Notice NOT-AI-17-029 from the NIH Guide for Grants and Contracts

EBV infection and MSI status significantly influence the clinical outcomes of gastric cancer patients.

Clin Chim Acta. 2017 Jun 07;:

Authors: Shen H, Zhong M, Wang W, Liao P, Yin X, Rotroff D, Knepper TC, Mcleod HL, Zhou C, Xie S, Li W, Xu B, He Y

Abstract
BACKGROUND: Epstein-Barr virus (EBV) and microsatellite instability (MSI) are associated with the carcinogenesis of many kinds of tumors, including gastric cancer (GC). However, the impact of EBV and MSI status on the prognosis of stage II and III GC is still unclear. The aim of this study was to find out the prognostic value of EBV and MSI status in a population of GC patients from Southern China.
METHODS: Patients were genotyped for EBV infection based on the detection of EBV DNA from the formalin-fixed paraffin-embedded (FFPE) specimens. Sequentially, MSI status was measured by direct sequencing. Clinical characteristics and overall survival (OS) were analyzed in 202 GC patients. Additionally, the association of EBV and MSI status with chemotherapy-based toxicity was analyzed in 324 GC patients.
RESULTS: The survival analysis revealed EBV+ patients had a poorer OS than EBV- patients (HR=1.75, 95% CI: 1.08-2.82, FDR p=0.04). This survival advantage for EBV- patients was also found in patients <60y (FDR p=0.04) and patient with stage III disease (FDR p=0.04).
CONCLUSIONS: EBV infection and MSI status are associated with overall survival of gastric cancer patients. However, traditional chemotherapy showed no difference on outcome of patients in EBV and MSI subgroups.

PMID: 28601671 [PubMed - as supplied by publisher]

The changing face of nutrition in cystic fibrosis.

J Cyst Fibros. 2017 Jun 07;:

Authors: Wolfe SP, Collins C

PMID: 28601425 [PubMed - as supplied by publisher]

Genetic diagnostics of male infertility in clinical practice.

Best Pract Res Clin Obstet Gynaecol. 2017 May 10;:

Authors: Flannigan R, Schlegel PN

Abstract
Approximately 15% of couples are infertile. Male factors contribute to infertility in over 50% of cases. Identifiable genetic abnormalities contribute to 15%-20% of the most severe forms of male infertility, azoospermia. In this chapter, we explore known genetic causes of male infertility such as Klinefelter syndrome, XYY men, Kallmann syndrome, y-microdeletions, Robertsonian translocations, autosomal inversions, mixed gonadal dysgenesis, x-linked and autosomal gene mutations, and cystic fibrosis transmembrane conductance regulator abnormalities. We also briefly comment on novel biomarkers for male infertility.

PMID: 28601348 [PubMed - as supplied by publisher]

Mutation of Angiopoietin-1 Gene Associates with a New Type of Hereditary Angioedema.

J Allergy Clin Immunol. 2017 Jun 07;:

Authors: Bafunno V, Firinu D, D'Apolito M, Cordisco G, Loffredo S, Leccese A, Bova M, Barca MP, Santacroce R, Cicardi M, Del Giacco S, Margaglione M

Abstract
BACKGROUND: Hereditary angioedema (HAE) is a rare genetic disease usually due to mutation within the C1 inhibitor or the coagulation Factor XII gene. However, in a series of patients with HAE no causative variants have been described and the pathophysiology of the disease remains unknown (U-HAE). Identification of causative genes in U-HAE is valuable for understanding the cause of the disease.
OBJECTIVE: We conducted genetic studies in Italian patients with U-HAE to identify novel causative genes.
METHODS: Among patients belonging to 10 independent families and unrelated index patients with U-HAE disease recruited from the Italian network for C1-INH-HAE (ITACA), we selected a large multiplex family with U-HAE and performed whole-exome sequencing. The angiopoietin-1 gene (ANGPT1) was investigated in all patients with familial or sporadic U-HAE. The effect of ANGPT1 variants was investigated by in silico prediction and using patients and control plasmas and transfected cells.
RESULTS: We identified a missense mutation (ANGPT1, c.807G>T, p.A119S) in a family with U-HAE. The ANGPT1 p.A119S variant was detected in all members of the index family with U-HAE but not in asymptomatic family members, nor in an additional 20 patients with familial U-HAE, 22 patients with sporadic U-HAE, and 200 controls. Protein analysis of the plasma of patients revealed a reduction of multimeric forms and a reduced ability to bind the natural receptor "tunica interna endothelial cell kinase-2" (TIE2) of the ANGPT1 p.A119S variant. The recombinant mutated ANGPT1 p.A119S formed a reduced amount of multimers and showed a reduced binding capability to its receptor.
CONCLUSION: ANGPT1 impairment is associated with angioedema and ANGPT1 variants can be the basis of HAE.

PMID: 28601681 [PubMed - as supplied by publisher]

Comprehensive Genomic Characterization of Upper Tract Urothelial Carcinoma.

Eur Urol. 2017 Jun 07;:

Authors: Moss TJ, Qi Y, Xi L, Peng B, Kim TB, Ezzedine NE, Mosqueda ME, Guo CC, Czerniak BA, Ittmann M, Wheeler DA, Lerner SP, Matin SF

Abstract
BACKGROUND: Upper urinary tract urothelial cancer (UTUC) may have unique etiologic and genomic factors compared to bladder cancer.
OBJECTIVE: To characterize the genomic landscape of UTUC and provide insights into its biology using comprehensive integrated genomic analyses.
DESIGN, SETTING, AND PARTICIPANTS: We collected 31 untreated snap-frozen UTUC samples from two institutions and carried out whole-exome sequencing (WES) of DNA, RNA sequencing (RNAseq), and protein analysis.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Adjusting for batch effects, consensus mutation calls from independent pipelines identified DNA mutations, gene expression clusters using unsupervised consensus hierarchical clustering (UCHC), and protein expression levels that were correlated with relevant clinical variables, The Cancer Genome Atlas, and other published data.
RESULTS AND LIMITATIONS: WES identified mutations in FGFR3 (74.1%; 92% low-grade, 60% high-grade), KMT2D (44.4%), PIK3CA (25.9%), and TP53 (22.2%). APOBEC and CpG were the most common mutational signatures. UCHC of RNAseq data segregated samples into four molecular subtypes with the following characteristics. Cluster 1: no PIK3CA mutations, nonsmokers, high-grade <pT2 tumors, high recurrences. Cluster 2: 100% FGFR3 mutations, low-grade tumors, tobacco use, noninvasive disease, no bladder recurrences. Cluster 3: 100% FGFR3 mutations, 71% PIK3CA, no TP53 mutations, five bladder recurrences, tobacco use, tumors all <pT2. Cluster 4: KMT2D (62.5%), FGFR3 (50%), TP53 (50%) mutations, no PIK3CA mutations, high-grade pT2+ disease, tobacco use, carcinoma in situ, shorter survival. We identified a novel SH3KBP1-CNTNAP5 fusion.
CONCLUSIONS: Mutations in UTUC occur at differing frequencies from bladder cancer, with four unique molecular and clinical subtypes. A novel SH3KBP1 fusion regulates RTK signaling. Further studies are needed to validate the described subtypes, explore their responses to therapy, and better define the novel fusion mutation.
PATIENT SUMMARY: We conducted a comprehensive study of the genetics of upper urinary tract urothelial cancer by evaluating DNA, RNA and protein expression in 31 tumors. We identified four molecular subtypes with distinct behaviors. Future studies will determine if these subtypes appear to have different responses to treatments.

PMID: 28601352 [PubMed - as supplied by publisher]

Funding Opportunity PAS-17-311 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to fill gaps in our understanding of (a) the impact of substance abuse on HIV, HIV/HCV co-infection associated disease progression, (b) the pathogenic interactions between HIV and hepatitis C virus, (c) hepatic and non-hepatic co-morbidities associated with HIV/HCV-co-infections in people with substance abuse disorders (SUDs), and (d) the effectiveness of interferon-free direct acting antiviral (DAAs) drug regimens to treat HIV/HCV co-infections in people with SUDs. This FOA is informed by priority area in the NIH HIV/AIDS Research Priorities and Guidelines for Determining AIDS Funding: https://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-137.html and the HHS National Viral Hepatitis Action Plan 2017-2020: https://www.hhs.gov/hepatitis/blog/2017/01/19/updated-national-viral-hepatitis-action-plan-2017-2020.html

Funding Opportunity RFA-FD-18-002 from the NIH Guide for Grants and Contracts. The purpose of this announcement is to support the implementation of NEST through operations of the NEST CC toward sustainable operations for the future to coincide with the stated purposes and goals listed in Section IV.H of the draft Medical Device User Fee Act Performance Goals and Procedures, Fiscal Years 2018 Through 2022 letter (MDUFA IV Commitment Letter, Available at https://www.fda.gov/downloads/ForIndustry/UserFees/MedicalDeviceUserFee/UCM526395.pdf

Notice NOT-NS-17-034 from the NIH Guide for Grants and Contracts

Funding Opportunity PAR-17-309 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages research grant applications directed toward the discovery of the impact of alterations associated with complex brain disorders on the fundamental cellular and molecular substrates of neuronal function. The present announcement seeks R01 applications.

Funding Opportunity PAR-17-310 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages research grant applications directed toward the discovery of the impact of alterations associated with complex brain disorders on the fundamental cellular and molecular substrates of neuronal function. The present announcement seeks R21 applications.

Funding Opportunity PAR-17-312 from the NIH Guide for Grants and Contracts. The NIH Research Education Program (R25) supports research education activities in the mission areas of the NIH. The over-arching goal of this NINDS Neuroscience Development for Advancing the Careers of a Diverse Research Workforce R25 program is to support educational activities that enhance the diversity of the biomedical, behavioral and clinical research workforce by (1) increasing the pool of current and future Ph.D.-level research scientists from diverse backgrounds underrepresented in biomedical neuroscience research; and (2) facilitating the career advancement/transition of the participants to the next step of their neuroscience careers.

Related Articles

Pharmacogenetics-based optimisation of atazanavir treatment: potential role of new genetic predictors.

Drug Metab Pers Ther. 2017 May 24;32(2):115-117

Authors: Falvella FS, Ricci E, Cheli S, Resnati C, Cozzi V, Cattaneo D, Gervasoni C, Clementi E, Galli M, Riva A

PMID: 28599374 [PubMed - in process]

Related Articles

Pulmonary surfactant dysfunction in pediatric cystic fibrosis: Mechanisms and reversal with a lipid-sequestering drug.

J Cyst Fibros. 2017 Jun 06;:

Authors: Gunasekara L, Al-Saiedy M, Green F, Pratt R, Bjornson C, Yang A, Michael Schoel W, Mitchell I, Brindle M, Montgomery M, Keys E, Dennis J, Shrestha G, Amrein M

Abstract
BACKGROUND: Airway surfactant is impaired in cystic fibrosis (CF) and associated with declines in pulmonary function. We hypothesized that surfactant dysfunction in CF is due to an excess of cholesterol with an interaction with oxidation.
METHODS: Surfactant was extracted from bronchial lavage fluid from children with CF and surface tension, and lipid content, inflammatory cells and microbial flora were determined. Dysfunctional surfactant samples were re-tested with a lipid-sequestering agent, methyl-β-cyclodextrin (MβCD).
RESULTS: CF surfactant samples were unable to sustain a normal low surface tension. MβCD restored surfactant function in a majority of samples.Mechanistic studies showed that the dysfunction was due to a combination of elevated cholesterol and an interaction with oxidized phospholipids and their pro-inflammatory hydrolysis products.
CONCLUSION: We confirm that CF patients have impaired airway surfactant function which could be restored with MβCD. These findings have implications for improving lung function and mitigating inflammation in patients with CF.

PMID: 28599957 [PubMed - as supplied by publisher]

Related Articles

Editorial to Don't judge a book by its cover: the emerging challenge of diagnosing CF in non-Caucasians.

J Cyst Fibros. 2017 Jun 06;:

Authors: Chin M, Strug L, Stephenson AL

PMID: 28599956 [PubMed - as supplied by publisher]

Related Articles

Seasonality of acquisition of respiratory bacterial pathogens in young children with cystic fibrosis.

BMC Infect Dis. 2017 Jun 09;17(1):411

Authors: Psoter KJ, De Roos AJ, Wakefield J, Mayer JD, Rosenfeld M

Abstract
BACKGROUND: Seasonal variations are often observed for respiratory tract infections; however, limited information is available regarding seasonal patterns of acquisition of common cystic fibrosis (CF)-related respiratory pathogens. We previously reported differential seasonal acquisition of Pseudomonas aeruginosa in young children with CF and no such variation for methicillin-susceptible Staphylococcus aureus acquisition. The purpose of this study was to describe and compare the seasonal incidence of acquisition of other respiratory bacterial pathogens in young children with CF.
METHODS: We conducted a retrospective study to describe and compare the seasonal incidence of methicillin-resistant Staphylococcus aureus (MRSA), Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and Haemophilus influenzae acquisition in young CF patients residing in the U.S. using the Cystic Fibrosis Foundation National Patient Registry, 2003-2009. Log-linear overdispersed Poisson regression was used to evaluate seasonal acquisition of each of these pathogens.
RESULTS: A total of 4552 children met inclusion criteria. During follow-up 910 (20%), 1161 (26%), 228 (5%), and 2148 (47%) children acquired MRSA, S. maltophilia, A. xylosoxidans and H. influenzae, respectively. Compared to winter season, MRSA was less frequently acquired in spring (Incidence Rate Ratio [IRR]: 0.79; 95% Confidence Interval [CI]: 0.65, 0.96) and summer (IRR: 0.69; 95% CI: 0.57, 0.84) seasons. Similarly, a lower rate of A. xylosoxidans acquisition was observed in spring (IRR: 0.59; 95% CI: 0.39, 0.89). For H. influenzae, summer (IRR: 0.88; 95% CI: 0.78, 0.99) and autumn (IRR: 0.78; 95% CI: 0.69, 0.88) seasons were associated with lower acquisition rates compared to winter. No seasonal variation was observed for S. maltophilia acquisition.
CONCLUSION: Acquisition of CF-related respiratory pathogens displays seasonal variation in young children with CF, with the highest rate of acquisition for most pathogens occurring in the winter. Investigation of factors underlying these observed associations may contribute to our understanding of the aetiology of these infections and guide future infection control strategies.

PMID: 28599639 [PubMed - in process]

Related Articles

The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes.

Hum Genet. 2017 Jun 09;:

Authors: Monies D, Abouelhoda M, AlSayed M, Alhassnan Z, Alotaibi M, Kayyali H, Al-Owain M, Shah A, Rahbeeni Z, Al-Muhaizea MA, Alzaidan HI, Cupler E, Bohlega S, Faqeih E, Faden M, Alyounes B, Jaroudi D, Goljan E, Elbardisy H, Akilan A, Albar R, Aldhalaan H, Gulab S, Chedrawi A, Al Saud BK, Kurdi W, Makhseed N, Alqasim T, El Khashab HY, Al-Mousa H, Alhashem A, Kanaan I, Algoufi T, Alsaleem K, Basha TA, Al-Murshedi F, Khan S, Al-Kindy A, Alnemer M, Al-Hajjar S, Alyamani S, Aldhekri H, Al-Mehaidib A, Arnaout R, Dabbagh O, Shagrani M, Broering D, Tulbah M, Alqassmi A, Almugbel M, AlQuaiz M, Alsaman A, Al-Thihli K, Sulaiman RA, Al-Dekhail W, Alsaegh A, Bashiri FA, Qari A, Alhomadi S, Alkuraya H, Alsebayel M, Hamad MH, Szonyi L, Abaalkhail F, Al-Mayouf SM, Almojalli H, Alqadi KS, Elsiesy H, Shuaib TM, Seidahmed MZ, Abosoudah I, Akleh H, AlGhonaium A, Alkharfy TM, Al Mutairi F, Eyaid W, Alshanbary A, Sheikh FR, Alsohaibani FI, Alsonbul A, Al Tala S, Balkhy S, Bassiouni R, Alenizi AS, Hussein MH, Hassan S, Khalil M, Tabarki B, Alshahwan S, Oshi A, Sabr Y, Alsaadoun S, Salih MA, Mohamed S, Sultana H, Tamim A, El-Haj M, Alshahrani S, Bubshait DK, Alfadhel M, Faquih T, El-Kalioby M, Subhani S, Shah Z, Moghrabi N, Meyer BF, Alkuraya FS

Abstract
In this study, we report the experience of the only reference clinical next-generation sequencing lab in Saudi Arabia with the first 1000 families who span a wide-range of suspected Mendelian phenotypes. A total of 1019 tests were performed in the period of March 2016-December 2016 comprising 972 solo (index only), 14 duo (parents or affected siblings only), and 33 trio (index and parents). Multigene panels accounted for 672 tests, while whole exome sequencing (WES) represented the remaining 347 tests. Pathogenic or likely pathogenic variants that explain the clinical indications were identified in 34% (27% in panels and 43% in exomes), spanning 279 genes and including 165 novel variants. While recessive mutations dominated the landscape of solved cases (71% of mutations, and 97% of which are homozygous), a substantial minority (27%) were solved on the basis of dominant mutations. The highly consanguineous nature of the study population also facilitated homozygosity for many private mutations (only 32.5% of the recessive mutations are founder), as well as the first instances of recessive inheritance of previously assumed strictly dominant disorders (involving ITPR1, VAMP1, MCTP2, and TBP). Surprisingly, however, dual molecular diagnosis was only observed in 1.5% of cases. Finally, we have encountered candidate variants in 75 genes (ABHD6, ACY3, ADGRB2, ADGRG7, AGTPBP1, AHNAK2, AKAP6, ASB3, ATXN1L, C17orf62, CABP1, CCDC186, CCP110, CLSTN2, CNTN3, CNTN5, CTNNA2, CWC22, DMAP1, DMKN, DMXL1, DSCAM, DVL2, ECI1, EP400, EPB41L5, FBXL22, GAP43, GEMIN7, GIT1, GRIK4, GRSF1, GTRP1, HID1, IFNL1, KCNC4, LRRC52, MAP7D3, MCTP2, MED26, MPP7, MRPS35, MTDH, MTMR9, NECAP2, NPAT, NRAP, PAX7, PCNX, PLCH2, PLEKHF1, PTPN12, QKI, RILPL2, RIMKLA, RIMS2, RNF213, ROBO1, SEC16A, SIAH1, SIRT2, SLAIN2, SLC22A20, SMDT1, SRRT, SSTR1, ST20, SYT9, TSPAN6, UBR4, VAMP4, VPS36, WDR59, WDYHV1, and WHSC1) not previously linked to human phenotypes and these are presented to accelerate post-publication matchmaking. Two of these genes were independently mutated in more than one family with similar phenotypes, which substantiates their link to human disease (AKAP6 in intellectual disability and UBR4 in early dementia). If the novel candidate disease genes in this cohort are independently confirmed, the yield of WES will have increased to 83%, which suggests that most "negative" clinical exome tests are unsolved due to interpretation rather than technical limitations.

PMID: 28600779 [PubMed - as supplied by publisher]

Related Articles

Permeability-driven selection in a semi-empirical protocell model: the roots of prebiotic systems evolution.

Sci Rep. 2017 Jun 09;7(1):3141

Authors: Piedrafita G, Monnard PA, Mavelli F, Ruiz-Mirazo K

Abstract
The origin-of-life problem has been traditionally conceived as the chemical challenge to find the type of molecule and free-solution reaction dynamics that could have started Darwinian evolution. Different autocatalytic and 'self-replicative' molecular species have been extensively investigated, together with plausible synthetic pathways that might have led, abiotically, to such a minimalist scenario. However, in addition to molecular kinetics or molecular evolutionary dynamics, other physical and chemical constraints (like compartmentalization, differential diffusion, selective transport, osmotic forces, energetic couplings) could have been crucial for the cohesion, functional integration, and intrinsic stability/robustness of intermediate systems between chemistry and biology. These less acknowledged mechanisms of interaction and molecular control might have made the initial pathways to prebiotic systems evolution more intricate, but were surely essential for sustaining far-from-equilibrium chemical dynamics, given their functional relevance in all modern cells. Here we explore a protocellular scenario in which some of those additional constraints/mechanisms are addressed, demonstrating their 'system-level' implications. In particular, an experimental study on the permeability of prebiotic vesicle membranes composed of binary lipid mixtures allows us to construct a semi-empirical model where protocells are able to reproduce and undergo an evolutionary process based on their coupling with an internal chemistry that supports lipid synthesis.

PMID: 28600550 [PubMed - in process]

Related Articles

Conserved amino acid networks modulate discrete functional properties in an enzyme superfamily.

Sci Rep. 2017 Jun 09;7(1):3207

Authors: Narayanan C, Gagné D, Reynolds KA, Doucet N

Abstract
In this work, we applied the sequence-based statistical coupling analysis approach to characterize conserved amino acid networks important for biochemical function in the pancreatic-type ribonuclease (ptRNase) superfamily. This superfamily-wide analysis indicates a decomposition of the RNase tertiary structure into spatially distributed yet physically connected networks of co-evolving amino acids, termed sectors. Comparison of this statistics-based description with new NMR experiments data shows that discrete amino acid networks, termed sectors, control the tuning of distinct functional properties in different enzyme homologs. Further, experimental characterization of evolutionarily distant sequences reveals that sequence variation at sector positions can distinguish homologs with a conserved dynamic pattern and optimal catalytic activity from those with altered dynamics and diminished catalytic activities. Taken together, these results provide important insights into the mechanistic design of the ptRNase superfamily, and presents a structural basis for evolutionary tuning of function in functionally diverse enzyme homologs.

PMID: 28600532 [PubMed - in process]

Related Articles

Synergistic action of auxin and cytokinin mediates aluminum-induced root growth inhibition in Arabidopsis.

EMBO Rep. 2017 Jun 09;:

Authors: Yang ZB, Liu G, Liu J, Zhang B, Meng W, Müller B, Hayashi KI, Zhang X, Zhao Z, De Smet I, Ding Z

Abstract
Auxin acts synergistically with cytokinin to control the shoot stem-cell niche, while both hormones act antagonistically to maintain the root meristem. In aluminum (Al) stress-induced root growth inhibition, auxin plays an important role. However, the role of cytokinin in this process is not well understood. In this study, we show that cytokinin enhances root growth inhibition under stress by mediating Al-induced auxin signaling. Al stress triggers a local cytokinin response in the root-apex transition zone (TZ) that depends on IPTs, which encode adenosine phosphate isopentenyltransferases and regulate cytokinin biosynthesis. IPTs are up-regulated specifically in the root-apex TZ in response to Al stress and promote local cytokinin biosynthesis and inhibition of root growth. The process of root growth inhibition is also controlled by ethylene signaling which acts upstream of auxin. In summary, different from the situation in the root meristem, auxin acts with cytokinin in a synergistic way to mediate aluminum-induced root growth inhibition in Arabidopsis.

PMID: 28600354 [PubMed - as supplied by publisher]