hypertrophic activity in a cardiac myocyte , wherein the polypeptide is a mutant derived from wild-type PDE3A1 protein and wherein the wild-type PDE3A1 protein has the amino-acid sequence given in SEQ ID NO:1 at amino acid position 146 to 1141 in a cardiac myocyte , said vector being genetically modified by insertion of at least one therapeutic gene into said vector to produce functional molecules in a sufficient amount to prevent , inhibit or reverse myocardial hypertrophy in the cell.57103.-. (canceled)104. The method of claim 56 , wherein the mutant derived from wild-type PDE3A1 protein is a catalytically compromised mutant of PDE3A1 protein.105. The method of claim 104 , wherein the catalytically compromised mutant of PDE3A1 protein is a catalytically inactive mutant of PDE3A1 protein or a catalytically reduced mutant of PDE3A1 protein.106. The method of or claim 104 , wherein the catalytically compromised claim 104 , reduced or inactive mutant of PDE3A1 protein is a result of a mutation affecting tyrosine-751 (Y751) claim 104 , histidine-836 (H836) claim 104 , histidine-840 (H840) claim 104 , glutamic acid-866 (E866) claim 104 , aspartic acid-950 (D950) claim 104 , or phenylalanine-1004 (F1004).107. The method of claim 105 , wherein the catalytically inactive mutant of PDE3A1 protein has a mutation at phenylalanine-1004 (F1004).108. The method of or claim 105 , wherein the mutation is an amino acid change to an alanine.109. The method of or claim ...