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A novel PAX1 null homozygous mutation in autosomal recessive otofaciocervical syndrome associated with severe combined immunodeficiency.

Clin Genet. 2017 Dec;92(6):664-668

Authors: Paganini I, Sestini R, Capone GL, Putignano AL, Contini E, Giotti I, Gensini F, Marozza A, Barilaro A, Porfirio B, Papi L

Abstract
Otofaciocervical syndrome (OFCS) is a rare disorder characterized by facial anomalies, cup-shaped low-set ears, preauricular fistulas, hearing loss, branchial defects, skeletal anomalies, and mild intellectual disability. Autosomal dominant cases are caused by deletions or point mutations of EYA1. A single family with an autosomal recessive form of OFCS and a homozygous missense mutation in PAX1 gene has been described. We report whole exome sequencing of 4 members of a consanguineous family in which 2 children, showing features of OFCS, expired from severe combined immunodeficiency (SCID). To date, the co-occurrence of OFCS and SCID has never been reported. We found a nonsense homozygous mutation in PAX1 gene in the 2 affected children. In mice, Pax1 is required for the formation of specific skeletal structures as well as for the development of a fully functional thymus. The mouse model strongly supports the hypothesis that PAX1 depletion in our patients caused thymus aplasia responsible for SCID. This report provides evidence that bi-allelic null PAX1 mutations may lead to a multi-system autosomal recessive disorders, where SCID might represent the main feature.

PMID: 28657137 [PubMed - indexed for MEDLINE]

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Acute myeloid leukaemia in a case with Tatton-Brown-Rahman syndrome: the peculiar DNMT3A R882 mutation.

J Med Genet. 2017 Dec;54(12):805-808

Authors: Hollink IHIM, van den Ouweland AMW, Beverloo HB, Arentsen-Peters STCJM, Zwaan CM, Wagner A

Abstract
BACKGROUND: Recently a novel syndromic form of overgrowth with intellectual disability and distinct facial features was identified caused by constitutional mutations in the epigenetic regulator DNA-methyltransferase 3A (DNMT3A), referred to as Tatton-Brown-Rahman syndrome (TBRS). Somatically acquired mutations in DNMT3A occur in haematological malignancies and are frequently present in acute myeloid leukaemia (AML) affecting in more than 50% the arginine residue at position 882 (R882). To date, additional cases with TBRS have been published but so far none of the reported cases with TBRS developed AML.
METHODS AND RESULTS: Here we present the first case of TBRS who developed AML at the age of 15 years. Whole-exome sequencing identified a constitutional heterozygous DNMT3A R882C mutation. Our case exhibits macrocephaly, intellectual disability, distinct facial dysmorphism and other recurrent features fitting with the TBRS phenotype. The AML of the myelomonocytic subtype harboured only few additional somatically acquired mutations, that is, an aberrant karyotype and a recurrent PTPN11 mutation.
DISCUSSION: The peculiarity of the specific R882 mutation in contrast to other DNMT3A mutations is discussed, including the hypothesis of the more aggressive nature of this variant.Our case represents the first evidence of the possible increased risk of the development of haematological malignancies in particular AML in cases with TBRS.

PMID: 28432085 [PubMed - indexed for MEDLINE]

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Novel mutations in the SEC24D gene in Chinese families with autosomal recessive osteogenesis imperfecta.

Osteoporos Int. 2017 Apr;28(4):1473-1480

Authors: Zhang H, Yue H, Wang C, Gu J, He J, Fu W, Hu W, Zhang Z

Abstract
We sought to characterize the phenotypes and identify the SEC24D gene mutations associated with Chinese families of osteogenesis imperfecta (OI). Using whole-exome sequencing, we discovered two novel compound SEC24D mutations of OI patients. Our study extended both the phenotypic and the genotype of the OI patients with SEC24D mutations.
INTRODUCTION: To date, only three compound heterozygous mutations in the SEC24D gene have been found to cause recessively inherited forms of OI. We sought to characterize the phenotypes and to identify the SEC24D gene mutations associated with Chinese families with OI.
METHODS: Using whole-exome sequencing in two probands, we identified two novel compound heterozygous mutations in SEC24D. In family 1, the proband was a 23-year-old male; he had recurrent fractures and dentinogenesis imperfecta. His anterior fontanel was not closed, and he showed facial dysmorphism. A computed tomography three-dimensional imaging of the cranium showed skull deformities associated with a broad ossification defect in the frontoapical area, a widened sagittal suture, and Wormian bones. In family 2, the proband was a 7-year-old boy, who also had recurrent fractures and dentinogenesis imperfecta. His anterior fontanel was not closed, and he did not have obvious facial dysmorphism.
RESULTS: We identified one novel compound heterozygous missense substitution in the proband in family 1, including c.2723G>A (p. Cys908Tyr) and c.2842T>C (p. Ser948Pro). In the proband in family 2, we identified another novel compound heterozygous missense substitution, including c.938G>A (p. Arg313His) and c.875C>T (p. Pro292Leu).
CONCLUSIONS: We discovered two novel compound SEC24D mutations of autosomal recessive OI patients. Our study extended both the phenotypic and the genotypic spectrum of the autosomal recessive OI patients with SEC24D mutations.

PMID: 27942778 [PubMed - indexed for MEDLINE]

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Immediate hypersensitivity to penicillins. Identification of a new antigenic determinant.

J Pharm Biomed Anal. 2018 Jan 30;148:17-23

Authors: Matas S, Broto M, Corominas M, Lleonart R, Babington R, Marco MP, Galve R

Abstract
The study of adverse drug reactions (ADRs) constitutes a challenge in the area of Medicine. Drugs generate a large number of the total registered hypersensitivity reactions, where penicillins are responsible for more than half of them. In vitro tests in the market are not efficient enough since they lack in sensitivity and specificity. This is the reason why in vivo tests are carried out, with the subsequent danger to the patient's life. It is essential to discover new β-lactam antigenic determinants to develop more effective detection systems and thus, obtain better explanations of the allergic mechanisms related to these drugs. We propose a strategy based on the use of "peptide probes", small labeled and chemical active peptides which have been structurally modified for reacting with the β-lactam moiety at different conditions. The probes also contain a biotin group for application in an immunoassay format. Three different amoxicillin adducts have been obtained, purified and characterized by HPLC-MS and NMR techniques. These results have helped us to elucidate and propose a new antigenic determinant for β-lactams, named the "penamidyl" epitope. All the adducts have been validated and evaluated with sera from different penicillin allergic patients by means of a Magneto-ELISA, immunochemical technique that has allowed us to detect specific IgEs in a very high percentage of the serum samples. An immunoassay has been developed, validated and applied as a diagnostic tool for the detection of specific IgEs in the sera of penicillin allergic patients using a new antigenic determinant.

PMID: 28987997 [PubMed - indexed for MEDLINE]

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Prescribing cascade. A proposed new way to evaluate it.

Medicina (B Aires). 2017;77(1):13-16

Authors: Ponte ML, Wachs L, Wachs A, Serra HA

Abstract
Prescribing cascade is defined as the situation in which a first drug administered to a patient causes adverse event signs and symptoms, that are misinterpreted as a new condition, resulting in a new medication being prescribed. The cascade may have multiple steps and differ in complexity and severity. Despite being well identified, prescribing cascade is an increasingly common problem in medical practice. It constitutes a warning about irrational use of medicines that puts health at risk and increases treatment costs if it is not taken into account. In this article, representative cases taken from Hospital General de Agudos Dr. Cosme Argerich pharmacovigilance database were selected to assess a proper score and an algorithm that define the probable prescribing cascade.

PMID: 28140305 [PubMed - indexed for MEDLINE]

Funding Opportunity RFA-ES-18-008 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) solicits Phase I (R43) Small Business Innovative Research (SBIR) grant applications from small business concerns (SBCs) to develop and/or adapt novel technologies to enable the characterization of human exposures to engineered nanomaterials (ENMs) and to monitor or assess ENMs in diverse media ranging from biological samples to air and water.

Notice NOT-CA-18-089 from the NIH Guide for Grants and Contracts

Notice NOT-GM-18-038 from the NIH Guide for Grants and Contracts

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

Funding Opportunity RFA-DC-19-001 from the NIH Guide for Grants and Contracts. This funding opportunity announcement (FOA) encourages Exploratory/Developmental Phased Innovation (R21/R33) grant applications to support research and/or infrastructure needs in emerging scientific areas leading to more accessible and affordable hearing health care for adults with mild to moderate hearing loss. The proposed research aims should be milestone-driven and lead to better hearing healthcare, targeting enhanced access and affordability, in an effort to improve outcomes for adults with hearing loss. The total project period for an application submitted in response to this FOA may not exceed five years. This FOA provides support for up to two years (R21 phase) for preliminary/developmental studies, followed by possible transition of up to four years of expanded research and development support (R33). This FOA requires measurable R21 milestones.

Funding Opportunity RFA-AI-18-037 from the NIH Guide for Grants and Contracts. The objectives of this Funding Opportunity Announcement are to promote research to: 1) understand the critical drivers of TB transmission at the individual and population levels in high-burden settings, particularly where high incidence of HIV co-infection contributes to TB rates. (This may include the aerobiology of infectious particles and environmental- and population-based factors.) 2) develop potential interventions to prevent TB transmission in HIV-endemic and other high-transmission settings and to measure the rate of transmission underpinned by an increased understanding of the biomedical basis of transmission and related risk factors.

Notice NOT-HD-18-012 from the NIH Guide for Grants and Contracts

Notice NOT-OD-18-202 from the NIH Guide for Grants and Contracts

Funding Opportunity RFA-MH-19-101 from the NIH Guide for Grants and Contracts. This NIMH Research Career Enhancement Award (K18) program invites applications from experienced investigators seeking to redirect or expand their research programs through the acquisition of new skills and knowledge in areas beyond and complementary to their current areas of expertise. The program will support research training and career development experiences and a small-scale research project that will provide experienced investigators with the scientific competencies required to conduct research relevant to services for adults and transition-age youth with Autism Spectrum Disorders. Eligible candidates are independent investigators at any faculty rank or level. This Funding Opportunity Announcement (FOA) is designed specifically for applicants proposing to serve as the lead investigator of an independent clinical trial, a clinical trial feasibility study, or a separate ancillary study to an existing trial, as part of their research and career development. Applicants not planning an independent clinical trial, or proposing to gain research experience in a clinical trial led by another investigator, must apply to companion FOA (FOA #).

Funding Opportunity RFA-MH-19-100 from the NIH Guide for Grants and Contracts. This NIMH Research Career Enhancement Award (K18) program invites applications from experienced investigators seeking to redirect or expand their research programs through the acquisition of new skills and knowledge in areas beyond and complementary to their current areas of expertise. The program will support research training and career development experiences and a small-scale research project that will provide experienced investigators with the scientific competencies required to conduct research relevant to services for adults and transition-age youth with Autism Spectrum Disorders. Eligible candidates are independent investigators at any faculty rank or level. This Funding Opportunity Announcement (FOA) is designed specifically for applicants proposing research that does not involve leading an independent clinical trial, a clinical trial feasibility study, or an ancillary study to a clinical trial. Applicants to this FOA are permitted to propose research experience in a clinical trial led by a mentor or co-mentor. Applicants proposing a clinical trial or an ancillary study to an ongoing clinical trial as lead investigator, should apply to the companion FOA RFA-MH-19-101.

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Drug repositioning, a new alternative in infectious diseases.

Braz J Infect Dis. 2018 Jun 28;:

Authors: Serafin MB, Hörner R

PMID: 29963991 [PubMed - as supplied by publisher]

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"Hard" Drug Repurposing for Precision Oncology: The Missing Link?

Front Pharmacol. 2018;9:637

Authors: Pantziarka P, Bouche G, André N

PMID: 29962954 [PubMed]

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Copper Complexes in Cancer Therapy.

Met Ions Life Sci. 2018 02 05;18:

Authors: Denoyer D, Clatworthy SAS, Cater MA

Abstract
Copper homeostasis is tightly regulated in both prokaryotic and eukaryotic cells to ensure sufficient amounts for cuproprotein biosynthesis, while limiting oxidative stress production and toxicity. Over the last century, copper complexes have been developed as antimicrobials and for treating diseases involving copper dyshomeostasis (e.g., Wilson's disease). There now exists a repertoire of copper complexes that can regulate bodily copper through a myriad of mechanisms. Furthermore, many copper complexes are now being appraised for a variety of therapeutic indications (e.g., Alzheimer's disease and amyotrophic lateral sclerosis) that require a range of copper-related pharmacological affects. Cancer therapy is also drawing considerable attention since copper has been recognized as a limiting factor for multiple aspects of cancer progression including growth, angiogenesis, and metastasis. Consequently, 'old copper complexes' (e.g., tetrathiomolybdate and clioquinol) have been repurposed for cancer therapy and have demonstrated anticancer activity in vitro and in preclinical models. Likewise, new tailor-made copper complexes have been designed based on structural and biological features ideal for their anticancer activity. Human clinical trials continue to evaluate the therapeutic efficacy of copper complexes as anticancer agents and considerable progress has been made in understanding their pharmacological requirements. In this chapter, we present a historical perspective on the main copper complexes that are currently being repurposed for cancer therapy and detail several of the more recently developed compounds that have emerged as promising anticancer agents. We further provide an overview of the known mechanisms of action, including molecular targets and we discuss associated clinical trials.

PMID: 29394035 [PubMed - indexed for MEDLINE]