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- Abstract: Birth defect x
- Abstract: Drugs x
Department of Analysis, Universidade Federal do Rio Grande do Sul (UFRGS), School of Pharmacy, Porto Alegre, RS, Brazil
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Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil
Department of Pediatrics, Universidade Federal do Rio Grande do Sul (UFRGS), Medical School, Porto Alegre, RS, Brazil
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Congenital adrenal hyperplasia (CAH) occurs due to enzyme defects in adrenal steroidogenesis. The 21-hydroxylase deficiency accounts for 90–95% of cases, triggering accumulation of 17-hydroxyprogesterone (17-OHP). Early diagnosis through neonatal screening allows adequate treatment and reduced mortality. The purpose of the study was to determine 17-OHP cutoffs for the diagnosis of CAH in a public newborn screening program in Southern Brazil. A retrospective, descriptive, cross-sectional study was conducted to analyze 17-OHP levels in dried blood samples collected on filter paper of 317,745 newborns screened at a public newborn screening center from May 2014 to April 2017. Neonatal 17-OHP was measured in DBS samples using a time-resolved fluoroimmunoassay (GSP® kit 3305-0010; PerkinElmer). Different cutoffs were determined and stratified by birth weight. The incidence of CAH was 1:15,887 live births in the state of Rio Grande do Sul, with 20 cases of classical CAH diagnosed during the study period. Most newborns (80.73%) were white, and the prematurity rate was 9.8% in the study population. The combination of different percentiles, 98.5th for birth weight 2001–2500 g and 99.8th for the other birth weight groups, decreased false-positive results and increased specificity compared with current reference values to identify classical CAH cases. The local 17-OHP cutoffs determined were higher than those currently used by this screening program for all birth weight groups. The calculation of reference values from local population data and the combination of percentiles proved to be a valuable tool for proper diagnosis of CAH and reduction in the number of false positives.
European Institute for Molecular Imaging (EIMI), University of Münster, Münster, Germany
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Objective
Anaplastic thyroid cancer (ATC) is one of the most lethal human cancers with meager treatment options. We aimed to identify the targeted drugs already approved by the Food and Drug Administration (FDA) for solid cancer in general, which could be effective in ATC.
Design
Database mining.
Methods
FDA-approved drugs for targeted therapy were identified by screening the databases of MyCancerGenome and the National Cancer Institute. Drugs were linked to the target genes by querying Drugbank. Subsequently, MyCancerGenome, CIViC, TARGET and OncoKB were mined for genetic alterations which are predicted to lead to drug sensitivity or resistance. We searched the Cancer Genome Atlas database (TCGA) for patients with ATC and probed their sequencing data for genetic alterations which predict a drug response.
Results
In the study,155 FDA-approved drugs with 136 potentially targetable genes were identified. Seventeen (52%) of 33 patients found in TCGA had at least one genetic alteration in targetable genes. The point mutation BRAF V600E was seen in 45% of patients. PIK3CA occurred in 18% of cases. Amplifications of ALK and SRC were detected in 3% of cases, respectively. Fifteen percent of the patients displayed a co-mutation of BRAF and PIK3CA. Besides BRAF-inhibitors, the PIK3CA-inhibitor copanlisib showed a genetically predicted response. The 146 (94%) remaining drugs showed no or low (under 4% cases) genetically predicted drug response.
Conclusions
While ATC carrying BRAF mutations can benefit from BRAF inhibitors and this effect might be enhanced by a combined strategy including PIK3CA inhibitors in some of the patients, alterations in BRAFWT ATC are not directly targeted by currently FDA-approved options.
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The terms ‘idiopathic short stature’ (ISS) and ‘small for gestational age’ (SGA) were first used in the 1970s and 1980s. ISS described non-syndromic short children with undefined aetiology who did not have growth hormone (GH) deficiency, chromosomal defects, chronic illness, dysmorphic features or low birth weight. Despite originating in the pre-molecular era, ISS is still used as a diagnostic label today. The term ‘SGA’ was adopted by paediatric endocrinologists to describe children born with low birth weight and/or length, some of whom may experience lack of catch-up growth and present with short stature. GH treatment was approved by the FDA for short children born SGA in 2001, and by the EMA in 2003, and for the treatment of ISS in the US, but not Europe, in 2003. These approvals strengthened the terms ‘SGA’ and ‘ISS’ as clinical entities. While clinical and hormonal diagnostic techniques remain important, it is the emergence of genetic investigations that have led to numerous molecular discoveries in both ISS and SGA subjects. The primary message of this article is that the labels ISS and SGA are not definitive diagnoses. We propose that the three disciplines of clinical evaluation, hormonal investigation and genetic sequencing should have equal status in the hierarchy of short stature assessments and should complement each other to identify the true pathogenesis in poorly growing patients.
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Neuroendocrinology Division – Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, Brazil
Endocrinology Division – Hospital Federal de Bonsucesso, Rio de Janeiro Brazil
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Neuroendocrinology Division – Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, Brazil
Neuropatology and Molecular Genetics Laboratory – Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, Brazil
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Acromegaly is a systemic disease associated with increased morbidity and mortality. Most of these comorbidities can be prevented or delayed with adequate disease treatment. Although three modalities of treatment (surgery, medical treatment, and radiotherapy) are available and new drugs were approved in the last decades, there are still some patients that maintain disease activity despite treatment. Therefore, there is a need for novel therapies for acromegaly and for that purpose new formulations of currently used drugs and also new drugs are currently under study. In this review, we summarize the novel therapies for acromegaly.
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To optimize the treatment plan for patients with type 2 diabetes mellitus (T2DM) and hyperuricemia, this narrative literature review summarizes the effect of antidiabetic drugs on serum uric acid (SUA) levels using data from observational studies, prospective clinical trials, post hoc analyses, and meta-analyses. SUA is an independent risk factor for T2DM, and evidence has shown that patients with both gout and T2DM exhibit a mutually interdependent effect on higher incidences. We find that insulin and dipeptidyl peptidase 4 inhibitor (DPP-4i) except linagliptin could increase the SUA and other drugs including metformin, thiazolidinediones (TZDs), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), linagliptin, sodium–glucose cotransporter 2 inhibitors (SGLT2i), and α-glucosidase inhibitors have a reduction effect on SUA. We explain the mechanisms of different antidiabetic drugs above on SUA and analyze them compared with actual data. For sulfonylureas, meglitinides, and amylin analogs, the underlying mechanism remains unclear. We think the usage of linagliptin and SGLT2i is the most potentially effective treatment of patients with T2DM and hyperuricemia currently. Our review is a comprehensive summary of the effects of antidiabetic drugs on SUA, which includes actual data, the mechanisms of SUA regulation, and the usage rate of drugs.
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Turner syndrome (TS), although considered a rare disease, is the most common sex chromosome abnormality in women, with an incident of 1 in 2500 female births. TS is characterized by distinctive physical features such as short stature, ovarian dysgenesis, an increased risk for heart and renal defects as well as a specific cognitive and psychosocial phenotype. Given the complexity of the condition, patients face manifold difficulties which increase over the lifespan. Furthermore, failures during the transitional phase to adult care result in moderate health outcomes and decreased quality of life. Guidelines on the optimal screening procedures and medical treatment are easy to find. However, recommendations for the treatment of the incriminating psychosocial aspects in TS are scarce. In this work, we first reviewed the literature on the cognitive and psychosocial development of girls with TS compared with normal development, from disclosure to young adulthood, and then introduce a psychosocial approach to counseling and treating patients with TS, including recommendations for age-appropriate psychological diagnostics. With this work, we aim to facilitate the integration of emphasized psychosocial care in state-of-the-art treatment for girls and women with TS.
Department of Health Sciences, University of Florence, Florence, Italy
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NEUROFARBA Department, University of Florence, Florence, Italy
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Department of Clinical and Experimental Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
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Department of Health Sciences, University of Florence, Florence, Italy
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Context
Cytochrome C oxidase (COX) is the fourth component of the respiratory chain and is located within the internal membrane of mitochondria. COX deficiency causes an inherited mitochondrial disease with significant genetic and phenotypic heterogeneity. Four clinical subtypes have been identified, each with distinct phenotypes and genetic variants. Mitochondrial complex IV deficiency nuclear type 4 (MC4DN4) is a form of COX deficiency associated with pathogenic variants in the SCO1 gene.
Case description
We describe three patients with MC4DN4 with developmental and epileptic encephalopathy (DEE), hypopituitarism, and SCO1 pathogenic variants. These patients’ phenotypes considerably differ from previously reported MC4DN4 phenotypes as they associate DEE with progressive hypopituitarism and survival beyond the first months after birth. Pituitary deficiency in these patients progressively worsened and mainly involved growth hormone secretion and thyroid function.
Conclusions
Our findings expand knowledge of phenotypic variability in MC4DN4 and suggest that SCO1 is a candidate gene for genetic hypopituitarism and DEE.
Significance statement
Our paper describes three patients affected by MC4DN4 with hypopituitarism and developmental and epileptic encephalopathy (DEE), two features that have never been associated with this condition. In addition, we reviewed the clinical features of all previous cases of MC4DN4 to give the other clinicians a wide picture of the clinical phenotype of this genetic disease. We hope that the publication of our data may help others to identify this disease and consider the chance to analyze the SCO1 gene in cases of DEE associated with pituitary dysfunction. Our article contributes to expanding the spectrum of genetic hypopituitarism and proposes a model to explain an association between this condition, mitochondrial anomalies, and neurodevelopmental defects.
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Preclinical trials of medullary thyroid cancer (MTC) therapeutics require both in vitro and in vivo analyses. Human tumour xenografted rodent models, which are considered the ‘gold standard’ to study and validate the efficacy and toxicity of lead compounds before translation to clinical trials, are very expensive, subject to organismal variability and ethical controversies. The avian chorioallantoic membrane (CAM) assay provides an alternative versatile, cost-effective and ethically less objectionable short-term, in vivo model for reliable screening of drugs. In this work, we grafted two MTC cell lines and patient-derived MTC tumour samples onto the avian CAM and characterised the resulted tumours histologically and immunohistochemically. Our findings provide the evidence that the CAM assay is a suitable model for studying the pathophysiology of MTC and can even be used as in vivo system for drug testing.
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In patients with type 2 diabetes mellitus (T2DM), the intestinal flora is out of balance and accompanied by leaky gut. The flora is characterized by an increase in mucus-degrading bacteria and a decrease in fiber-degrading bacteria. Short-chain fatty acids (SCFAs), as the major fiber-degrading bacteria fermentation, not only ameliorate the leaky gut, but also activate GPR43 to increase the mass of functional pancreatic β-cells and exert anti-inflammation effect. At present, the gut microbiota is considered as the potential target for anti-diabetes drugs, and how to reverse the imbalance of gut microbiota has become a therapeutic strategy for T2DM. This review briefly summarizes the drugs or compounds that have direct or potential therapeutic effects on T2DM by modulating the gut microbiota, including biguanides, isoquinoline alkaloids, stilbene and C7N-aminocyclic alcohols.
Dipartimento di Medicina Clinica e Chirurgia, Università Federico II, Naples, Italy
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Adrenocortical carcinomas (ACCs) are rare tumors with scant treatment options for which new treatments are required. The mTOR pathway mediates the intracellular signals of several growth factors, including the insulin-like growth factors (IGFs), and therefore represents a potential attractive pathway for the treatment of several malignancies including ACCs. Several mTOR inhibitors, including sirolimus, temsirolimus and everolimus, have been clinically developed. This review summarizes the results of the studies evaluating the expression of the mTOR pathway components in ACCs, the effects of the mTOR inhibitors alone or in combination with other drugs in preclinical models of ACCs and the early experience with the use of these compounds in the clinical setting. The mTOR pathway seems a potential target for treatment of patients with ACC, but further investigation is still required to define the potential role of mTOR inhibitors alone or in combination with other drugs in the treatment of ACC patients.
