Deciphering cellular biological processes to clinical application: a new perspective for Tα1 treatment targeting multiple diseases.

Expert Opin Biol Ther. 2018 Jul;18(sup1):23-31

Authors: Matteucci C, Argaw-Denboba A, Balestrieri E, Giovinazzo A, Miele M, D'Agostini C, Pica F, Grelli S, Paci M, Mastino A, Sinibaldi Vallebona P, Garaci E, Tomino C

Abstract
BACKGROUND: Thymosin alpha 1 (Tα1) is a well-recognized immune response modulator in a wide range of disorders, particularly infections and cancer. The bioinformatic analysis of public databases allows drug repositioning, predicting a new potential area of clinical intervention. We aimed to decipher the cellular network induced by Tα1 treatment to confirm present use and identify new potential clinical applications.
RESEARCH DESIGN AND METHODS: We used the transcriptional profile of human peripheral blood mononuclear cells treated in vitro with Tα1 to perform the enrichment network analysis by the Metascape online tools and the disease enrichment analysis by the DAVID online tool.
RESULTS: Networked cellular responses reflected Tα1 regulated biological processes including immune and metabolic responses, response to compounds and oxidative stress, ion homeostasis, peroxisome biogenesis and drug metabolic process. Beyond cancer and infections, the analysis evidenced the association with disorders such as kidney chronic failure, diabetes, cardiovascular, chronic respiratory, neuropsychiatric, neurodegenerative and autoimmune diseases.
CONCLUSIONS: In addition to the known ability to promote immune response pathways, the network enrichment analysis demonstrated that Tα1 regulates cellular metabolic processes and oxidative stress response. Notable, the analysis highlighted the association with several diseases, suggesting new translational implication of Tα1 treatment in pathological conditions unexpected until now.

PMID: 30063863 [PubMed - in process]

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A Small-molecule Kinase Inhibitor, CEP-1347, Inhibits Survivin Expression and Sensitizes Ovarian Cancer Stem Cells to Paclitaxel.

Anticancer Res. 2018 Aug;38(8):4535-4542

Authors: Togashi K, Okada M, Yamamoto M, Suzuki S, Sanomachi T, Seino S, Yamashita H, Kitanaka C

Abstract
BACKGROUND: Chemoresistance of cancer stem cells (CSCs) is considered a major cause of post-treatment recurrence that negatively impacts the prognosis of patients with ovarian cancer.
MATERIALS AND METHODS: Using CSCs derived from two different ovarian cancer cell lines, we searched for molecules implicated in the chemoresistance of ovarian CSCs and also drugs with which to target those molecules.
RESULTS: Knockdown of survivin overexpressed in ovarian CSCs resulted in increased sensitivity to paclitaxel. Treatment at clinically relevant concentrations with CEP-1347, a mixed lineage kinase inhibitor with a known safety profile in humans, reduced survivin expression in ovarian CSCs and sensitized them to paclitaxel.
CONCLUSION: Survivin overexpression plays a key role in the chemoresistance of ovarian CSCs. Introduction of CEP-1347, which targets survivin expression in ovarian CSCs, as a chemosensitizer for conventional ovarian cancer chemotherapy may serve as a rational and feasible approach for better management of ovarian cancer.

PMID: 30061219 [PubMed - in process]

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Penile refracture: a preliminary report.

Int Braz J Urol. 2018 Jul-Aug;44(4):800-804

Authors: Barros R, Guimarães M, Nascimento C, Araújo LR, Koifman L, Favorito LA

Abstract
OBJECTIVE: To report our institutional experience with penile refracture, including demographic data, recurrence time, etiology and operative findings in the first and second episodes.
MATERIALS AND METHODS: Between January 1982 and September 2017, 281 patients underwent surgical treatment for penile fracture (PF) at our institution. Demographic data, clinical presentation, besides operative findings and follow-up of patients with relapsed PF were retrospectively assessed by reviewing medical records.
RESULTS: Of a total of 281 cases of PF operated at our institution, 3 (1.06%) patients experienced two episodes of trauma. Age ranged from 38 - 40 years (mean: 39.3). The recurrence time varied from 45 to 1560 days (mean: 705). Two patients presented the new fracture episode at the same site of the previous lesion, while in the other case the lesion was observed at another site.
CONCLUSION: Recurrent FP is an extremely rare entity. The risk factors for its occurrence are still unknown. Although the lesion of the corpus cavernosum ipsilateral to the scar tissue of the prior FP is more common, contralateral rupture may be present. Nevertheless, prospective studies with larger samples should be conducted.

PMID: 29757574 [PubMed - indexed for MEDLINE]

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Mistletoe and Garlic Extracts as Polyurethane Carriers - A Possible Remedy for Choroidal Melanoma.

Curr Drug Deliv. 2017;14(8):1178-1188

Authors: Munteanu MF, Ardelean A, Borcan F, Trifunschi SI, Gligor R, Ardelean SA, Coricovac D, Pinzaru I, Andrica F, Borcan LC

Abstract
BACKGROUND: Melanoma is known as the most dangerous form of skin cancer; whereas the malignant choroidal melanoma is an orphan disease known as the most common primary intraocular malignancy in adults. Literature suggests that the consumption of garlic and mistletoe leads to a reduced risk of developing cancer.
OBJECTIVE: The aim of this study was the obtaining and the characterization of polymer structures containing mistletoe or garlic extract.
METHODS: The structures were obtained in a polyaddition process combined with a spontaneous emulsification; they were characterized by pH, size, Zeta potential and DSC measurements, evaluation of encapsulation efficacy, penetrability through membranes and in vitro cytotoxicity tests.
RESULTS: The microstructures present sizes between 1.05 and 2.60 µm and Zeta potentials between -7 and +36 mV. A good encapsulation was observed on different evaluations (88-92%). It was determined that approx. 30% of polymer microstructures containing vegetal extracts pass through an artificial membrane in 4 days. An in vitro cytotoxicity test revealed that these products are safe for administration. The analysis of antitumor efficacy indicates that garlic extracts have important effects after 48 and 72 hours on A375 cells; however, polymer microstructures with herbal extracts did not reveal antiproliferative activities on A375 cells because these polymer structures present a slow degradation.
CONCLUSION: Sterile eye drops solutions based on polymer microstructures containing garlic or mistletoe extracts were obtained; the sample based on garlic extracts may be used in the pharmaceutical field as drug carrier with an antiproliferative effect which occurs after a prolong period.

PMID: 28128068 [PubMed - indexed for MEDLINE]

Current Statistical Metrics Are Pragmatic Measures to Compare the Predictive Quality of Preclinical Assays.

Toxicol Sci. 2018 Jun 22;:

Authors: Ingelman-Sundberg M, Lauschke VM

PMID: 30063796 [PubMed - as supplied by publisher]

Alpha adducin (ADD1) gene polymorphism and new onset of diabetes under the influence of selective antihypertensive therapy in essential hypertension.

Curr Hypertens Rev. 2018 Jul 30;:

Authors: Gupta S, Jhawat V, Agarwal BK, Roy P, Saini V

Abstract
BACKGROUND: Different antihypertensive therapies (especially diuretics) are reported to induce new onset of diabetes in some hypertensive patients. α-adducin-1 (ADD1) gene is salt sensitive gene which has its role in etiology of hypertension via salt sensitivity. Therefore, the G460T polymorphism of ADD1 gene may be associated with new onset of diabetes under the influence of diuretic and other antihypertensive therapies.
AIM: To assess the correlation between genetic polymorphism (ADD1 G460T polymorphism) and glycaemic disturbance under influence of diuretic and other antihypertensive drug therapies.
MATERIALS AND METHODS: We recruited study subjects, 270 normotensive as control (150 male and 120 females), 270 hypertensive patients (95 male and 175 females) and 240 hypertensive with new onset of diabetes patients (80 male and 160 females). All study samples were genotyped for ADD1 polymorphic alleles and analyzed the relationship between different genotypes with respect to anthropometric and clinical parameters along with drug therapies.
RESULTS: Clinical and anthropometric parameters (such as age, SBP, DBP, FBG, height, weight, WC, HP, W/H ratio, and BMI) of study population were found highly statistically significant (p<0.05) at base value. Further, genotype wise comparison of all above parameters revealed most of them as non-significant (p>0.05). Whereas, comparison between genotype and different antihypertensive drug therapy of hypertensive patients, specifically, diuretic therapy as mono in male (p=0.0227) and female (p=0.0292) and in combination with BBs in both male (p=0.0023) and female (p=0.0079) revealed a higher FBG level in variant T allele. In case of hypertensive with new onset of diabetes patients, only female population showed a slightly statistical significant (p=0.0413) difference in FBG level with diuretic mono therapy. Other antihypertensive drug therapies were safe and effective either as mono or in combination therapy.
DISCUSSION: Anthropometric parameters may be the indicative factors for hypertension and diabetes. Variant T allele of ADD1 gene may be considered as the risk factor for development of diabetes in hypertensive patients. Diuretics as mono therapy and in combination with BBs may be considered as the risk factor for new onset of diabetes in EH patients carrying variant T allele (either as TG or TT).

PMID: 30062972 [PubMed - as supplied by publisher]

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Hepatic mitochondrial adaptations to physical activity: impact of sexual dimorphism, PGC1α, and BNIP3 mediated mitophagy.

J Physiol. 2018 Jul 31;:

Authors: Von Schulze A, McCoin CS, Onyekere C, Allen J, Geiger P, Dorn GW, Morris EM, Thyfault JP

Abstract
KEY POINTS SUMMARY: Hepatic mitochondrial adaptations to physical activity may be regulated by mitochondrial biogenesis (PGC1α) and mitophagy (BNIP3). Additionally, these adaptations may be sex-dependent. Chronic increases in physical activity lowers basal mitochondrial respiratory capacity in mice. Female mice have higher hepatic ETS protein content, elevated respiratory capacity, lowered mitophagic flux, and emit less mitochondrial H2 O2 independent of physical activity. Males require chronic daily physical activity to attain a similar mitochondrial phenotype compared to females. In contrast, females have limited hepatic adaptations to chronic physical activity. Livers deficient in PGC1α and BNIP3 display similar mitochondrial adaptations to physical activity as those found in wild type mice.
ABSTRACT: Hepatic mitochondrial adaptations to physical activity may be regulated by biogenesis- and mitophagy-associated pathways in a sex-dependent manner. Here, we tested if mice with targeted deficiencies in liver-specific PGC1α (LPGC1α+/- ) and BNIP3-mediated mitophagy (BNIP3-/- ) would have reduced physical activity induced adaptations in respiratory capacity, H2 O2 emission, and mitophagy compared to wild type (WT) controls and if these effects were impacted by sex. Male and female WT, LPGC1α+/- , and BNIP3-/- C57BL6/J mice were divided into groups that remained sedentary (SED) or had access to daily physical activity via voluntary running wheels (VWR) (n = 6-10/group) for 4 weeks. Mice had ad libitum access to low-fat diet and water. VWR reduced basal mitochondrial respiration, increased mitochondrial coupling and altered ubiquitin-mediated mitophagy in a sex-specific manner in WT mice. Female mice in all genotypes displayed higher electron transport system content, increased ADP-stimulated respiration, produced less mitochondrial derived ROS, exhibited reduced mitophagic flux, and were less responsive to VWR compared to males. Males responded more robustly to VWR-induced changes in hepatic mitochondrial function resulting in a match to adaptations found in females. Deficiencies in PGC1α and BNIP3 alone did not largely alter mitochondrial adaptations to VWR. However, VWR restored sex-dependent abnormalities in mitophagic flux in LPGC1α+/- . Finally, BNIP3-/- mice had elevated mitochondrial content and increased mitochondrial respiration putatively through repressed mitophagic flux. In conclusion, mitochondrial adaptations to physical activity are more dependent on sex than PGC1α and BNIP3. This article is protected by copyright. All rights reserved.

PMID: 30062822 [PubMed - as supplied by publisher]

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Entrepreneurialism in the Translational Biologic Sciences: Why, How, and However.

JACC Basic Transl Sci. 2018 Feb;3(1):1-8

Authors: Bristow MR, Leinwand LA, Olson EN

Abstract
Because they are perceived as distinct from the biological sciences, entrepreneurial pursuits may be daunting to the average researcher. In this report, we explain why academic scientists and in particular translational researchers should be naturally as well as rationally attracted to entrepreneurial endeavors. We go into some detail of how entrepreneurial achievements are actually accomplished and offer a few caveats for consideration when embarking down entrepreneurial pathways. We conclude that, although not for everyone, for translational investigators in the biologic sciences, entrepreneurial pursuits are desirable, accomplishable, and professionally rewarding.

PMID: 30062188 [PubMed]

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Two common mutations within CYP2C19 affected platelet aggregation in Chinese patients undergoing PCI: a one-year follow-up study.

Pharmacogenomics J. 2018 Jul 31;:

Authors: Wang Z, Liu Z, Wang W, Fu Y, Chen W, Li W, Zhang X, Tang Y, Zhou Z

Abstract
The effect of dual antiplatelet therapy, clopidogrel combined with aspirin, was influenced by CYP2C19 gene mutation and heterogeneity of population. Related studies remained controversial and limited, especially in Chinese. Total 3295 unrelated ACS Chinese patients undergoing percutaneous coronary intervention (PCI) were recruited and followed up to 1 year. Meanwhile, baseline and clinical data were retrieved. CYP2C19*2 and *3 were genotyped by sequencing. Associations of variants and metabolic types with platelet reactivity (PR) were analyzed by a logistic regression model. And, a Cox proportional hazards model was utilized to analyze survival data. Confounders included gender, age, smoking status, dosage of aspirin and clopidogrel, and BMI. It was found that patients with allele A in CYP2C19*2 and *3 were susceptibility to high PR (OR, 95%CI and P values were 1.34, 1.20-1.50, <0.0001 and 1.42, 1.13-1.79, 0.0029, respectively) after taking clopidogrel. The PR increased along with the number of loss of function (LOF) allele increased and did in order of haplotype*1, *2, and *3. This research suggested that LOF alleles and risk haplotypes in CYP2C19 could significantly attenuate the response to clopidogrel, which resulted in platelet aggregation.

PMID: 30061570 [PubMed - as supplied by publisher]

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Pharmacogenetics of ugt genes in North African populations.

Pharmacogenomics J. 2018 Jul 31;:

Authors: Gaibar M, Novillo A, Romero-Lorca A, Esteban ME, Fernández-Santander A

PMID: 30061569 [PubMed - as supplied by publisher]

Further delineation of spondyloepimetaphyseal dysplasia Faden-Alkuraya type: A RSPRY1-associated spondylo-epi-metaphyseal dysplasia with cono-brachydactyly and craniosynostosis.

Am J Med Genet A. 2018 Jul 31;:

Authors: Simsek-Kiper PO, Taskiran EZ, Kosukcu C, Urel-Demir G, Akgun-Dogan O, Yilmaz G, Utine GE, Nishimura G, Boduroglu K, Alikasifoglu M

Abstract
Our understanding of the molecular basis of the genetic disorders of the skeleton has steadily increased, as the application of high-throughput sequencing technology has expanded. One of the newcomers is Spondyloepimetaphyseal dysplasia Faden-Alkuraya type. In this study, we aimed to further delineate the clinical, radiographic, and molecular findings of this entity in five affected individuals from two unrelated families. All patients have short stature, extremity deformities, facial dysmorphism and intellectual disability. The skeletal hallmarks include (a) mild spondylar dysplasia, (b) epimetaphyseal dysplasia of the long bones associated with coxa vara and genu valgum, (c) brachymesophalangy with cone-shaped epiphyses, and (d) craniosynostosis. Unlike the previously reported clinical findings, all patients except one are normocephalic, and all share the clinical findings including craniosynostosis, varying degrees of intellectual disability, facial dysmorphism, and skeletal findings including pes planus, prominent heels, and pectus deformity. Interestingly one of the patients presented with a cemento-ossifying fibrous lesion of the maxilla. Whole exome sequencing revealed a novel homozygous [c.377delT] [p.Ile126fs*] frameshift mutation at exon 2 in one family, while Sanger sequencing revealed a novel homozygous splice site mutation [c.516+2T>A] at exon 4/intron 4 border of RSPRY1 in the other family. In conclusion; we provide further evidence that Spondyloepimetaphyseal dysplasia Faden-Alkuraya type is a RSPRY1-associated skeletal dysplasia with a distinctive phenotype composed of spondyloepimetaphyseal dysplasia, cono-brachydactyly, and craniosynostosis along with recognizable facial features and intellectual disability.

PMID: 30063090 [PubMed - as supplied by publisher]

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Detection of variants in dystroglycanopathy-associated genes through the application of targeted whole-exome sequencing analysis to a large cohort of patients with unexplained limb-girdle muscle weakness.

Skelet Muscle. 2018 07 30;8(1):23

Authors: Johnson K, Bertoli M, Phillips L, Töpf A, Van den Bergh P, Vissing J, Witting N, Nafissi S, Jamal-Omidi S, Łusakowska A, Kostera-Pruszczyk A, Potulska-Chromik A, Deconinck N, Wallgren-Pettersson C, Strang-Karlsson S, Colomer J, Claeys KG, De Ridder W, Baets J, von der Hagen M, Fernández-Torrón R, Zulaica Ijurco M, Espinal Valencia JB, Hahn A, Durmus H, Willis T, Xu L, Valkanas E, Mullen TE, Lek M, MacArthur DG, Straub V

Abstract
BACKGROUND: Dystroglycanopathies are a clinically and genetically heterogeneous group of disorders that are typically characterised by limb-girdle muscle weakness. Mutations in 18 different genes have been associated with dystroglycanopathies, the encoded proteins of which typically modulate the binding of α-dystroglycan to extracellular matrix ligands by altering its glycosylation. This results in a disruption of the structural integrity of the myocyte, ultimately leading to muscle degeneration.
METHODS: Deep phenotypic information was gathered using the PhenoTips online software for 1001 patients with unexplained limb-girdle muscle weakness from 43 different centres across 21 European and Middle Eastern countries. Whole-exome sequencing with at least 250 ng DNA was completed using an Illumina exome capture and a 38 Mb baited target. Genes known to be associated with dystroglycanopathies were analysed for disease-causing variants.
RESULTS: Suspected pathogenic variants were detected in DPM3, ISPD, POMT1 and FKTN in one patient each, in POMK in two patients, in GMPPB in three patients, in FKRP in eight patients and in POMT2 in ten patients. This indicated a frequency of 2.7% for the disease group within the cohort of 1001 patients with unexplained limb-girdle muscle weakness. The phenotypes of the 27 patients were highly variable, yet with a fundamental presentation of proximal muscle weakness and elevated serum creatine kinase.
CONCLUSIONS: Overall, we have identified 27 patients with suspected pathogenic variants in dystroglycanopathy-associated genes. We present evidence for the genetic and phenotypic diversity of the dystroglycanopathies as a disease group, while also highlighting the advantage of incorporating next-generation sequencing into the diagnostic pathway of rare diseases.

PMID: 30060766 [PubMed - in process]

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CASP9 germline mutation in a family with multiple brain tumors.

Brain Pathol. 2018 Jan;28(1):94-102

Authors: Ronellenfitsch MW, Oh JE, Satomi K, Sumi K, Harter PN, Steinbach JP, Felsberg J, Capper D, Voegele C, Durand G, McKay J, Le Calvez-Kelm F, Schittenhelm J, Klink B, Mittelbronn M, Ohgaki H

Abstract
We report a novel CASP9 germline mutation that may increase susceptibility to the development of brain tumors. We identified this mutation in a family in which three brain tumors had developed within three generations, including two anaplastic astrocytomas occurring in cousins. The cousins were diagnosed at similar ages (29 and 31 years), and their tumors showed similar histological features. Genetic analysis revealed somatic IDH1 and TP53 mutations in both tumors. However, no germline TP53 mutations were detected, despite the fact that this family fulfills the criteria of Li-Fraumeni-like syndrome. Whole exome sequencing revealed a germline stop-gain mutation (R65X) in the CASP9 gene, which encodes caspase-9, a key molecule for the p53-dependent mitochondrial death pathway. This mutation was also detected in DNA extracted from blood samples from the two siblings who were each a parent of one of the affected cousins. Caspase-9 immunohistochemistry showed the absence of caspase-9 immunoreactivity in the anaplastic astrocytomas and normal brain tissues of the cousins. These observations suggest that CASP9 germline mutations may have played a role at least in part to the susceptibility of development of gliomas in this Li-Fraumeni-like family lacking a TP53 germline mutation.

PMID: 27935156 [PubMed - indexed for MEDLINE]

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Funding Opportunity RFA-HL-18-035 from the NIH Guide for Grants and Contracts. The National Institutes of Health (NIH), participating NIH Institutes and Centers, in coordination with the U.S. Food and Drug Administration, invite cooperative agreement (U44) applications to support small business research studies aimed at furthering the field of regenerative medicine (RM) using adult stem cells. These applications are expected to focus on innovative projects that propose solutions to widely recognized issues in the development of safe and effective RM therapies. Emphasis will be given to projects that address critical issues in product development relevant for regulatory submissions. Areas of focus may include improved tools, methods, standards, or applied science that support a better understanding and improved evaluation of in-depth product characterization, manufacturing, potency, identity, quality, safety, in vivo function and integration, or effectiveness. Toward these ends, the NIH will consider applications for late stage preclinical research studies involving adult stem cells in the context of generating or supplementing the necessary evidence for clinical development, including, but not limited to, the submission of an Investigational New Drug (IND) or Investigational New Device Exemption (IDE) package; or to support such research conducted under an authorized IND or IDE.

Funding Opportunity RFA-HL-18-033 from the NIH Guide for Grants and Contracts. The National Institutes of Health (NIH), participating NIH Institutes and Centers, in coordination with the U.S. Food and Drug Administration, invite cooperative agreement (UT2) applications to support small business research studies aimed at furthering the field of regenerative medicine (RM) using adult stem cells. These applications are expected to focus on innovative projects that propose solutions to widely recognized issues in the development of safe and effective RM therapies. Emphasis will be given to projects that address critical issues in product development relevant for regulatory submissions. Areas of focus may include improved tools, methods, standards, or applied science that support a better understanding and improved evaluation of in-depth product characterization, manufacturing, potency, identity, quality, safety, in vivo function and integration, or effectiveness. Toward these ends, the NIH will consider applications for late stage preclinical research studies involving adult stem cells in the context of generating or supplementing the necessary evidence for clinical development, including, but not limited to, the submission of an Investigational New Drug (IND) or Investigational New Device Exemption (IDE) package; or to support such research conducted under an authorized IND or IDE.

Funding Opportunity RFA-HL-18-031 from the NIH Guide for Grants and Contracts. The National Institutes of Health (NIH), participating NIH Institutes and Centers, in coordination with the U.S. Food and Drug Administration, invite exploratory/developmental phased award cooperative agreement (UG3/UH3) applications to support investigator-initiated clinical trials (Phase I or later phase) aimed at furthering the field of regenerative medicine (RM) using adult stem cells. These applications are expected to focus on innovative projects that propose solutions to widely recognized issues in the development of safe and effective RM therapies. Emphasis will be given to projects that use RM products with demonstrated readiness to be advanced into clinical trials through appropriate product development and pre-clinical studies. Trials for which this FOA applies must be relevant to the research mission of one or more participating NIH Institutes and Centers and meet the NIH definition of a clinical trial (see NOT-OD-15-015). This FOA utilizes a bi-phasic, milestone-driven cooperative agreement mechanism of award. This FOA seeks applications that present a strong scientific rationale for the clinical trial and a comprehensive scientific and operational plan. It is anticipated that applications will consist of plans for project management, subject recruitment and retention, performance milestones, scientific conduct of the trial, data sharing, and dissemination of results. Before the time of award and if applicable, successful applicants must obtain an Investigational New Drug (IND) or Investigational New Device Exemption (IDE) application authorization or approval, respectively, to administer the product to humans. Due to the complex nature of conducting a clinical trial, applicants are strongly encouraged to contact the appropriate Scientific/Research contact prior to submitting an application. Staff will be able to assist applicants in meeting the objectives of this FOA.

Funding Opportunity RFA-HL-18-030 from the NIH Guide for Grants and Contracts. The National Institutes of Health (NIH) participating Institutes and Centers, in coordination with the U.S. Food and Drug Administration, invite cooperative agreement (U01) applications to support investigator-initiated clinical research studies aimed at furthering the field of regenerative medicine (RM) using adult stem cells. These applications are expected to focus on innovative projects that propose solutions to widely recognized issues in the development of safe and effective RM therapies. Emphasis will be given to projects that address critical issues in product development relevant for regulatory submissions. Areas of focus may include improved tools, methods, standards, or applied science that support a better understanding and improved evaluation of in-depth product characterization, manufacturing, potency, identity, quality, safety, in vivo function and integration, or effectiveness. Toward these ends, the NIH will consider applications for late-stage preclinical research studies involving adult stem cells in the context of generating or supplementing the necessary evidence for clinical development, including, but not limited to, the submission of an Investigational New Drug (IND) or Investigational New Device Exemption (IDE) package; or to support such research conducted under an authorized IND or IDE.

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