Related Articles

Phase II study of idelalisib, a selective inhibitor of PI3Kδ, for relapsed/refractory classical Hodgkin lymphoma.

Ann Oncol. 2017 May 01;28(5):1057-1063

Authors: Gopal AK, Fanale MA, Moskowitz CH, Shustov AR, Mitra S, Ye W, Younes A, Moskowitz AJ

Abstract
Background: The phosphatidylinositol-3-kinase delta (PI3Kδ) inhibitor idelalisib has been shown to block downstream intracellular signaling, reduce the production of prosurvival chemokines and induce apoptosis in classical Hodgkin lymphoma (HL) cell lines. It has also been shown to inhibit regulatory T cells and myeloid-derived suppressor cells in other tumor models. We hypothesized that inhibiting PI3Kδ would have both direct and indirect antitumor effects by directly targeting the malignant cells as well as modulating the inflammatory microenvironment. We tested this hypothesis in a phase II study.
Patients and methods: We enrolled 25 patients with relapsed/refractory HL with a median age of 42 years and who had previously received a median of five therapies including 18 (72%) with failed autologous stem cell transplant, 23 (92%) with failed brentuximab vedotin, and 11 (44%) with prior radiation therapy. Idelalisib was administered at 150 mg two times daily; an increase to 300 mg two times daily was permitted at the time of disease progression.
Results: The overall response rate to idelalisib therapy was 20% (95% confidence interval: 6.8%, 40.7%) with a median time to response of 2.0 months. Seventeen patients (68%) experienced reduction in target lesions with one complete remission and four partial remissions. The median duration of response was 8.4 months and median progression-free survival was 2.3 months. The most common grade ≥3 adverse event was elevation of alanine aminotransferase (two patients, 8%). Diarrhea/colitis was seen in three patients and was grade 1-2. There was one adverse event leading to death (hypoxia).
Conclusions: Idelalisib was tolerable and had modest single-agent activity in heavily pretreated patients with HL. Rational combinations with other novel agents may improve response rate and duration of response.
Clinical trial registration: ClinicalTrials.gov # NCT01393106.

PMID: 28327905 [PubMed - indexed for MEDLINE]

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

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12 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

(exome OR "exome sequencing") AND disease

These pubmed results were generated on 2018/03/03

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

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"systems biology"

These pubmed results were generated on 2018/03/03

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Notice NOT-RM-18-012 from the NIH Guide for Grants and Contracts

Notice NOT-EB-18-011 from the NIH Guide for Grants and Contracts

Notice NOT-EB-18-010 from the NIH Guide for Grants and Contracts

Notice NOT-EB-18-009 from the NIH Guide for Grants and Contracts

Notice NOT-CA-18-036 from the NIH Guide for Grants and Contracts

Funding Opportunity PAR-18-692 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages applications for short-term mentored career development (K18) awards that improve synergies among researchers in basic and applied behavioral-social sciences, human subjects and model animals settings; and biomedical and behavioral-social sciences. This Funding Opportunity Announcement (FOA) is designed specifically for applicants proposing to serve as the lead investigator of an independent clinical trial, or a clinical trial feasibility study, as part of their research and career development. Applicants not planning an independent clinical trial, or proposing to gain research experience in a clinical trial led by another investigator, must apply to companion FOA, PAR-18-349.

Funding Opportunity RFA-EY-18-001 from the NIH Guide for Grants and Contracts. A central goal of the BRAIN Initiative is to understand how electrical and chemical signals code information in neural circuits and give rise to sensations, thoughts, emotions and actions. While currently available technologies can provide some understanding, they may not be sufficient to accomplish this goal. For example, non-invasive technologies are low resolution and/or provide indirect measures such as blood flow, which are imprecise; invasive technologies can provide information at the level of single neurons producing the fundamental biophysical signals, but they can only be applied to tens or hundreds of neurons, out of a total number in the human brain estimated at 85 billion. Other BRAIN FOAs seek to develop novel technology (RFA-NS-17-003) or to optimize existing technology ready for in-vivo proof-of-concept testing and collection of preliminary data (RFA-NS-17-004) for recording or manipulating neural activity on a scale that is beyond what is currently possible. This FOA seeks applications for unique and innovative technologies that are in an even earlier stage of development than that sought in other FOAs, including new and untested ideas that are in the initial stages of conceptualization. In addition to experimental approaches, the support provided under this FOA might enable calculations, simulations, computational models, or other mathematical techniques for demonstrating that the signal sources and/or measurement technologies are theoretically capable of meeting the demands of large-scale recording or manipulation of circuit activity in humans or in animal models. The support might also be used for building and testing phantoms, prototypes, in-vitro or other bench-top models in order to validate underlying theoretical assumptions in preparation for future FOAs aimed at testing in animal models.

Funding Opportunity RFA-HD-18-103 from the NIH Guide for Grants and Contracts. The purpose of this FOA issued by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH is to announce the re-competition of the Reproductive Scientist Development Program (RSDP). This program constitutes a national network of mentors and scholars, in contrast to K12 programs that are based solely at a single applicant institution. The purpose of the RSDP is to provide career development support for obstetricians and gynecologists who have completed their clinical training, and who are committed to a career conducting basic science research in an academic setting. The overall goal of the Program is to strengthen the field of obstetrics and gynecology by encouraging the application of contemporary science advances to clinical practice and facilitating the transition to independence of physician-scientists in areas related to obstetrics and gynecology and its subspecialties.

Funding Opportunity RFA-NS-18-025 from the NIH Guide for Grants and Contracts. This funding opportunity announcement(FOA) supports the development of PET radioligands that identify proteinopathies or pathological processes associated with the human biology of Alzheimer's disease related dementias (ADRDs). Activities supported under this FOA include, but are not limited to the in vitro screening of existing ligands against human ADRD brain tissue, medicinal chemistry support for improvement of ligand specificity and selectivity, initial screening of ligands in appropriated animal models, and radioligand formulation and first-in-human testing. Applications must include an administrative core, a medicinal chemistry core, a clincial core, a scientific governance structure, and a minimum of two research projects with milestone plans that address workflows for screening of existing and newly derived ligands against human ADRD tissue and appropriate animal models. Synergy must be evident among Center research projects and cores, such that successful completion of the aims could not be accomplished without the Center structure. This FOA is in response to the Alzheimer's Disease Related Dementias (ADRD) challenges outlined in the 2016 update to the National Plan to Address Alzheimer's Disease.

23 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

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Related Articles

The mutational landscape of MYCN, Lin28b and ALKF1174L driven murine neuroblastoma mimics human disease.

Oncotarget. 2018 Feb 02;9(9):8334-8349

Authors: De Wilde B, Beckers A, Lindner S, Kristina A, De Preter K, Depuydt P, Mestdagh P, Sante T, Lefever S, Hertwig F, Peng Z, Shi LM, Lee S, Vandermarliere E, Martens L, Menten B, Schramm A, Fischer M, Schulte J, Vandesompele J, Speleman F

Abstract
Genetically engineered mouse models have proven to be essential tools for unraveling fundamental aspects of cancer biology and for testing novel therapeutic strategies. To optimally serve these goals, it is essential that the mouse model faithfully recapitulates the human disease. Recently, novel mouse models for neuroblastoma have been developed. Here, we report on the further genomic characterization through exome sequencing and DNA copy number analysis of four of the currently available murine neuroblastoma model systems (ALK, Th-MYCN, Dbh-MYCN and Lin28b). The murine tumors revealed a low number of genomic alterations - in keeping with human neuroblastoma - and a positive correlation of the number of genetic lesions with the time to onset of tumor formation was observed. Gene copy number alterations are the hallmark of both murine and human disease and frequently affect syntenic genomic regions. Despite low mutational load, the genes mutated in murine disease were found to be enriched for genes mutated in human disease. Taken together, our study further supports the validity of the tested mouse models for mechanistic and preclinical studies of human neuroblastoma.

PMID: 29492199 [PubMed]

Identification of cisapride as new inhibitor of putrescine uptake in Trypanosoma cruzi by combined ligand- and structure-based virtual screening.

Eur J Med Chem. 2018 Feb 13;149:22-29

Authors: Dietrich RC, Alberca LN, Ruiz MD, Palestro PH, Carrillo C, Talevi A, Gavernet L

Abstract
Nowadays, the pharmacological therapy for the treatment of Chagas disease is based on two old drugs, benznidazole and nifurtimox, which have restricted efficacy against the chronic phase of the illness. To overcome the lack of efficacy of the traditional drugs (and their considerable toxicity), new molecular targets have been studied as starting points to the discovery of new antichagasic compounds. Among them, polyamine transporter TcPAT12 (also known as TcPOT1.1) represents an interesting macromolecule, since polyamines are essential for Trypanosoma cruzi, the parasite that causes the illness, but it cannot synthesize them de novo. In this investigation we report the results of a combined ligand- and structure-based virtual screening for the discovery of new inhibitors of TcPAT12. Initially we filtered out ZINC and Drugbank databases with similarity and QSAR models and then we submitted the candidates to a validated docking based screening. Four structures were selected and tested in T. cruzi epimastigotes proliferation and two of them, Cisapride and [2-(cyclopentyloxy)phenyl]methanamine showed inhibitory effects. Additionally, we performed transport assays which demonstrated that Cisapride interferes with putrescine uptake in a specific mode.

PMID: 29494842 [PubMed - as supplied by publisher]

Related Articles

Challenges of using new and repurposed drugs for the treatment of multidrug-resistant tuberculosis in children.

Expert Rev Clin Pharmacol. 2018 Mar;11(3):233-244

Authors: Schaaf HS, Garcia-Prats AJ, McKenna L, Seddon JA

Abstract
INTRODUCTION: New and repurposed antituberculosis drugs are urgently needed to more safely and effectively treat multidrug-resistant (MDR) tuberculosis (TB) in children. Multiple challenges limit timely access to new MDR-TB treatments in children. Areas covered: Diagnosis of MDR-TB in children remains a barrier, with few children with MDR-TB diagnosed and treated. Other barriers to timely access to new and repurposed drugs are discussed, and include delayed initiation of paediatric trials, limited funding for paediatric drug development, fragmented regulatory systems and operational challenges. The status of access to current repurposed and novel drugs is presented. Expert commentary: More timely initiation of paediatric trials is needed and paediatric work should happen and be funded in parallel with each phase of adult trials. Better quality data, increased regulator resources and expertise, harmonization of regulatory requirements across borders/organisations and registration fee waivers would improve registration timelines. Improved diagnosis, recording and reporting will establish better demand. Improved systems for procurement and supply chain management would reduce in-country operational barriers to getting medications to children. The challenges must be addressed to ensure timely and equitable access to new drugs and regimens that are urgently needed for effective, safe and shorter treatment of children with MDR-TB.

PMID: 29280409 [PubMed - indexed for MEDLINE]

Related Articles

Application of Pharmacokinetics and Pharmacodynamics in Product Life Cycle Management. A Case Study with a Carbidopa-Levodopa Extended-Release Formulation.

AAPS J. 2017 May;19(3):607-618

Authors: Modi NB

Abstract
Increasing costs in discovering and developing new molecular entities and the continuing debate on limited company pipelines mean that pharmaceutical companies are under significant pressure to maximize the value of approved products. Life cycle management in the context of drug development comprises activities to maximize the effective life of a product. Life cycle approaches can involve new formulations, new routes of delivery, new indications or expansion of the population for whom the product is indicated, or development of combination products. Life cycle management may provide an opportunity to improve upon the current product through enhanced efficacy or reduced side effects and could expand the therapeutic market for the product. Successful life cycle management may include the potential for superior efficacy, improved tolerability, or a better prescriber or patient acceptance. Unlike generic products where bioequivalence to an innovator product may be sufficient for drug approval, life cycle management typically requires a series of studies to characterize the value of the product. This review summarizes key considerations in identifying product candidates that may be suitable for life cycle management and discusses the application of pharmacokinetics and pharmacodynamics in developing new products using a life cycle management approach. Examples and a case study to illustrate how pharmacokinetics and pharmacodynamics contributed to the selection of dosing regimens, demonstration of an improved therapeutic effect, or regulatory approval of an improved product label are presented.

PMID: 28120254 [PubMed - indexed for MEDLINE]

Tenosynovial Giant Cell Tumors in Children: A Similar Entity Compared With Adults.

Clin Orthop Relat Res. 2018 Feb 08;:

Authors: Mastboom MJL, Verspoor FGM, Uittenbogaard D, Schaap GR, Jutte PC, Schreuder HWB, van de Sande MAJ

Abstract
BACKGROUND: Tenosynovial giant cell tumor (TGCT) is a rare, benign, monoarticular entity. Many case-series in adults are described, whereas TGCT is only incidentally reported in children. Therefore, its incidence rate and natural history in children are unknown.
QUESTIONS/PURPOSES: (1) How many cases have been reported of this condition, and what were their characteristics? (2) What is the standardized pediatric incidence rate for TGCT? (3) Is there a clinical difference in TGCT between children and adults? (4) What is the risk of recurrence after open resection in children compared with adults?
METHODS: Data were derived from three sources: (1) a systematic review on TGCT in children, seeking sources published between 1990 and 2016, included 17 heterogeneous, small case-series; (2) the nationwide TGCT incidence study: the Dutch pediatric incidence rate was extracted from this nationwide study by including patients younger than 18 years of age. This registry-based study, in which eligible patients with TGCT were clinically verified, calculated Dutch incidence rates for localized and diffuse-type TGCT in a 5-year timeframe. Standardized pediatric incidence rates were obtained by using the direct method; (3) from our nationwide bone and soft tissue tumor data registry, a clinical data set was derived. Fifty-seven children with histologically proven TGCT of large joints, diagnosed and treated between 1995 and 2015, in all four tertiary sarcoma centers in The Netherlands, were included. These clinically collected data were compared with a retrospective database of 423 adults with TGCT. Chi-square test and independent t-test were used to compare children and adults for TGCT type, sex, localization, symptoms before diagnosis, first treatment, recurrent disease, followup status, duration of symptoms, and time to followup. The Kaplan-Meier method was used to evaluate recurrence-free survival at 2.5 years.
RESULTS: TGCT is seldom reported because only 76 pediatric patients (39 female), 29 localized, 38 diffuse, and nine unknown type, were identified from our systematic review. The standardized pediatric TGCT incidence rate of large joints was 2.42 and 1.09 per million person-years in localized and diffuse types, respectively. From our clinical data set, symptoms both in children and adults were swelling, pain, and limited ROM with a median time before diagnosis of 12 months (range, 1-72 months). With the numbers available, we did not observe differences in presentation between children and adults in terms of sex, symptoms before diagnosis, first treatment, recurrent disease, followup status, or median time to followup. The 2.5-year recurrence-free TGCT survival rate after open resection was not different with the numbers available between children and adults: 85% (95% confidence interval [CI], 67%-100%) versus 89% (95% CI, 83%-96%) in localized, respectively (p = 0.527) and 53% (95% CI, 35%-79%) versus 56% (95% CI, 49%-64%) in diffuse type, respectively (p = 0.691).
CONCLUSIONS: Although the incidence of pediatric TGCT is low, it should be considered in the differential diagnosis in children with chronic monoarticular joint effusions. Recurrent disease after surgical treatment of this orphan disease seems comparable between children and adults. With targeted therapies being developed, future research should define the most effective treatment strategies for this heterogeneous disease.
LEVEL OF EVIDENCE: Level III, therapeutic study.

PMID: 29494352 [PubMed - as supplied by publisher]

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Dietary Interventions for Rare Metabolic Disorders - Now Available in India!

Indian Pediatr. 2017 11 15;54(11):909-910

Authors: Sachdeva A

PMID: 29217800 [PubMed - indexed for MEDLINE]