Notice NOT-DA-18-006 from the NIH Guide for Grants and Contracts

Funding Opportunity RFA-DK-17-028 from the NIH Guide for Grants and Contracts. This FOA seeks applications for clinical trials testing interventions targeting diabetes distress in individuals with T1D and/or their caregivers, with the goal of understanding whether lowering diabetes distress will improve glycemic control and quality of life.

Funding Opportunity RFA-DK-17-027 from the NIH Guide for Grants and Contracts. This FOA will support research to test approaches in the healthcare setting to using Patient-Reported Outcomes (PROs) as tools to enhance patient-centered treatment and improve outcomes in individuals with type 1 diabetes.

Funding Opportunity RFA-DK-17-020 from the NIH Guide for Grants and Contracts. Type 1 diabetes (T1D) results in part from the autoimmune-mediated dysfunction or destruction of insulin-producing pancreatic beta cells. This funding opportunity is for projects that seek to discover ways to change the course of the disease by directly establishing tolerance. Immune responses could be engineered for tolerance induction through the manipulation of antigens, cells, or cellular microenvironments. Collaborations between T1D experts and investigators from other fields, including (but not limited to) cancer immunology and biomaterials engineering, are especially encouraged.

Funding Opportunity RFA-DK-17-032 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) invites applications for studies of etiology and pathogenesis related to development of type 1 diabetes (T1D) and/or its complications. Studies must involve subjects enrolled and followed in clinical trials, long term follow-up, or observational studies. This opportunity is intended to fund collaborative projects that bring new expertise and innovative approaches to enhance the value of major ongoing clinical research projects.

Funding Opportunity RFA-DK-17-026 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement is intended to foster the development of a diverse and highly trained workforce of endocrinologists to assume leadership roles related to the Nations biomedical and behavioral research efforts in the area of type 1 diabetes (T1D). T1D is an autoimmune disease that occurs in both children and adults. Therefore, the NIDDK will award physician scientist career development program (K12) grants to eligible institutions to provide a program to prepare adult and/or pediatric endocrinologists, selected by the institution, for careers in basic or clinical research related to T1D. This Funding Opportunity Announcement (FOA) allows appointment of Scholars (K12) proposing to serve as the lead investigator of an independent clinical trial; or proposing a separate ancillary study to an existing trial; or proposing to gain research experience in a clinical trial led by another investigator, as part of their research and career development. Scholars may also propose fundamental research or human subjects research that is not a clinical trial.

Funding Opportunity RFA-DK-17-019 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages applications from institutions/organizations proposing the development of targeted mass spectrometric assays (e.g. Multiple Reaction Monitoring) for proteins and peptides of primary interest to the type 1 diabetes research community (e.g. glucagon, somatostatin, C-peptide, insulin). The proposed assays should be highly reproducible, easily transferable to other laboratories, easy to multiplex, and validated in human plasma or serum.

8 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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pharmacogenomics

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(exome OR "exome sequencing") AND disease

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"systems biology"

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("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

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SOX2 regulates common and specific stem cell features in the CNS and endoderm derived organs.

PLoS Genet. 2018 Feb 12;14(2):e1007224

Authors: Hagey DW, Klum S, Kurtsdotter I, Zaouter C, Topcic D, Andersson O, Bergsland M, Muhr J

Abstract
Stem cells are defined by their capacities to self-renew and generate progeny of multiple lineages. The transcription factor SOX2 has key roles in the regulation of stem cell characteristics, but whether SOX2 achieves these functions through similar mechanisms in distinct stem cell populations is not known. To address this question, we performed RNA-seq and SOX2 ChIP-seq on embryonic mouse cortex, spinal cord, stomach and lung/esophagus. We demonstrate that, although SOX2 binds a similar motif in the different cell types, its target regions are primarily cell-type-specific and enriched for the distinct binding motifs of appropriately expressed interacting co-factors. Furthermore, cell-type-specific SOX2 binding in endodermal and neural cells is most often found around genes specifically expressed in the corresponding tissue. Consistent with this, we demonstrate that SOX2 target regions can act as cis-regulatory modules capable of directing reporter expression to appropriate tissues in a zebrafish reporter assay. In contrast, SOX2 binding sites found in both endodermal and neural tissues are associated with genes regulating general stem cell features, such as proliferation. Notably, we provide evidence that SOX2 regulates proliferation through conserved mechanisms and target genes in both germ layers examined. Together, these findings demonstrate how SOX2 simultaneously regulates cell-type-specific, as well as core transcriptional programs in neural and endodermal stem cells.

PMID: 29432416 [PubMed - as supplied by publisher]

Quantitative high-throughput phenotypic screening of pediatric cancer cell lines identifies multiple opportunities for drug repurposing.

Oncotarget. 2018 Jan 12;9(4):4758-4772

Authors: Shen M, Asawa R, Zhang YQ, Cunningham E, Sun H, Tropsha A, Janzen WP, Muratov EN, Capuzzi SJ, Farag S, Jadhav A, Blatt J, Simeonov A, Martinez NJ

Abstract
Drug repurposing approaches have the potential advantage of facilitating rapid and cost-effective development of new therapies. Particularly, the repurposing of drugs with known safety profiles in children could bypass or streamline toxicity studies. We employed a phenotypic screening paradigm on a panel of well-characterized cell lines derived from pediatric solid tumors against a collection of ∼3,800 compounds spanning approved drugs and investigational agents. Specifically, we employed titration-based screening where compounds were tested at multiple concentrations for their effect on cell viability. Molecular and cellular target enrichment analysis indicated that numerous agents across different therapeutic categories and modes of action had an antiproliferative effect, notably antiparasitic/protozoal drugs with non-classic antineoplastic activity. Focusing on active compounds with dosing and safety information in children according to the Children's Pharmacy Collaborative database, we identified compounds with therapeutic potential through further validation using 3D tumor spheroid models. Moreover, we show that antiparasitic agents induce cell death via apoptosis induction. This study demonstrates that our screening platform enables the identification of chemical agents with cytotoxic activity in pediatric cancer cell lines of which many have known safety/toxicity profiles in children. These agents constitute attractive candidates for efficacy studies in pre-clinical models of pediatric solid tumors.

PMID: 29435139 [PubMed]

Related Articles

The antihelminthic drug niclosamide effectively inhibits the malignant phenotypes of uveal melanoma in vitro and in vivo.

Theranostics. 2017;7(6):1447-1462

Authors: Zhou J, Jin B, Jin Y, Liu Y, Pan J

Abstract
Uveal melanoma (UM) is a lethal intraocular malignancy with an average survival of only 2~8 months in patients with hepatic metastasis. Currently, there is no effective therapy for metastatic UM. Here, we reported that niclosamide, an effective repellence of tapeworm that has been approved for use in patients for approximately 50 years, exhibited strong antitumor activity in UM cells in vitro and in vivo. We showed that niclosamide potently inhibited UM cell proliferation, induced apoptosis and reduced migration and invasion. p-Niclosamide, a water-soluble niclosamide, exerted potent in vivo antitumor activity in a UM xenograft mouse model. Mechanistically, niclosamide abrogated the activation of the NF-κB pathway induced by tumor necrosis factor α (TNFα) in UM cells, while niclosamide elevated the levels of intracellullar and mitochondrial reactive oxygen species (ROS) in UM cells. Quenching ROS by N-acetylcysteine (NAC) weakened the ability of niclosamide-mediated apoptosis. Matrix metalloproteinase 9 (MMP-9) knockdown by shRNA potentiated, while ectopic expression of MMP-9 rescued, the niclosamide-attenuated invasion, implying that MMP-9 is pivotal for invasion blockage by niclosamide in UM cells. Furthermore, our results showed that niclosamide eliminated cancer stem-like cells (CSCs) as reflected by a decrease in the Aldefluor+ percentage and serial re-plating melanosphere formation, and these phenotypes were associated with the suppressed Wnt/β-catenin pathway by niclosamide in UM. Niclosamide caused a dose- and time-dependent reduction of β-catenin and the key components [e.g., DVLs, phospho-GSK3β (S9), c-Myc and Cyclin D1] in the canonical Wnt/β-catenin pathway. Additionally, niclosamide treatment in UM cells reduced ATP and cAMP contents, and decreased PKA-dependent phosphorylation of β-catenin at S552 and S675 which determine the stability of β-catenin protein, suggesting that niclosamide may work as a mitochondrial un-coupler. Taken together, our results shed light on the mechanism of antitumor action of niclosamide and warrant clinical trial for treatment of UM patients.

PMID: 28529629 [PubMed - indexed for MEDLINE]

Clinical Determinants of Incremental Shuttle Walk Test in Adults with Bronchiectasis.

Lung. 2018 Feb 12;:

Authors: Yildiz S, Inal-Ince D, Calik-Kutukcu E, Vardar-Yagli N, Saglam M, Arikan H, Coplu L

Abstract
INTRODUCTION: Exercise capacity is impaired in patients with bronchiectasis. Incremental shuttle walk test (ISWT) stresses cardiorespiratory system physiologically to symptom-limited maximal exercise capacity. The purpose of this study was to investigate the clinical determinants of ISWT in adults with non-cystic fibrosis (CF) bronchiectasis.
METHODS: Forty-one clinically stable bronchiectasis patients aged 18-72 years (27 females, 14 males) participated in the study. Subjects' demographics and physical characteristics were recorded. Bronchiectasis Severity Index was used to identify disease severity. Pulmonary function test was performed. Dyspnea perception was assessed using the modified Medical Research Council Dyspnea Scale. Maximum inspiratory and expiratory pressures were measured. Peripheral muscle strength using a hand held dynamometer was measured. ISWT was performed to determine exercise capacity. Fatigue Severity Scale, Hospital Anxiety and Depression Scale, Leicester Cough Questionnaire were used to determine fatigue, psychosocial status, and quality of life.
RESULTS: Patients' mean ISWT distance was 469.5 m. The ISWT distance was significantly related with age (r = - 0.472), height (r = 0.469), gender (r = 0.520), FEV1 (r = 0.651), and FVC (r = 0.545, p < 0.05). Quadriceps muscle strength was higher in males (p = 0.001) as compared to females. Age and gender were identified as independent predictors of the ISWT, explaining 42% of variance in ISWT distance (r = 0.649, r2 = 0.421, F(2,38) = 13.794, p < 0.001).
CONCLUSION: The clinical determinants of ISWT in clinically stable patients with non-CF bronchiectasis are age and gender. Pulmonary function, dyspnea perception, muscle strength, disease severity, fatigue, psychosocial factors, and health-related quality of life seems to have an independent effect on ISWT in this group of patients with bronchiectasis.

PMID: 29435737 [PubMed - as supplied by publisher]

Relationship between Physical Activity and Fatigue in Adults with Cystic Fibrosis.

Physiother Can. 2018;70(1):42-48

Authors: Orava C, Fitzgerald J, Figliomeni S, Lam D, Naccarato A, Szego E, Yoshida K, Fox P, Sykes J, Wu K

Abstract
Purpose: We examined the relationship between the amount of physical activity and level of fatigue in adults with cystic fibrosis (CF). Method: Participants were recruited from the Toronto Adult Cystic Fibrosis Centre at St. Michael's Hospital. Participants completed the Habitual Activity Estimation Scale, the Multidimensional Fatigue Inventory, and the Depression subscale of the Hospital Anxiety and Depression Scale, in that order. Descriptive statistics and linear and multiple regressions were computed. Results: Over a 6-month period, 51 individuals were approached, and 22 (10 men, 12 women) participated in this study. The participants' median age was 33, and forced expiratory volume in 1 second (FEV1) was 64% predicted. When holding both FEV1 and depression constant, a significant negative correlation was found between total active hours per weekday and general fatigue (β=-0.735, p=0.03); there was a negative trend between total active hours per weekday and physical fatigue (β=-0.579, p=0.09). Conclusions: This study is the first to demonstrate that among adults with CF, a higher level of physical activity is associated with a lower level of general and physical fatigue when controlling for lung function and level of depression. Physical activity may be used as a means of mitigating the levels of general and physical fatigue in people with CF.

PMID: 29434417 [PubMed - in process]

Glucose tolerance & insulin secretion & sensitivity characteristics in Indian children with cystic fibrosis: A pilot study.

Indian J Med Res. 2017 Oct;146(4):483-488

Authors: Jain V, Kumar S, Vikram NK, Kalaivani M, Bhatt SP, Sharma R, Sushil KK

Abstract
Background & objectives: Cystic fibrosis (CF) is a life-limiting genetic condition resulting in chronic respiratory infections, pancreatic enzyme insufficiency and associated complications. This pilot study was undertaken to assess the glucose tolerance and insulin secretion and sensitivity among Indian children with CF.
Methods: Children with CF under regular follow up at the Paediatric Pulmonology Clinic of a tertiary care hospital in New Delhi, India, were enrolled. Children who had a history of acute exacerbation or intake of systemic steroids within the last two weeks were excluded. Anthropometry, pulmonary function and disease severity (Shwachman) score were assessed. Fasting venous sample was drawn to assess glucose, insulin, haemoglobin and calcium. Oral glucose tolerance test was performed, and blood glucose and insulin were assessed at 30, 60, 90 and 120 min. Insulin secretion and sensitivity indices were calculated.
Results: Twenty nine patients with a mean age of 11.2±4.1 yr were enrolled. Stunting, thinness, anaemia and hypocalcaemia were present in 31.0, 13.8, 37.0 and 48.3 per cent of the patients, respectively. Abnormal glucose tolerance (AGT) was present in 21.4 per cent. Insulin secretion was similar in individuals with AGT and normal glucose tolerance (NGT), but insulin sensitivity index was lower (0.12±0.02 vs 0.15±0.01, P<0.001) and homeostatic model assessment of insulin resistance higher [1.63 (0.53-1.76) vs 0.83 (0.28-4.43), P<0.05] in individuals with AGT compared to NGT.
Interpretation & conclusions: AGT was observed in 21.4 per cent of children with CF. The CF patients with AGT had significantly lower insulin sensitivity compared to patients with NGT. Future multicentric studies with a large sample should be conducted to assess insulin secretion and sensitivity indices in CF patients compared to healthy controls.

PMID: 29434062 [PubMed - in process]

Reference percentiles of FEV1 for the Canadian cystic fibrosis population: comparisons across time and countries.

Thorax. 2018 Feb 06;:

Authors: Kim SO, Corey M, Stephenson AL, Strug LJ

Abstract
BACKGROUND: Forced expiratory volume in 1 s (FEV1) indicates lung health in cystic fibrosis (CF). FEV1 is commonly communicated as a per cent predicted of a healthy individual sharing the same age, sex, race and height. CF-specific reference equations are complementary and calibrate a patient's FEV1 to that of their CF peers.
OBJECTIVES: (1) To derive Canadian CF-specific FEV1 reference percentiles (FEV1%iles), (2) characterize how they have changed over time and (3) compare the Canadian FEV1%iles to those for USA and European CF populations.
METHOD: CF FEV1%iles are calculated using the Canadian CF Registry and quantile regression.
RESULTS: The Canadian FEV1%iles demonstrated better lung function in more recent time periods within Canada, especially below the 50% percentile and in males. When compared to USA and European FEV1%iles for the same time period, Canadian FEV1%iles were higher.
CONCLUSION: CF-specific FEV1%iles can provide useful information about changes in lung health. An online calculator (available at cfpercentile.
RESEARCH: sickkids.ca) makes these FEV1%iles accessible.

PMID: 29434047 [PubMed - as supplied by publisher]

13C-Mixed Triglyceride Breath Test and Fecal Elastase as an Indirect Pancreatic Function Test in Cystic Fibrosis Infants.

J Pediatr Gastroenterol Nutr. 2018 Feb 10;:

Authors: Kent DS, Remer T, Blumenthal C, Hunt S, Simonds S, Egert S, Gaskin KJ

Abstract
BACKGROUND: The 'gold standard' test for the indirect determination of pancreatic function status in infants with cystic fibrosis (CF), the 72-hour faecal fat excretion test, is likely to become obsolete in the near future. Alternative indirect pancreatic function tests with sufficient sensitivity and specificity to determine pancreatic phenotype need further evaluation in CF infants.
OBJECTIVE: Evaluation of the clinical utility of both the non-invasive, non-radioactive C-mixed triglyceride (MTG) breath test and fecal elastase-1 (FE1) in comparison with the 72-hour faecal fat assessment in infants with CF.
METHODS: C MTG breath test and the monoclonal and polyclonal FE1 assessment in stool was compared with the 72-hour faecal fat assessment in 24 infants with CF. Oral pancreatic enzyme substitution (PERT) (if already commenced) was stopped before the tests.
RESULTS: Sensitivity rates between 82-100% for CF patients with pancreatic insufficiency assessed by both the C MTG breath test and the FE1 tests proved to be high and promising. However the C MTG breath test (31-38%), as well as both FE1 tests assessed by the monoclonal (46-54%) and the polyclonal (45%) ELISA-kits showed unacceptably low sensitivity rates for the detection of pancreatic sufficient CF patients in the current study.
CONCLUSION: The C MTG breath test with Non Dispersive Infrared Spectroscopy (NDIRS) technique, as well as both FE1 tests, are not alternatives to the faecal fat balance test for the evaluation of pancreatic function in CF infants during the first year of life.Supplemental Table 1, Supplemental Digital Content, http://links.lww.com/MPG/B281.

PMID: 29432279 [PubMed - as supplied by publisher]