Physiological and pharmacological characterization of the N1303K mutant CFTR.

J Cyst Fibros. 2018 Jun 07;:

Authors: DeStefano S, Gees M, Hwang TC

Abstract
BACKGROUND: N1303K, one of the common, severe disease-causing mutations in the CFTR gene, causes both defective biogenesis and gating abnormalities of the CFTR protein. The goals of the present study are to quantitatively assess the gating defects associated with the N1303K mutation and its pharmacological response to CFTR modulators including potentiators VX-770 and GLPG1837 and correctors VX-809, and VX-661.
METHODS: Gating behavior and pharmacological responses to CFTR potentiators were assessed using patch-clamp technique in the excised, inside-out mode. We also examined the effects of GLPG1837, VX-770, VX-809 and VX-661 on N1303K-CFTR surface expression using Western blot analysis.
RESULTS: Like wild-type (WT) CFTR, N1303K-CFTR channels were activated by protein kinase A-dependent phosphorylation, but the open probability (Po) of phosphorylated N1303K-CFTR was extremely low (~0.03 vs ~0.45 in WT channels). N1303K mutants showed abnormal responses to ATP analogs or mutations that disrupt ATP hydrolysis and/or dimerization of CFTR's two nucleotide-binding domains (NBDs). However, the Po of N1303K-CFTR was dramatically increased by GLPG1837 (~17-fold) and VX-770 (~8-fold). VX-809 or VX-661 enhanced N1303K-CFTR maturation by 2-3 fold, and co-treatment with GLPG1837 or VX-770 did not show any negative drug-drug interaction.
CONCLUSION: N1303K has a severe gating defect, reduced ATP-dependence and aberrant response to ATP analogs. These results suggest a defective function of the NBDs in N1303K-CFTR. An improvement of channel function by GLPG1837 or VX-770 and an increase of Band C protein by VX-809 or VX-661 support a therapeutic strategy of combining CFTR potentiator and corrector for patients carrying the N1303K mutation.

PMID: 29887518 [PubMed - as supplied by publisher]

Related Articles

Lung clearance index is sensitive to small airway disease in pediatric lung transplant recipients.

J Heart Lung Transplant. 2017 Sep;36(9):980-984

Authors: Kao JE, Zirbes JM, Conrad CK, Milla CE

Abstract
BACKGROUND: The principal obstacle to long-term survival after lung transplant is chronic lung allograft dysfunction (CLAD), which primarily affects the small airways. After transplant, patients are monitored with spirometry, which is a generally insensitive detector of small airways obstruction. The lung clearance index (LCI) is a measure obtained during multiple breath washout (MBW) maneuvers. We hypothesized that among lung allograft recipients, LCI would detect small airways disease not detected with spirometry.
METHODS: This study enrolled 15 patients, 5 of whom already had a diagnosis of CLAD. We added MBW as an additional index of peripheral airway function to the established post-transplant routine care protocol.
RESULTS: Of trials, 87.9% yielded valid measurements, and single maneuvers were 2-8 minutes. LCI did not yield any false-negative findings-no patients were considered obstructed by forced expiratory volume in 1 second (FEV1) but normal by LCI. At enrollment, 6 patients without CLAD had an elevated LCI, and 4 progressed to CLAD. Only 2 of these 4 patients would have been identified by a decrease in FEV1.
CONCLUSIONS: LCI identified lung allograft dysfunction in more patients than the use of standardized spirometric measures, including patients with abnormal FEV1. These data suggest that LCI from MBW may be a more sensitive means to detect allograft peripheral airway disease than standard methods for measurement of small airways function.

PMID: 28651906 [PubMed - indexed for MEDLINE]

Related Articles

Exome sequencing reveals a novel homozygous splice site variant in the WNT1 gene underlying osteogenesis imperfecta type 3.

Pediatr Res. 2017 Nov;82(5):753-758

Authors: Umair M, Alhaddad B, Rafique A, Jan A, Haack TB, Graf E, Ullah A, Ahmad F, Strom TM, Meitinger T, Ahmad W

Abstract
BackgroundOsteogenesis imperfecta (OI) is a heritable bone fragility disorder usually caused by dominant variants in COL1A1 or COL1A2 genes. Over the last few years, 17 genes including 12 autosomal recessive and five autosomal dominant forms of OI, involved in various aspects of bone formation, have been identified.MethodsWhole-exome sequencing followed by conventional Sanger sequencing was performed in a single affected individual (IV-3) in a family.ResultsHere, we report the clinical and genetic characterization of OI type 3 in a consanguineous family with four affected members. Clinical examinations revealed low bone density, short stature, severe vertebral compression fractures, and multiple long bone fractures in the affected members. Exome sequencing revealed a biallelic pathogenic splice acceptor site variant (c.359-3C>G) in a wingless-type mouse mammary tumor virus integration site family 1 (WNT1) gene located on chromosome 12q13.12.ConclusionWe report a biallelic splice site variant underlying OI type 3 and the first case from the Pakistani population.

PMID: 28665926 [PubMed - indexed for MEDLINE]

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Association between vitamin D receptor gene polymorphism and ankylosing spondylitis in Han Chinese.

Int J Rheum Dis. 2017 Oct;20(10):1510-1516

Authors: Zhang P, Li Q, Qi J, Lv Q, Zheng X, Wu X, Gu J

Abstract
OBJECTIVES: To investigate whether vitamin D receptor (VDR) gene polymorphisms confer susceptibility to aankylosing spondylitis (AS) and study its polymorphisms in Han Chinese.
METHODS: We screened single nucleotide polymorphisms (SNPs) in the VDR region through genome-wide genotyping chips in AS cases and healthy controls, then used the exome sequencing result to analyze all the potential AS-associated SNPs in the VDR gene.
RESULTS: Thirty-two SNPs were found in the VDR gene in the genome-wide genotyping chips and the logistic regression result showed no significant difference between AS cases and controls. A total of 46 SNPs in the VDR region were genotyped through exome sequencing, including four functional SNPs (rs731236 [TaqI], rs2228570 [FokI], rs7975232 [ApaI], rs1544410 [BsmI]) and two newly discovered SNPs (12:48259222 and 12:48276730). To note, rs731236 and rs2228570 locate in the exons of VDR, which cause synonymous and missense mutation. The association test showed there was no significant difference between AS cases and controls in the allele frequency distribution, but haplotype analysis of rs11168266-rs11168267 show nominal significance (P = 0.01268).
CONCLUSION: Our preliminary study indicates the haplotypes (TG) of rs11168266-rs11168267 in the VDR gene confers susceptibility to AS, which is worth further research.

PMID: 27778467 [PubMed - indexed for MEDLINE]

Funding Opportunity PAR-18-827 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) is issued by the Food and Drug Administration (FDA), Center for Veterinary Medicine (CVM), and solicits Research Project (R01) grant applications from institutions or organizations that propose to develop, or support the development of new animal drugs intended for minor use in major species or for use in minor species.

Funding Opportunity RFA-DK-18-009 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) seeks to bring together investigators with complementary expertise in HIV and in gastrointestinal mucosal pathobiology to dissect fundamental processes within the gastrointestinal tract that impact HIV infection, persistence, and comorbidities. This multidisciplinary approach should lead to comprehensive, in-depth mechanistic analyses and advance progress toward alleviating comorbidities that afflict people living with HIV and toward developing a cure.

Funding Opportunity RFA-AI-18-006 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to stimulate the development of new and innovative sustained/extended release drugs and drug delivery systems (DDS) that can achieve extended durations (months to years) of HIV prevention in at-risk individuals. This FOA requires an industry partner, milestones linked to Go/No Go decisions and year 5 funding requires communication with/ pre-IND submission to the FDA.

Association of Allelic Interaction of Single Nucleotide Polymorphisms of Influx and Efflux Transporters Genes With Nonhematologic Adverse Events of Docetaxel in Breast Cancer Patients.

Clin Breast Cancer. 2018 May 04;:

Authors: Jabir RS, Ho GF, Annuar MABA, Stanslas J

Abstract
PURPOSE: Nonhematologic adverse events (AEs) of docetaxel constitute an extra burden in the treatment of cancer patients and necessitate either a dose reduction or an outright switch of docetaxel for other regimens. These AEs are frequently associated with genetic polymorphisms of genes encoding for proteins involved docetaxel disposition. Therefore, we investigated that association in Malaysian breast cancer patients.
MATERIALS AND METHODS: A total of 110 Malaysian breast cancer patients were enrolled in the present study, and their blood samples were investigated for different single nucleotide polymorphisms using polymerase chain reaction restriction fragment length polymorphism. AEs were evaluated using the Common Terminology Criteria for Adverse Events, version 4.0.
RESULTS: Fatigue, nausea, oral mucositis, and vomiting were the most common nonhematologic AEs. Rash was associated with heterozygous and mutant genotypes of ABCB1 3435C>T (P < .05). Moreover, patients carrying the GG genotype of ABCB1 2677G>A/T reported more fatigue than those carrying the heterozygous genotype GA (P < .05). The presence of ABCB1 3435-T, ABCC2 3972-C, ABCC2 1249-G, and ABCB1 2677-G alleles was significantly associated with nausea and oral mucositis. The coexistence of ABCB1 3435-C, ABCC2 3972-C, ABCC2 1249-G, and ABCB1 2677-A was significantly associated with vomiting (P < .05).
CONCLUSION: The prevalence of nonhematologic AEs in breast cancer patients treated with docetaxel has been relatively high. The variant allele of ABCB1 3435C>T polymorphism could be a potential predictive biomarker of docetaxel-induced rash, and homozygous wild-type ABCB1 2677G>A/T might predict for a greater risk of fatigue. In addition, the concurrent presence of specific alleles could be predictive of vomiting, nausea, and oral mucositis.

PMID: 29885788 [PubMed - as supplied by publisher]

Role of habit in treatment adherence among adults with cystic fibrosis.

Thorax. 2018 Jun 09;:

Authors: Hoo ZH, Gardner B, Arden MA, Waterhouse S, Walters SJ, Campbell MJ, Hind D, Maguire C, Dewar J, Wildman MJ

Abstract
Among adults with cystic fibrosis (CF), medication adherence is low and reasons for low adherence are poorly understood. Our previous exploratory study showed that stronger 'habit' (ie, automatically experiencing an urge to use a nebuliser) was associated with higher nebuliser adherence. We performed a secondary analysis of pilot trial data (n=61) to replicate the earlier study and determine whether habit-adherence association exists in other cohorts of adults with CF. In this study, high adherers also reported stronger habit compared with low adherers. Habit may be a promising target for self-management interventions.
TRIAL REGISTRATION NUMBER: ACtiF pilot, ISRCTN13076797.

PMID: 29886416 [PubMed - as supplied by publisher]

A New Therapeutic Avenue for Bronchiectasis: Dry Powder Inhaler of Ciprofloxacin Nanoplex Exhibits Superior Ex Vivo Mucus Permeability and Antibacterial Efficacy to Its Native Ciprofloxacin Counterpart.

Int J Pharm. 2018 Jun 07;:

Authors: Tran TT, Vidaillac C, Yu H, Yong VFL, Roizman D, Chandrasekaran R, Lim AYH, Boon Low T, Liang Tan G, Abisheganaden JA, Siyue Koh M, Teo J, Chotirmall SH, Hadinoto K

Abstract
Non-cystic fibrosis bronchiectasis (NCFB) characterized by permanent bronchial dilatation and recurrent infections has been clinically managed by long-term intermittent inhaled antibiotic therapy among other treatments. Herein we investigated dry powder inhaler (DPI) formulation of ciprofloxacin (CIP) nanoplex with mannitol/lactose as the excipient for NCFB therapy. The DPI of CIP nanoplex was evaluated against DPI of native CIP in terms of their (1) dissolution characteristics in artificial sputum medium, (2) ex vivo mucus permeability in sputum from NCFB and healthy individuals, (3) antibacterial efficacy in the presence of sputum against clinical Pseudomonas aeruginosa strains (planktonic and biofilm), and (4) cytotoxicity towards human lung epithelial cells. Despite their similarly fast dissolution rates in sputum, the DPI of CIP nanoplex exhibited superior mucus permeability to the native CIP (5-7 times higher) attributed to its built-in ability to generate highly supersaturated CIP concentration in the sputum. The superior mucus permeability led to the CIP nanoplex's higher antibacterial efficacy (> 3 log10 CFU/mL). The DPI of CIP nanoplex exhibited similar cytotoxicity towards the lung epithelial cells as the native CIP indicating its low risk of toxicity. These results established the promising potential of DPI of CIP nanoplex as a new therapeutic avenue for NCFB.

PMID: 29886096 [PubMed - as supplied by publisher]

Treatment of cystic fibrosis in infants.

Lancet Respir Med. 2018 Jun 06;:

Authors: Accurso FJ

PMID: 29886025 [PubMed - as supplied by publisher]

Ivacaftor treatment of cystic fibrosis in children aged 12 to <24 months and with a CFTR gating mutation (ARRIVAL): a phase 3 single-arm study.

Lancet Respir Med. 2018 Jun 06;:

Authors: Rosenfeld M, Wainwright CE, Higgins M, Wang LT, McKee C, Campbell D, Tian S, Schneider J, Cunningham S, Davies JC, ARRIVAL study group

Abstract
BACKGROUND: Ivacaftor is generally safe and effective in patients aged 2 years and older who have cystic fibrosis and specific CFTR mutations. We assessed its use in children aged 12 to <24 months.
METHODS: The ARRIVAL study is a phase 3, single-arm, two-part, multicentre study. Eligible children were aged 12 to <24 months at enrolment and had a confirmed diagnosis of cystic fibrosis and a CFTR gating mutation on at least one allele and could participate in one or both parts of the study. Children received 50 mg (bodyweight 7 to <14 kg) or 75 mg (bodyweight ≥14 to <25 kg) ivacaftor orally every 12 h. In study part A, children received ivacaftor for 3 days plus one morning. In study part B, children received 24 weeks of treatment. Children were enrolled into part A at seven sites in Australia (one site), the UK (one), and the USA (five) and into part B at 13 sites in Australia (two sites), Canada (one), the UK (three), and the USA (seven). Primary endpoints were pharmacokinetics (part A) and safety (parts A and B) in children who received at least one dose of ivacaftor. Secondary endpoints in part B were pharmacokinetics in children who received at least one dose of ivacaftor and absolute change from baseline in sweat chloride concentration. We also explored changes in growth parameters and markers of pancreatic function. This study is registered with ClinicalTrials.gov, number NCT02725567.
FINDINGS: Children aged 12 to <24 months were enrolled between Aug 25, 2016, and Nov 1, 2017. Seven children were enrolled in part A, of whom five received 50 mg and two received 75 mg ivacaftor. All completed treatment. Of 19 children enrolled in part B, including one from part A, all received 50 mg ivacaftor and 18 completed treatment (one withdrew because of difficulty with blood draws). All children received at least one dose of ivacaftor. Pharmacokinetics indicated exposure was similar to that in children aged 2 to <6 years and adults. No children discontinued because of adverse events or safety findings. In part A, three (43%) of seven children had treatment-emergent adverse events, all of which were mild and deemed not to be or unlikely to be related to ivacaftor. By 24 weeks in part B, treatment-emergent adverse events had been reported in 18 (95%) of 19 children, of which most were mild or moderate and the most frequent was cough (14 [74%] children). Two children in part B had four serious adverse events: one had constipation (possibly related to ivacaftor), distal intestinal obstruction syndrome, and eczema herpeticum, and one had persistent cough, all needing hospital admission. In five (28%) of 18 children aspartate or alanine aminotransferase concentrations rose to more than three times the upper limit of normal (to more than eight times in two children with concurrent infections). At week 24, the mean absolute change from baseline in sweat chloride concentration was -73·5 (SD 17·5) mmol/L. Growth parameters for age were normal at baseline and at week 24. At week 24, concentrations of faecal elastase-1 had increased and concentrations of immunoreactive trypsinogen had decreased from baseline. Mean serum lipase and amylase were raised at baseline and rapidly decreased after treatment was started.
INTERPRETATION: Ivacaftor was generally safe and well tolerated in children aged 12 to <24 months for up to 24 weeks and was associated with rapid and sustained reductions in sweat chloride concentrations. Improvements in biomarkers of pancreatic function suggest that ivacaftor preserves exocrine pancreatic function if started early. The study is continuing in infants younger than 12 months.
FUNDING: Vertex Pharmaceuticals Incorporated.

PMID: 29886024 [PubMed - as supplied by publisher]

Interventional Procedures in Patients with Pulmonary Vascular Obstruction.

Ann Thorac Surg. 2018 Jun 07;:

Authors: Cullivan S, Redmond K, Ridge C, O'Connell OJ

Abstract
A 21-year-old patient presented with a short history of fatigue and dyspnea on a background of a double lung transplant for cystic fibrosis and pre-existing chronic superior vena cava obstruction (SVCO). Computed tomography of the chest demonstrated a 3-cm mass occluding the right pulmonary veins, with associated right upper and lower lobe parenchymal pulmonary infiltrates. Two invasive procedures were performed with similar complications in both procedures.

PMID: 29885978 [PubMed - as supplied by publisher]

Calcium-activated Chloride Channel Regulator 1 (CLCA1) Controls Mucus Expansion in Colon by Proteolytic Activity.

EBioMedicine. 2018 Jun 06;:

Authors: Nyström EEL, Birchenough GMH, van der Post S, Arike L, Gruber AD, Hansson GC, Johansson MEV

Abstract
Many epithelial surfaces of the body are covered with protective mucus, and disrupted mucus homeostasis is coupled to diseases such as ulcerative colitis, helminth infection, cystic fibrosis, and chronic obstructive lung disease. However, little is known how a balanced mucus system is maintained. By investigating the involvement of proteases in colonic mucus dynamics we identified metalloprotease activity to be a key contributor to mucus expansion. The effect was mediated by calcium-activated chloride channel regulator 1 (CLCA1) as application of recombinant CLCA1 on intestinal mucus in freshly dissected tissue resulted in increased mucus thickness independently of ion and mucus secretion, but dependent on its metallohydrolase activity. Further, CLCA1 modulated mucus dynamics in both human and mouse, and knock-out of CLCA1 in mice was compensated for by cysteine proteases. Our results suggest that CLCA1 is involved in intestinal mucus homeostasis by facilitating processing and removal of mucus to prevent stagnation. In light of our findings, we suggest future studies to investigate if upregulation of CLCA1 in diseases associated with mucus accumulation could facilitate removal of mucus in an attempt to maintain homeostasis.

PMID: 29885864 [PubMed - as supplied by publisher]

Continuous glucose monitoring guided insulin therapy is associated with improved clinical outcomes in cystic fibrosis-related diabetes.

J Cyst Fibros. 2018 Jun 06;:

Authors: Frost F, Dyce P, Nazareth D, Malone V, Walshaw MJ

Abstract
INTRODUCTION: Continuous glucose monitoring (CGM) allows assessment of day to day glycaemic excursions and detects early glucose handling abnormalities that may not be apparent on oral glucose tolerance testing (OGTT). However, there is little published evidence as to whether these early dysglycaemic changes are amenable to treatment. We present outcomes following CGM guided insulin initiation at our centre.
METHODS: Adults without a prior diagnosis of cystic fibrosis related diabetes (CFRD) whom underwent >72 h CGM at our adult CF centre were included in the study. Clinical outcomes including weight and pulmonary function changes over the next 12 months were compared between groups based on CGM results and subsequent management.
RESULTS: CGM profiles for 59 patients were analysed. Insulin was commenced in 37 patients who had evidence of hyperglycaemia on CGM. Significant improvements in mean [95% confidence intervals] forced expiratory volume in 1 s (FEV1) (+4.3% predicted [1.06-7.48], p = 0.01) and weight (+1.2 kg [0.32-2.15], p = 0.01) were observed at 3 months in the insulin group. Annual rate of pulmonary function decline was also improved following insulin initiation.
CONCLUSION: Insulin treatment targeted towards glycaemic excursions seen on CGM is associated with improvements in lung function and weight with subsequent reduced pulmonary function decline.

PMID: 29885744 [PubMed - as supplied by publisher]

Rare genetic mutations in Pakistani patients with dilated cardiomyopathy.

Gene. 2018 Jun 07;:

Authors: Shakeel M, Irfan M, Khan IA

Abstract
Dilated cardiomyopathy (DCM) is a leading cause of heart failure, and heart transplantation globally. There is enlargement of left ventricle of the heart impairing the systolic function in this disorder. The involvement of genetic factors in the pathogenesis of DCM has been reported in up to 50% of the cases. However, due to the complexity and heterogeneity of the disease, the complete pathophysiology remains unclear. In this study, whole exomes of five unrelated patients of idiopathic DCM were sequenced to an average depth of 100× using Illumina HiSeq4000 system. The analysis of the data with in silico tools SIFT, Polyphen2, and CADD showed 494 rare (AF < 1.0%) missense SNVs predicted as deleterious. Detrimental variants in genes highly expressed in cardiac tissue included 3 rare allele frequency loss-of-function SNVs in C2orf40, MYOM3, and TMED4 genes, a homozygous frameshift insertion in RTKN2, and a splice site homozygous deletion in SLC6A6 in at least one of the patients. The stop-gained SNV rs143187236 of MYOM3 (myomesin 3) was found in perfect linkage disequilibrium (r2 = 1.0) with its neighboring missense SNV rs149105212 in two of the patients, representing the role of myomesin 3 in pathophysiology of DCM. Allele frequency comparison showed three variants rs375563861 (C2orf40), rs143187236 (MYOM3), and rs564181443 (RTKN2) having 3 fold or higher allele frequency in South Asians than in the global populations. The identified pathogenic variants can be used in risk assessment and precision therapy in DCM patients.

PMID: 29886034 [PubMed - as supplied by publisher]

Short exposure to low concentrations of alcohol during embryonic development has only subtle and strain- dependent effect on the levels of five amino acid neurotransmitters in zebrafish.

Neurotoxicol Teratol. 2018 Jun 07;:

Authors: Mahabir S, Chatterjee D, Gerlai R

Abstract
The zebrafish has been successfully employed to model and study the effects of embryonic alcohol exposure. Short exposure to low alcohol concentrations during embryonic development has been shown to significantly disrupt social behavior as well as the dopaminergic and serotoninergic systems in zebrafish. However, analysis of potential effects of embryonic alcohol exposure on other amino acid neurotransmitter systems has not been performed. Here we analyzed neurochemicals obtained from adult AB and TU strain zebrafish that were immersed in 0.00% (control), 0.25%, 0.50%, 0.75% or 1.00% alcohol solution (vol/vol%) at 24 h post-fertilization for 2 h. From whole brain extracts, we quantified glutamate, aspartate, glycine, taurine and GABA levels using high performance liquid chromatography (HPLC). We found embryonic alcohol exposure not to have any significant effect on the levels of glutamate, aspartate, glycine and GABA in both AB and TU zebrafish. AB zebrafish showed a significant elevation of taurine levels, but only in the highest alcohol dose group compared to control. These results, albeit mainly negative, together with prior findings suggest that behavioral abnormalities resulting from embryonic alcohol exposure described before for AB zebrafish may primarily be due to altered dopaminergic and serotoninergic mechanisms. Furthermore, a Principal Component Analysis conducted with all neurochemicals tested in this and in our prior study, found a strain-dependent correlation structure response to embryonic alcohol treatment, confirming that embryonic alcohol effects may be genotype dependent.

PMID: 29886245 [PubMed - as supplied by publisher]

Encoding Growth Factor Identity in the Temporal Dynamics of FOXO3 under the Combinatorial Control of ERK and AKT Kinases.

Cell Syst. 2018 May 31;:

Authors: Sampattavanich S, Steiert B, Kramer BA, Gyori BM, Albeck JG, Sorger PK

Abstract
Extracellular growth factors signal to transcription factors via a limited number of cytoplasmic kinase cascades. It remains unclear how such cascades encode ligand identities and concentrations. In this paper, we use live-cell imaging and statistical modeling to study FOXO3, a transcription factor regulating diverse aspects of cellular physiology that is under combinatorial control. We show that FOXO3 nuclear-to-cytosolic translocation has two temporally distinct phases varying in magnitude with growth factor identity and cell type. These phases comprise synchronous translocation soon after ligand addition followed by an extended back-and-forth shuttling; this shuttling is pulsatile and does not have a characteristic frequency, unlike a simple oscillator. Early and late dynamics are differentially regulated by Akt and ERK and have low mutual information, potentially allowing the two phases to encode different information. In cancer cells in which ERK and Akt are dysregulated by oncogenic mutation, the diversity of states is lower.

PMID: 29886111 [PubMed - as supplied by publisher]

Notice NOT-EB-18-021 from the NIH Guide for Grants and Contracts

Notice NOT-EB-18-020 from the NIH Guide for Grants and Contracts