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

Funding Opportunity PAR-18-704 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages research projects focused on adducts to cellular macromolecules as indicators of exposures to cancer risk factors relevant to human populations. The priority is on projects that will focus on adductomic approaches, i.e., address some aspects of the totality of adducts. These projects should explore the basic aspects of adducts/adductomics that may have a potential utility in cancer detection, cancer prevention, and/or assessing cancer risks. The projects should be relevant to adducts in humans and human populations but may be conducted using various model systems (e.g., cultured cells, animals, etc.). The use of human biospecimens is encouraged and expected if appropriate but not required. In well-justified cases, innovative studies using the adductomic approaches in the context of cancer etiology and/or gene-environment interaction research may also be appropriate. For projects intended for NIEHS support, the focus may be on innovative technology and method development.

Funding Opportunity PAR-18-703 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages research projects focused on adducts to cellular macromolecules as indicators of exposures to cancer risk factors relevant to human populations. The priority is on projects that will focus on adductomic approaches, i.e., address some aspects of the totality of adducts. These projects should explore the basic aspects of adducts/adductomics that may have a potential utility in cancer detection, cancer prevention, and/or assessing cancer risks. The projects should be relevant to adducts in humans and human populations but may be conducted using various model systems (e.g., cultured cells, animals, etc.). The use of human biospecimens is encouraged and expected if appropriate but not required. In well-justified cases, innovative studies using the adductomic approaches in the context of cancer etiology and/or gene-environment interaction research may also be appropriate. For projects intended for NIEHS support, the focus may be on innovative technology and method development.

Funding Opportunity PA-18-705 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages Small Business Innovation Research (SBIR) grant applications from small business concerns (SBCs) for projects to transfer technology out of the NIH intramural research labs into the private sector. If selected for SBIR funding, the SBC will be granted a royalty-free, non-exclusive patent license agreement for internal research use for the term of and within the field of use of the SBIR award to technologies held by NIH with the intent that the SBC will develop the invention into a commercial product to benefit the public.

Notice NOT-OD-18-138 from the NIH Guide for Grants and Contracts

Funding Opportunity PA-18-702 from the NIH Guide for Grants and Contracts. The purpose of the administrative supplement is to provide support for NIH-funded investigators to participate in an entrepreneurship training course, the Concept to Clinic: Commercializing Innovation (C3i) Program. The C3i Program is designed to provide medical device innovators with the specialized business frameworks and essential tools for successful translation of biomedical technologies from the lab (concept) to the market (clinic). Through this program, the NIH fosters the development and commercialization of early-stage biomedical technologies by engaging investigators who are interested in better understanding the value of their innovation in addressing an unmet market need. The curriculum and customized mentoring provided by the C3i Program are intended to guide investigators as they assess the commercial viability and potential business opportunity for their innovation. Prospective applicants are strongly encouraged to contact NIH Scientific/Research staff for more information about the program before applying.

Funding Opportunity PA-18-700 from the NIH Guide for Grants and Contracts. The purpose of the NIDCD Research Dissertation Fellowship for Au.D. Audiologists (F32) program is to support a comprehensive, rigorous biomedical research training, and dissertation research leading to a research doctorate (i.e., Ph.D.) in the biomedical, behavioral, or clinical sciences.

Notice NOT-AR-18-018 from the NIH Guide for Grants and Contracts

Notice NOT-NS-18-049 from the NIH Guide for Grants and Contracts

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pharmacogenomics

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Related Articles

Statins in conditions other than hypocholesterolemic effects for chronic subdural hematoma therapy, old drug, new tricks?

Oncotarget. 2017 Apr 18;8(16):27541-27546

Authors: Zou H, Zhu XX, Ding YH, Zhang GB, Geng Y, Huang DS

Abstract
Chronic subdural hematoma (CSDH) is one of the most common intracranial hematomas worldwide with a high incidence in the general population. However, the optimum treatment for CSDH is Burr-hole drainage with or without rinse Considering the poor outcomes of CSDH in aged patients, and ambiguous prediction of recurrence in many sides of recurrent CSDHs who have been analyzed, new effective therapies are needed for those CSDHs who are predicated to have poor prognosis for surgery and/or have a higher risk of recurrence. Statins, which is the first-line treatment for patients with high cholesterol and coronary heart disease. However, statins are still not solely limited in the treatment of these diseases. It has been demonstrated that statins could improve CSDH due to its effect of regulation of angiogenesis and inflammation. In this review, in order to provide potential new treatment for CSDH we summarize the recent findings of statins in CSDH in order to try to clarify the mechanisms of this effect.

PMID: 28177914 [PubMed - indexed for MEDLINE]

Related Articles

New use of an old drug: inhibition of breast cancer stem cells by benztropine mesylate.

Oncotarget. 2017 Jan 03;8(1):1007-1022

Authors: Cui J, Hollmén M, Li L, Chen Y, Proulx ST, Reker D, Schneider G, Detmar M

Abstract
Cancer stem cells (CSCs) play major roles in cancer initiation, metastasis, recurrence and therapeutic resistance. Targeting CSCs represents a promising strategy for cancer treatment. The purpose of this study was to identify selective inhibitors of breast CSCs (BCSCs). We carried out a cell-based phenotypic screening with cell viability as a primary endpoint, using a collection of 2,546 FDA-approved drugs and drug-like molecules in spheres formed by malignant human breast gland-derived cells (HMLER-shEcad cells, representing BCSCs) and control immortalized non-tumorigenic human mammary cells (HMLE cells, representing normal stem cells). 19 compounds were identified from screening. The chemically related molecules benztropine mesylate and deptropine citrate were selected for further validation and both potently inhibited sphere formation and self-renewal of BCSCs in vitro. Benztropine mesylate treatment decreased cell subpopulations with high ALDH activity and with a CD44+/CD24- phenotype. In vivo, benztropine mesylate inhibited tumor-initiating potential in a 4T1 mouse model. Functional studies indicated that benztropine mesylate inhibits functions of CSCs via the acetylcholine receptors, dopamine transporters/receptors, and/or histamine receptors. In summary, our findings identify benztropine mesylate as an inhibitor of BCSCs in vitro and in vivo. This study also provides a screening platform for identification of additional anti-CSC agents.

PMID: 27894093 [PubMed - indexed for MEDLINE]

Targeted sequencing reveals complex, phenotype-correlated genotypes in cystic fibrosis.

BMC Med Genomics. 2018 Feb 13;11(Suppl 1):13

Authors: Ivanov M, Matsvay A, Glazova O, Krasovskiy S, Usacheva M, Amelina E, Chernyak A, Ivanov M, Musienko S, Prodanov T, Kovalenko S, Baranova A, Khafizov K

Abstract
BACKGROUND: Cystic fibrosis (CF) is one of the most common life-threatening genetic disorders. Around 2000 variants in the CFTR gene have been identified, with some proportion known to be pathogenic and 300 disease-causing mutations have been characterized in detail by CFTR2 database, which complicates its analysis with conventional methods.
METHODS: We conducted next-generation sequencing (NGS) in a cohort of 89 adult patients negative for p.Phe508del homozygosity. Complete clinical and demographic information were available for 84 patients.
RESULTS: By combining MLPA with NGS, we identified disease-causing alleles in all the CF patients. Importantly, in 10% of cases, standard bioinformatics pipelines were inefficient in identifying causative mutations. Class IV-V mutations were observed in 38 (45%) cases, predominantly ones with pancreatic sufficient CF disease; rest of the patients had Class I-III mutations. Diabetes was seen only in patients homozygous for class I-III mutations. We found that 12% of the patients were heterozygous for more than two pathogenic CFTR mutations. Two patients were observed with p.[Arg1070Gln, Ser466*] complex allele which was associated with milder pulmonary obstructions (FVC 107 and 109% versus 67%, CI 95%: 63-72%; FEV 90 and 111% versus 47%, CI 95%: 37-48%). For the first time p.[Phe508del, Leu467Phe] complex allele was reported, observed in four patients (5%).
CONCLUSION: NGS can be a more information-gaining technology compared to standard methods. Combined with its equivalent diagnostic performance, it can therefore be implemented in the clinical practice, although careful validation is still required.

PMID: 29504914 [PubMed - in process]

On Burkholderiales order microorganisms and cystic fibrosis in Russia.

BMC Genomics. 2018 Feb 09;19(Suppl 3):74

Authors: Voronina OL, Kunda MS, Ryzhova NN, Aksenova EI, Sharapova NE, Semenov AN, Amelina EL, Chuchalin AG, Gintsburg AL

Abstract
BACKGROUND: Microbes infecting cystic fibrosis patients' respiratory tract are important in determining patients' functional status. Representatives of Burkholderiales order are the most dangerous. The goal of our investigation was to reveal the diversity of Burkholderiales, define of their proportion in the microbiome of various parts of respiratory tract and determine the pathogenicity of the main representatives.
RESULTS: In more than 500 cystic fibrosis patients, representing all Federal Regions of Russia, 34.0% were infected by Burkholderia cepacia complex (Bcc), 21.0% by Achromobacter spp. and 12.0% by Lautropia mirabilis. B. cenocepacia was the most numerous species among the Bcc (93.0%), and A. ruhlandii was the most numerous among Achromobacter spp. (58.0%). The most abundant genotype in Bcc was sequence type (ST) 709, and in Achromobacter spp. it was ST36. These STs constitute Russian epidemic strains. Whole genome sequencing of strains A. ruhlandii SCCH3:Ach33-1365 ST36 and B. cenocepacia GIMC4560:Bcn122 ST709 revealed huge resistomes and many virulence factors, which may explain the difficulties in eradicating these strains. An experience of less dangerous B. cenocepcia ST710 elimination was described. Massively parallel sequencing of 16S rDNA amplicons, including V1-V4 hypervariable regions, was used to definite "healthy" microbiome characteristics. Analysis of maxillary sinus lavage of 7 patients revealed infection with Proteobacteria of the same ST as pathogens from sputum, suggesting that the maxillary sinus is a source of infection in cystic fibrosis patients.
CONCLUSIONS: Characterization of the Russian epidemic bacterial strains in the sputum and sinuses of cystic fibrosis patients have better defined the importance of Burkholderiales bacteria. This information may aid in the development of effective approaches for treatment of this disease.

PMID: 29504898 [PubMed - in process]

Related Articles

Emergence and spread of worldwide Staphylococcus aureus clones among cystic fibrosis patients.

Infect Drug Resist. 2018;11:247-255

Authors: Garbacz K, Piechowicz L, Podkowik M, Mroczkowska A, Empel J, Bania J

Abstract
Background: The aim of this study was to assess the relatedness of molecular types of Staphylococcus aureus isolates colonizing cystic fibrosis (CF) patients with their antimicrobial resistance and prevalence of toxin genes.
Methods: A total of 215 isolates from the airways of 107 patients with CF were tested for spa and SCCmec type, antimicrobial resistance and carriage of toxin genes.
Results: t015, t084, t091, t700 and t002 were the largest group (approximately 25%) among all 69 identified spa types. Five new spa types, t14286, t14287, t14288, t14289 and t14290, were identified and registered. Isolates from CF patients were clustered into 11 multi-locus sequence typing clonal complexes, with CC30, CC22, CC97, CC45, CC15 and CC5 being the most frequent ones. Twelve (5.6%) methicillin-resistant S. aureus (MRSA) isolates and 102 (47.7%) multidrug-resistant isolates were identified, along with three SCCmec types (I, III and V). All isolates (both MRSA and methicillin-sensitive S. aureus) were Panton-Valentine leucocidin-negative, and 56.7% harbored egc genes. This was the first study documenting the presence of ST398-V-t571 livestock-associated MRSA in a European patient with CF.
Conclusion: These findings imply that individuals with CF can also be colonized with animal-related ST398 MRSA, and justify constant monitoring of staphylococcal colonization and identification of epidemic S. aureus clones in this group.

PMID: 29503574 [PubMed]

Related Articles

Incidence and Carrier Frequency of CFTR Gene Mutations in Pregnancies With Echogenic Bowel in Nova Scotia and Prince Edward Island.

J Obstet Gynaecol Can. 2018 Mar 01;:

Authors: Miller ME, Allen VM, Brock JK

Abstract
OBJECTIVE: Fetal echogenic bowel (echogenic bowel) is associated with cystic fibrosis (CF), with a reported incidence ranging from 1% to 13%. Prenatal testing for CF in the setting of echogenic bowel can be done by screening parental or fetal samples for pathogenic CFTR variants. If only one pathogenic variant is identified, sequencing of the CFTR gene can be undertaken, to identify a second pathogenic variant not covered in the standard screening panel. Full gene sequencing, however, also introduces the potential to identify variants of uncertain significance (VUSs) that can create counselling challenges and cause parental anxiety. To provide accurate counselling for families in the study population, the incidence of CF associated with echogenic bowel and the carrier frequency of CFTR variants were investigated.
METHODS: All pregnancies for which CF testing was undertaken for the indication of echogenic bowel (from Nova Scotia and Prince Edward Island) were identified (January 2007-July 2017). The CFTR screening and sequencing results were reviewed, and fetal outcomes related to CF were assessed.
RESULTS: A total of 463 pregnancies with echogenic bowel were tested. Four were confirmed to be affected with CF, giving an incidence of 0.9% in this cohort. The carrier frequency of CF among all parents in the cohort was 5.0% (1 in 20); however, when excluding parents of affected fetuses, the carrier frequency for the population was estimated at 4.1% (1 in 25). CFTR gene sequencing identified an additional VUS in two samples.
CONCLUSION: The incidence of CF in pregnancies with echogenic bowel in Nova Scotia and Prince Edward Island is 0.9%, with an estimated population carrier frequency of 4.1%. These results provide the basis for improved counselling to assess the risk of CF in the pregnancy, after parental carrier screening, using Bayesian probability. Counselling regarding VUSs should be undertaken before gene sequencing.

PMID: 29503250 [PubMed - as supplied by publisher]

Related Articles

Chaperone-Independent Peripheral Quality Control of CFTR by RFFL E3 Ligase.

Dev Cell. 2018 Feb 22;:

Authors: Okiyoneda T, Veit G, Sakai R, Aki M, Fujihara T, Higashi M, Susuki-Miyata S, Miyata M, Fukuda N, Yoshida A, Xu H, Apaja PM, Lukacs GL

Abstract
The peripheral protein quality control (QC) system removes non-native membrane proteins, including ΔF508-CFTR, the most common CFTR mutant in cystic fibrosis (CF), from the plasma membrane (PM) for lysosomal degradation by ubiquitination. It remains unclear how unfolded membrane proteins are recognized and targeted for ubiquitination and how they are removed from the apical PM. Using comprehensive siRNA screens, we identified RFFL, an E3 ubiquitin (Ub) ligase that directly and selectively recognizes unfolded ΔF508-CFTR through its disordered regions. RFFL retrieves the unfolded CFTR from the PM for lysosomal degradation by chaperone-independent K63-linked poly-ubiquitination. RFFL ablation enhanced the functional expression of cell-surface ΔF508-CFTR in the presence of folding corrector molecules, and this effect was further improved by inhibiting the Hsc70-dependent ubiquitination machinery. We propose that multiple peripheral QC mechanisms evolved to dispose of non-native PM proteins and to preserve cellular proteostasis, even at the cost of eliminating partially functional polypeptides.

PMID: 29503157 [PubMed - as supplied by publisher]

Related Articles

Implementing the International Committee on Mental Health in Cystic Fibrosis (ICMH) guidelines: Screening accuracy and referral-treatment pathways.

J Cyst Fibros. 2018 Mar 01;:

Authors: Verkleij M, de Winter D, Hurley MA, Abbott J

Abstract
BACKGROUND: The International Committee on Mental Health (ICMH) published screening guidelines in Cystic Fibrosis (CF). This work 1) evaluated the sensitivity of the recommended screening tools against the 'gold standard' clinical psychological assessment and 2) investigated referral and treatment pathways.
METHODS: Ninety-six participants (79 caregivers; 17 adolescents with CF) completed the screening tools prior to formal assessment. Agreement between screening data and psychological assessment was evaluated, sensitivity analyses performed and referral pathways tracked.
RESULTS: All participants with an elevated screen (moderate/severe range) were subsequently assessed as requiring treatment for major depression/anxiety disorders. However, many were referred for treatment without elevated scores. Hence, sensitivity was poor with the recommended threshold score of 10, but with a threshold of 5 the sensitivity was 76% for adults and 46% for adolescents. The area under the ROC curve (diagnostic test ability) was 0.89 for caregivers but lower at 0.68 for adolescents.
CONCLUSION: Mental health screening is complex, particularly in adolescents. Nonetheless, it is a first valuable step to improve mental health care in CF. The need for psychological support is greater than anticipated by the TIDES study.

PMID: 29503039 [PubMed - as supplied by publisher]