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73, 95% confidence interval 1.17-2.56, p ≈ 0.006) and analgesics (hazard ratio 1.24, 95% confidence interval 1.11-1.39, p  less then  0.001). Pain and depression are the first comorbidities to present in hidradenitis suppurativa pathogenesis.Mutations in the GDAP1 gene cause Charcot-Marie-Tooth (CMT) neuropathy. GDAP1 is an atypical glutathione S-transferase (GST) of the outer mitochondrial membrane and the mitochondrial membrane contacts with the endoplasmic reticulum (MAMs). Here, we investigate the role of this GST in the autophagic flux and the membrane contact sites (MCSs) between mitochondria and lysosomes in the cellular pathophysiology of GDAP1 deficiency. We demonstrate that GDAP1 participates in basal autophagy and that its depletion affects LC3 and PI3P biology in autophagosome biogenesis and membrane trafficking from MAMs. GDAP1 also contributes to the maturation of lysosome by interacting with PYKfyve kinase, a pH-dependent master lysosomal regulator. Selleck A-1210477 GDAP1 deficiency causes giant lysosomes with hydrolytic activity, a delay in the autophagic lysosome reformation, and TFEB activation. Notably, we found that GDAP1 interacts with LAMP-1, which supports that GDAP1-LAMP-1 is a new tethering pair of mitochondria and lysosome membrane contacts. We observed mitochondria-lysosome MCSs in soma and axons of cultured mouse embryonic motor neurons and human neuroblastoma cells. GDAP1 deficiency reduces the MCSs between these organelles, causes mitochondrial network abnormalities, and decreases levels of cellular glutathione (GSH). The supply of GSH-MEE suffices to rescue the lysosome membranes and the defects of the mitochondrial network, but not the interorganelle MCSs nor early autophagic events. Overall, we show that GDAP1 enables the proper function of mitochondrial MCSs in both degradative and nondegradative pathways, which could explain primary insults in GDAP1-related CMT pathophysiology, and highlights new redox-sensitive targets in axonopathies where mitochondria and lysosomes are involved.

Genome-wide association studies (GWAS) suggest that the combined effects of breast cancer (BC)-associated single nucleotide polymorphisms (SNPs) can improve BC risk stratification using polygenic risk scores (PRSs). The performance of PRSs in GWAS-independent clinical cohorts is poorly studied in individuals carrying mutations in moderately penetrant BC predisposition genes such as CHEK2.

760 female CHEK2 mutation carriers were included; 561 women were affected with BC, of whom 74 developed metachronous contralateral BC (mCBC). For PRS calculations, two SNP sets covering 77 (SNP set 1, developed for BC risk stratification in women unselected for their BRCA1/2 germline mutation status) and 88 (SNP set 2, developed for BC risk stratification in female BRCA1/2 mutation carriers) BC-associated SNPs were used. All statistical tests were two-sided.

Both SNP sets provided concordant PRS results at the individual level (r = 0.91, p < 2.20 × 10-16). Weighted cohort Cox regression analyses revealed statistically significant associations of PRSs with the risk for first BC. For SNP set 1, a hazard ratio (HR) of 1.71 per standard deviation of the PRS was observed (95% confidence interval [CI] = 1.36 to 2.15, p = 3.87x10-6). PRSs identify a subgroup of CHEK2 mutation carriers with a predicted lifetime risk for first BC that exceeds the surveillance thresholds defined by international guidelines. Association of PRS with mCBC was examined via Cox regression analysis (SNP set 1 HR = 1.23, 95%CI = 0.86 to 1.78, p = .26).

PRSs may be used to personalize risk-adapted preventive measures for women with CHEK2 mutations. Larger studies are required to assess the role of PRSs in mCBC predisposition.

PRSs may be used to personalize risk-adapted preventive measures for women with CHEK2 mutations. Larger studies are required to assess the role of PRSs in mCBC predisposition.

Patients with schizophrenia can generally manifest a broad variety of primary negative symptoms. The current study aimed to assess the efficacy and tolerability of resveratrol add-on therapy in the treatment of negative symptoms in patients with stable schizophrenia.

In a randomized, double-blind, and placebo-controlled setting, schizophrenia patients were assigned to receive either 200 mg/d resveratrol or matched placebo in addition to a stable dose of risperidone for 8 weeks. Patients were assessed using the positive and negative syndrome scale, the extrapyramidal symptom rating scale, and Hamilton Depression Rating Scale over the trial period. The primary outcome was considered as the change in positive and negative subscale score from baseline to week 8 between the treatment arms.

A total 52 patients completed the trial (26 in each arm). Baseline characteristics of both groups were statistically similar (P  > .05). Despite the statistically similar behavior of positive symptoms between the groups across time (Greenhouse-Geisser corrected F = 1.76, df = 1.88, P = .180), the resveratrol group demonstrated greater improvement in negative, general psychopathology, and total scores (Greenhouse-Geisser corrected F = 12.25, df = 2.04, P < .001; F = 5.42, df = 1.56, P = .011; F = 7.64, df = 1.48, P = .003). HDRS scores and its changes, ESRS score, and frequency of other complications were not significantly different between resveratrol and placebo groups.

Adding resveratrol to risperidone can exhibit remarkable efficacy and safety in terms of management of schizophrenia-related negative symptoms.

Adding resveratrol to risperidone can exhibit remarkable efficacy and safety in terms of management of schizophrenia-related negative symptoms.Nickel nanocrystals have received much attention for their ferromagnetic properties. The crystal properties are strongly dependent on their facets and therefore detailed study of their morphology, facets and orientation is critical for magnetic applications. In this work, equilibrium crystal shapes of self-assembled nickel nanocrystals on the (111) termination of strontium titanate (SrTiO3) at room temperature and under ultra-high vacuum (UHV) conditions have been investigated using scanning tunneling microscope (STM). SrTiO3 (111) substrate was sputtered (0.5 keV, 2.5 µA, 10 min) and annealed (900 °C, 1 h) under UHV conditions. Three different periodicities were observed (2.21 ± 0.01) nm corresponding to (4 × 4) reconstruction, (3.31 ± 0.02) nm corresponding to (6 × 6) reconstruction, and (2.85 ± 0.05) nm, rotated at 30° with respect to (4 × 4) reconstruction, corresponding to (3√3 × 3√3)R30° reconstruction. Nickel (~1 ML) was deposited using an e-beam evaporator on the substrate preheated to 320 °C and the sample was post-annealed multiple times. Nickel took platonic shapes of supported icosahedron comprising of (111) facets and truncated octahedron comprising of (001) and (111) facets. Based on surface energy ratios of truncated octahedrons at equilibrium the work of adhesion was calculated to be (3.889 ± 0.167) J/m2.It has been widely accepted that autophagic cell death exacerbates the progression of cerebral ischemia/reperfusion (I/R). Our previous study revealed that overexpression of reticulon protein 1-C (RTN1-C) is involved in cerebral I/R injury. However, the underlying mechanisms have not been studied intensively. This study was designed to evaluate the effect of RTN1-C on autophagy under cerebral I/R. Using an in vitro oxygen-glucose deprivation followed by reoxygenation and a transient middle cerebral artery occlusion model in rats, we found that the expression of RTN1-C protein was significantly upregulated. We also revealed that RTN1-C knockdown suppressed overactivated autophagy both in vivo and in vitro, as indicated by decreased expressions of autophagic proteins. The number of Beclin-1/propidium iodide-positive cells was significantly less in the LV-shRTN1-C group than in the LV-shNC group. In addition, rapamycin, an activator of autophagy, aggravated cerebral I/R injury. RTN1-C knockdown reduced brain infarct volume, improved neurological deficits, and attenuated cell vulnerability to cerebral I/R injury after rapamycin treatment. Taken together, our findings demonstrated that the modulation of autophagy from RTN1-C may play vital roles in cerebral I/R injury, providing a potential therapeutic treatment for ischemic brain injury.

PAOLA1 is a phase III study assessing olaparib maintenance therapy in advanced high-grade ovarian carcinoma patients responding to first-line platinum-taxane-based chemotherapy plus bevacizumab as standard of care. Randomization was stratified by treatment outcome and tumor BRCA1/2 status (tBRCA) at screening.

tBRCA was tested on FFPE tumor blocks on 5 French platforms using 2 Next-Generation Sequencing methods based either on hybrid capture or amplicon technology. One of the exploratory objectives was to assess the concordance between germline (gBRCA) and tBRCA testing in French patients. gBRCA testing was performed on blood samples on the same platforms.

From May 2015 to July 2017, tBRCA tests were performed for 1,176 screened patients. Only 52 (4.4%) tumor samples were non-contributive. The median interval between reception of the tumor sample and availability of the tBRCA status result was 37 days (range =8-260). A pathogenic variant (PV) was reported in 27.1% tumor samples (319 of 1,176 screened patients). tBRCA and gBRCA testing were both performed for 451 French patients with negative results for both tests in 306 patients (67.8%) and positive results for both tests in 85 patients (18.8%). Only one large genomic rearrangement of BRCA1 was detected, exclusively in the blood sample. Interestingly, tBRCA testing revealed 6.4% of PV (29 of 451) not detected by gBRCA testing.

tBRCA testing is an appropriate tool with an acceptable turnaround time for clinical practice and a low failure rate, ensuring reliable identification of patients likely to benefit from PARPi therapy.

tBRCA testing is an appropriate tool with an acceptable turnaround time for clinical practice and a low failure rate, ensuring reliable identification of patients likely to benefit from PARPi therapy.The measurement of the volume of blood cells is important for clinical diagnosis and patient management. While digital holography microscopy (DHM) has been used to obtain such information, previous off-axis setups usually involve a separated reference beam and are thus not very easy to implement. Here, we use the simple in-line Gabor setup without separation of a reference beam to measure the shape and volume of cells mounted on glass slides. Inherent to the in-line holograms, the reconstructed phase of the object is affected by the virtual image noise, producing errors in the cell volume measurement. We optimized our approach to use a single hologram without phase retrieval, increasing distance between cell and hologram plane to reduce the measurement error of cell volume to less than 6% in some instances. Therefore, the in-line Gabor setup can be a useful and simple tool to obtain volumetric and morphologic cellular information.

For over 30 years, the USNS Mercy hospital ship has provided surgical care on multiple humanitarian aid and disaster relief missions. During these missions, surgical support varies according to host nation needs, and the operative treatment of cancer patients remains controversial. We report the number of incidentally discovered surgical oncologic cases treated aboard the USNS Mercy on four missions and discuss challenges regarding oncologic care on these missions.

Between 2008 and 2016, operative cases and surgical pathology results from four multinational humanitarian missions were analyzed according to organ system, patient's geographic location, and diagnosis. Primary outcomes were total number and proportion of malignant cases, analyzed yearly and over all four missions. Secondary outcomes were malignant diagnoses by organ system and host nation health capacities (based on indicators from the WHO).

A total of 2,767 operations were performed during 18 port visits in 8 countries in Southeast Asia. In total, 1,193 pathology specimens (surgical biopsies, fine needle aspirations, etc.