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(A) GOT2 western blot of HeLa cells stably silenced for GOT2 expression by shRNA transfection compared to non-silenced scrambled (Scr) control cells. β-actin was used as a loading control. (B) Number of GOT2 KD HeLa cells after transfection with empty vector (EV), GOT2- WT cDNA, and GOT2- c.357A>T. Cells were seeded into 12-well plates and incubated for various times, as indicated. The counts are reported as means (n=3). A t-test was applied to test for differences. n.s.: not significant.

Purpose: Neuropathy is the dose-limiting toxicity of paclitaxel and a major cause for decreased quality of life. Genetic factors have been shown to contribute to paclitaxel neuropathy susceptibility; however, the major causes for interindividual differences remain unexplained. In this study, we identified genetic markers associated with paclitaxel-induced neuropathy through massive sequencing of candidate genes.Experimental Design: We sequenced the coding region of 4 EPHA genes, 5 genes involved in paclitaxel pharmacokinetics, and 30 Charcot–Marie–Tooth genes, in 228 cancer patients with no/low neuropathy or high-grade neuropathy during paclitaxel treatment. An independent validation series included 202 paclitaxel-treated patients. Variation-/gene-based analyses were used to compare variant frequencies among neuropathy groups, and Cox regression models were used to analyze neuropathy along treatment.Results: Gene-based analysis identified EPHA6 as the gene most significantly associated with paclitaxel-induced neuropathy. Low-frequency nonsynonymous variants in EPHA6 were present exclusively in patients with high neuropathy, and all affected the ligand-binding domain of the protein. Accumulated dose analysis in the discovery series showed a significantly higher neuropathy risk for EPHA5/6/8 low-frequency nonsynonymous variant carriers [HR, 14.60; 95% confidence interval (CI), 2.33–91.62; P = 0.0042], and an independent cohort confirmed an increased neuropathy risk (HR, 2.07; 95% CI, 1.14–3.77; P = 0.017). Combining the series gave an estimated 2.5-fold higher risk of neuropathy (95% CI, 1.46–4.31; P = 9.1 × 10−4).Conclusions: This first study sequencing EPHA genes revealed that low-frequency variants in EPHA6, EPHA5, and EPHA8 contribute to the susceptibility to paclitaxel-induced neuropathy. Furthermore, EPHA's neuronal injury repair function suggests that these genes might constitute important neuropathy markers for many neurotoxic drugs. Clin Cancer Res; 23(5); 1227–35. ©2016 AACR.

Supplementary Table 1. Non synonymous coding and splicing site variants in the discovery series targeted sequencing. Supplementary Table 2. Association of common non-synonymous coding variants with paclitaxel-induced neuropathy.

Genes included in the targeted next-generation sequencing panel

Legends of the Supplementary Figures

Purpose: Mutations in Krebs cycle genes are frequently found in patients with pheochromocytomas/paragangliomas. Disruption of SDH, FH or MDH2 enzymatic activities lead to accumulation of specific metabolites, which give rise to epigenetic changes in the genome that cause a characteristic hypermethylated phenotype. Tumors showing this phenotype, but no alterations in the known predisposing genes, could harbor mutations in other Krebs cycle genes.Experimental Design: We used downregulation and methylation of RBP1, as a marker of a hypermethylation phenotype, to select eleven pheochromocytomas and paragangliomas for targeted exome sequencing of a panel of Krebs cycle-related genes. Methylation profiling, metabolite assessment and additional analyses were also performed in selected cases.Results: One of the 11 tumors was found to carry a known cancer-predisposing somatic mutation in IDH1. A variant in GOT2, c.357A>T, found in a patient with multiple tumors, was associated with higher tumor mRNA and protein expression levels, increased GOT2 enzymatic activity in lymphoblastic cells, and altered metabolite ratios both in tumors and in GOT2 knockdown HeLa cells transfected with the variant. Array methylation-based analysis uncovered a somatic epigenetic mutation in SDHC in a patient with multiple pheochromocytomas and a gastrointestinal stromal tumor. Finally, a truncating germline IDH3B mutation was found in a patient with a single paraganglioma showing an altered α-ketoglutarate/isocitrate ratio.Conclusions: This study further attests to the relevance of the Krebs cycle in the development of PCC and PGL, and points to a potential role of other metabolic enzymes involved in metabolite exchange between mitochondria and cytosol. Clin Cancer Res; 23(20); 6315–24. ©2017 AACR.

Around 50% of the familial breast cancer (BC) cases are estimated to be caused by germline variants in known low-, moderate-, and high-risk susceptibility genes, while the other half is of unknown genetic origin. In the present study, we wanted to evaluate the role of the RECQ helicases, some of which have been studied in the past as candidates, with unclear results about their role in the disease. Using next-generation sequencing (NGS) technology, we analyzed the whole coding sequence of BLM, RECQL1, RECQL4, RECQL5, and WRN in almost 2000 index cases from BC Spanish families that had previously tested negative for the known BC susceptibility genes (BRCAX) and compared the results with the controls extracted from gnomAD. Our results suggest that BLM, RECQL1, RECQL4, and WRN do not play a major role in BC susceptibility. However, in the combined analysis, joining the present results with those previously reported in a series of 1334 BC Spanish patients and controls, we found a statistically significant association between Loss of Function (LoF) variants in RECQL5 and BC risk, with an OR of 2.56 (p = 0.009; 95% CI, 1.18–4.98). Our findings support our previous work and places the RECQL5 gene as a new moderate-risk BC gene., A.O. is partially funded by FIS PI19/00640 supported by FEDER funds and the Spanish Network on Rare Diseases (CIBERER). M.d.l.H. is partially funded by FIS PI20/00110 supported by FEDER funds.

Acute adrenal insufficiency (AAI) is a potentially fatal medical emergency whose prevention and treatment should be known by all medical professionals. AAI is an underdiagnosed condition because of its non-specific symptoms, but its diagnosis and early treatment with glucocorticoids is vital. It may be triggered by a de novo deficiency in cortisol synthesis or occur secondarily to omission of hormone replacement therapy (corticosteroids) or inadequate adjustment of the dose required in stress situations in patients previously diagnosed with adrenal insufficiency. AAI prevention significantly decreases death from cardiovascular diseases and infections in patients with adrenal insufficiency, and also improves their quality of life. Adequate education of patients, relatives, and all healthcare professionals is therefore essential. Therefore, the Adrenal Disorders Group of the Neuroendocrinology Area of the Spanish Society of Endocrinology and Nutrition (SEEN) has prepared, at the proposal of the SEEN's board, a guideline for optimal management of acute adrenal insufficiency. The guideline is intended to provide practical recommendations for all healthcare professionals who may be involved in the diagnosis, treatment, and prevention of AAI. It is also intended to provide patients and their families with action guidelines for AAI management and prevention.

Acute adrenal insufficiency (AAI) is a potentially fatal medical emergency whose prevention and treatment should be known by all medical professionals. AAI is an underdiagnosed condition because of its non-specific symptoms, but its diagnosis and early treatment with glucocorticoids is vital. It may be triggered by a de novo deficiency in cortisol synthesis or occur secondarily to omission of hormone replacement therapy (corticosteroids) or inadequate adjustment of the dose required in stress situations in patients previously diagnosed with adrenal insufficiency. AAI prevention significantly decreases death from cardiovascular diseases and infections in patients with adrenal insufficiency, and also improves their quality of life. Adequate education of patients, relatives, and all healthcare professionals is therefore essential. Therefore, the Adrenal Disorders Group of the Neuroendocrinology Area of the Spanish Society of Endocrinology and Nutrition (SEEN) has prepared, at the proposal of the SEEN's board, a guideline for optimal management of acute adrenal insufficiency. The guideline is intended to provide practical recommendations for all healthcare professionals who may be involved in the diagnosis, treatment, and prevention of AAI. It is also intended to provide patients and their families with action guidelines for AAI management and prevention.

Introduction: the pandemic originated by SARS-Cov-2 in 2019 led to eating habits and physical exercise changes due to home confinement measures. The follow-up of patients in treatment for weight loss through telematic consultation could be a useful tool to prevent treatment failure. Objective: to describe the evolution of anthropometric parameters of patients under follow-up for weight loss through telematic consultation. Methods: a two-stage prospective study (before and after confinement) with a telematic intervention in adult patients under regular follow-up for overweight and obesity. Demographic variables and body composition parameters were analyzed by bioimpendance. In addition, the differences in the presence of drug treatment with GLP-1 hormone (liraglutide or semaglutide) adjuvants were also analyzed. The variables were studied using Wilcoxon's test, Mann-Whitney U-test, and Spearman's correlation. Significance was considered for p ≤ 0.05. Results: a total of 97 patients were included, before confinement 42.3 % were overweight (BMI30 kg/m2), 36.1 % were obese grade I (BMI = 30-34.9 kg/m2), 16.4 % were obese grade II (BMI = 35-39.9 kg/m2), and 5.2 % had BMI40 kg/m2. In all, 30.9 % had prediabetes and 9.3 % had type-2 diabetes. Between both consultations, 81.4 % of patients lost 4.2 ± 3.4 % of their weight, with a significant mean decrease in fat mass of 3.16 ± 4.4 kg. The group on pharmacological treatment with GLP-1 hormone analogs presented a significantly higher average fat loss without significant loss of skeletal muscle mass. Conclusions: telematic monitoring seems to be a useful tool to prevent weight gain in patients with restricted mobility. A telematic intervention that contains dietary advice and exercise, as a reinforcement to hypocaloric diet, helps to achieve weight loss with a predominant fat component. The presence of drug treatment with GLP-1 hormone analogues appears to significantly help maintain skeletal muscle mass during weight loss.Introducción: la pandemia originada en 2019 por el SARS-CoV-2 supuso un cambio en los hábitos de alimentación y ejercicio físico por causa de las medidas de confinamiento domiciliario. El seguimiento de pacientes en tratamiento de pérdida de peso mediante una consulta telemática podría ser una herramienta útil para prevenir el fracaso terapéutico. Objetivo: describir la evolución de los parámetros antropométricos de pacientes en seguimiento para pérdida de peso mediante una consulta telemática. Métodos: estudio prospectivo en 2 tiempos (antes y después del confinamiento) de una intervención telemática sobre pacientes adultos en seguimiento habitual por sobrepeso y obesidad. Se analizaron las variables demográficas y los parámetros de composición corporal mediante bioimpendancia. Además se analizaron las diferencias en cuanto a presencia de tratamiento farmacológico adyuvante del tipo de los análogos de la hormona GLP1 (liraglutida o semaglutida). Las variables se estudiaron mediante la prueba de Wilcoxon, la U de Mann-Whitney y la correlación de Spearman. Se consideró la significación si p ≤ 0,05. Resultados: se incluyeron 97 pacientes. Antes del confinamiento, el 42,3 % presentaban sobrepeso (IMC30 kg/m2), el 36,1 % tenían obesidad de grado I (IMC = 30-34,9 kg/m2), el 16,4 % la tenían de grado II (IMC = 35-39,9 kg/m2) y el 5,2 % tenían un IMC40 kg/m2. El 30,9 % presentaban prediabetes y el 9,3 % tenían diabetes de tipo 2. Entre ambas visitas presenciales, el 81,4 % de los pacientes perdieron un 4,2 ± 3,4 % del peso, con una disminución media significativa de la masa grasa de 3,16 ± 4,4 kg. El grupo en tratamiento farmacológico con análogos de la hormona GLP-1 presentó una pérdida de masa grasa media significativamente superior sin pérdida de masa muscular esquelética significativa. Conclusiones: el seguimiento telemático parece una herramienta útil para prevenir la ganancia de peso en los pacientes con restricción de la movilidad. Una intervención telemática que contenga consejo dietético y ejercicio como refuerzo de la dieta hipocalórica ayuda a conseguir perder peso, predominando el componente graso. La presencia de un tratamiento farmacológico con análogos de la hormona GLP-1 parece ayudar significativamente al mantenimiento de la masa muscular esquelética durante la pérdida de peso.