Distinct disease phenotypes linked to different combinations of GAA mutations in a large late-onset GSDII sibship

Background: Glycogenosis type II (GSDII or Pompe disease) is an autosomal recessive disease, often characterized by a progressive accumulation of glycogen within lysosomes caused by a deficiency of \u3b1-1,4-glucosidase (GAA; acid maltase), a key enzyme of the glycogen degradation pathway. To date, more than 326 different mutations in the GAA gene have been identified in patients with GSDII but the course of the disease is difficult to be predicted on the basis of molecular genetic changes. Studies on large informative families are advisable to better define how genetics and non genetics factors like exercise and diet may influence the clinical phenotype. Methods and results. In this study, we report on clinical, instrumental, and pathological features as well as on molecular analysis of a family with 10 out of 13 siblings affected by late-onset Pompe disease. Three mutations segregated in the family, two of which are novel mutations. Siblings showing a more severe phenotype were compound heterozygous for c.118C > T [p.R40X] and c.2647-7G > A [p.N882fs] on GAA, whereas, two patients showing a mild phenotype were compound heterozygous c.2647-7G > A [p.N882fs] and c.2276G > C [p.G759A] mutations. Quantitative expression analysis showed, in the patients carrying p.R40X/ p.N882fs, a significant (p 0.01) correlation between the levels of expression of the mutated allele and the age at onset of the disease. Conclusions: As far as we know, this is the largest informative family with late-onset Pompe disease described in the literature showing a peculiar complex set of mutations of GAA gene that may partially elucidate the clinical heterogeneity of this family. \ua9 2013 Sampaolo et al.; licensee BioMed Central Ltd

miR-146a-5p impairs melanoma resistance to kinase inhibitors by targeting COX2 and regulating NFkB-mediated inflammatory mediators

BACKGROUND: Targeted therapy with BRAF and MEK inhibitors has improved the survival of patients with BRAF-mutated metastatic melanoma, but most patients relapse upon the onset of drug resistance induced by mechanisms including genetic and epigenetic events. Among the epigenetic alterations, microRNA perturbation is associated with the development of kinase inhibitor resistance. Here, we identified and studied the role of miR-146a-5p dysregulation in melanoma drug resistance.METHODS: The miR-146a-5p-regulated NFkB signaling network was identified in drug-resistant cell lines and melanoma tumor samples by expression profiling and knock-in and knock-out studies. A bioinformatic data analysis identified COX2 as a central gene regulated by miR-146a-5p and NFkB. The effects of miR-146a-5p/COX2 manipulation were studied in vitro in cell lines and with 3D cultures of treatment-resistant tumor explants from patients progressing during therapy.RESULTS: miR-146a-5p expression was inversely correlated with drug sensitivity and COX2 expression and was reduced in BRAF and MEK inhibitor-resistant melanoma cells and tissues. Forced miR-146a-5p expression reduced COX2 activity and significantly increased drug sensitivity by hampering prosurvival NFkB signaling, leading to reduced proliferation and enhanced apoptosis. Similar effects were obtained by inhibiting COX2 by celecoxib, a clinically approved COX2 inhibitor.CONCLUSIONS: Deregulation of the miR-146a-5p/COX2 axis occurs in the development of melanoma resistance to targeted drugs in melanoma patients. This finding reveals novel targets for more effective combination treatment. Video Abstract

High prevalence of chitotriosidase deficiency in Peruvian Amerindians exposed to chitin-bearing food and enteroparasites

The human genome encodes a gene for an enzymatically active chitinase (CHIT1) located in a single copy on Chromosome 1, which is highly expressed by activated macrophages and in other cells of the innate immune response. Several dysfunctional mutations are known in CHIT1, including a 24-bp duplication in Exon 10 causing catalytic deficiency. This duplication is a common variant conserved in many human populations, except in West and South Africans. Thus it has been proposed that human migration out of Africa and the consequent reduction of exposure to chitin from environmental factors may have enabled the conservation of dysfunctional mutations in human chitinases. Our data obtained from 85 indigenous Amerindians from Peru, representative of populations characterized by high prevalence of chitin-bearing enteroparasites and intense entomophagy, reveal a very high frequency of the 24-bp duplication (47.06%), and of other single nucleotide polymorphisms which are known to partially affect enzymatic activity (G102S: 42.7% and A442G/V: 25.5%). Our finding is in line with a founder effect, but appears to confute our previous hypothesis of a protective role against parasite infection and sustains the discussion on the redundancy of chitinolytic function

The (Still Unknown) Hypothetical Protective Role of COVID-19 Therapy in Bladder Cancer

The COVID-19 pandemic continues to put a strain on the entire world population. The common features of bladder cancer (BCa) and COVID infection have been widely reported and discussion may continue regarding treatment as well. We have highlighted how COVID-19 therapy has many implications with BCa therapy, in particular with potential protective role

ElectroMotive drug administration (EMDA) of Mitomycin C as first-line salvage therapy in high risk “BCG failure” non muscle invasive bladder cancer: 3 years follow-up outcomes

Abstract Background In case of high grade non-muscle invasive bladder cancer (HG-NMIBC), intravesical BCG represents the first-line treatment; despite the “gold” standard therapy, up to 50% of patients relapse, needing radical cystectomy. Hence, alternative therapeutic strategies have been developed. The aim of the study was to evaluate a first-line salvage treatment with EMDA®-MMC in patients with HGNMIBC unresponsive to BCG. Methods We carried out a prospective, single-center, single-arm Phase II study in order to evaluate the efficacy (in terms of recurrence and progression) and the safety of the EMDA®-MMC treatment in 26 (21 male, 5 female) consecutive patients with “BCG refractory” HGNMIBC on a 3 years follow-up. EMDA®-MMC treatment consisted of 40 mg of MMC diluted in 100 ml of sterile water retained in the bladder for 30 min with 20 mA pulsed electric current. EMDA®-MMC regimen consisted of an induction course of 6 weekly instillations followed by a maintenance course of 6 monthly instillations. Follow-up was performed with systematic mapping biopsies of the bladder (with sampling in the prostatic urethra for men), voiding and washing urinary cytology, radiological study of the upper urinary tract. We performed Survival Kaplan-Meier curves and Log-rank test in order to analyze high grade disease-free survival. Results At the end of follow-up, 16 patients (61.5%) preserved their native bladder; 10 patients (38.4%) underwent radical cystectomy, in 6 patients (23.1%) for recurrent HGNMIBC and in 4 patients (15.4%) for progression to muscle-invasive disease. At the end of follow-up, stratifying patients based on TNM classification (TaG3, T1G3, Cis, TaT1G3 + Cis), disease-free rates were 75, 71.4, 50 and 25%, respectively; survival curves showed statistically significant differences (p value < 0.05). Regarding toxicity, we reported severe adverse systemic event of hypersensitivity to the MMC in 3 patients (11.5%), and local side effects in 6 patients (26.1%). Conclusions In the field of alternative strategies to radical cystectomy, the EMDA®-MMC could be considered safe and effective in high-risk NMIBC unresponsive to BCG, as a “bladder sparing” therapy in selected patients. Multicenter studies with a larger number of patients and a longer follow-up might confirm our preliminary results. Trial registration EudraCT2017-002585-43. 17 June 2017 (retrospectively registered)

A novel inverse dynamic model for 3-DoF delta robots

Delta Robots belong to a class of parallel robots widely used in industrial production processes, mostly for pick-and-place operations. The most relevant characteristics are the high speed and the extremely favorable ratio between the maximum payload and the weight of the robot itself. A reliable dynamic model is needed to implement torque controllers that reduce unnecessary high accelerations and so mechanical vibrations. The state-of-art inverse dynamic models exploit simplifications in order to facilitate the derivation of the equations of motion and their implementation. In this work, a novel and more rigorous inverse dynamic model is presented which does not rely on simplifications of the kinematic structure. The model has been validated comparing its estimations with real torques data collected moving a Delta Robot D3-1200 by SIPRO Srl; the computational complexity of the algorithm has also been investigated

Gray-Box Model Identification and Payload Estimation for Delta Robots

Delta Robots belong to a class of parallel robots widely used in industrial production processes, mostly for pick-and-place operations. The most relevant characteristics are the high speed and the extremely favorable ratio between the maximum payload and the weight of the robot itself. A reliable dynamic model is needed to implement torque controllers that reduce unnecessary high accelerations and so mechanical vibrations. Moreover, when the mass of the pickable object is unknown, it is crucial to identify with sufficient precision the dynamic contribution of the payload and to accordingly adapt the dynamic model in order to guarantee high performance

Second-line intravesical therapy. What is the present role of device-assisted therapy?

Non-muscle-invasive bladder cancer is a common urinary malignancy whose management is a challenge: strong evidence supports the use of passive intravesical chemotherapy in the management of this tumor. Despite current guidelines, the treatment is suboptimal as illustrated by the high risk of recurrence and progression. Bacillus Calmette-Guérin (BCG) is the gold standard for the treatment of high-grade non-muscle-invasive bladder cancer, but in case of disease persistence, after 2 consecutive induction courses of BCG, patients must undergo radical cystectomy.
We discuss options for second-line adjuvant therapy for non-muscle-invasive bladder cancer in standard treatment non-responder patients. We investigated the use and application of device-assisted therapy for the intravesical treatment of bladder cancer, such as thermochemotherapy (TCT) and electromotive drug administration (EMDA). Many studies demonstrate their synergistic therapeutic effect, greater than the single treatment with chemotherapy, inducing an increased absorption of the chemotherapeutic agent (Mitomycin C) to the urothelium. TCT and EMDA are safe and effective in terms of outcomes. For the future it will be important to encourage the use of the existing technology within the appropriate clinical indications

Psychological aptitude for surgery: The importance of non-technical skills

Introduction: Psychological aptitude for surgery includes all the non-technical abilities that are necessary for the surgeons. However, differently from the other careers, these skills are not considered in the selection process and their role is definitively underestimated in the field of surgery. We perform a literature review of non-technical skills for surgery to identify their role and to understand how to train and evaluate these abilities among the surgeons. Results: Different methods have been presented for the evaluation and training of non-technical skills for surgeons; based on the model of aviation and anesthesia a wide range of simulated scenarios have been proposed to practice these aptitudes and abilities. Different behavioral markers systems have been developed for correct identification and definition of these skills, these can be used in the real surgical room and even learned and trained in the simulated operating theatre. Conclusion: This article shows the importance of non-practical abilities in the surgical performance and in defining the aptitude for surgery. Learning these skills and introducing them in surgical education can be useful to improve the surgical performance