Miracle-dz/UniFAR-FTUs huggingface dataset:
ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach.

BACKGROUND Cancers with a defective DNA mismatch repair (dMMR) system contain thousands of mutations most frequently located in monomorphic microsatellites and are thereby defined as having microsatellite instability (MSI). Therefore, MSI is a marker of dMMR. MSI/dMMR can be identified using immunohistochemistry to detect loss of MMR proteins and/or molecular tests to show microsatellite alterations. Together with tumour mutational burden (TMB) and PD-1/PD-L1 expression, it plays a role as a predictive biomarker for immunotherapy. METHODS To define best practices to implement the detection of dMMR tumours in clinical practice, the ESMO Translational Research and Precision Medicine Working Group launched a collaborative project, based on a systematic review-approach, to generate consensus recommendations on the: (i) definitions related to the concept of MSI/dMMR; (ii) methods of MSI/dMMR testing and (iii) relationships between MSI, TMB and PD-1/PD-L1 expression. RESULTS The MSI-related definitions, for which a consensus frame-work was used to establish definitions, included: 'microsatellites', 'MSI', 'DNA mismatch repair' and 'features of MSI tumour'. This consensus also provides recommendations on MSI testing; immunohistochemistry for the mismatch repair proteins MLH1, MSH2, MSH6 and PMS2 represents the first action to assess MSI/dMMR (consensus with strong agreement); the second method of MSI/dMMR testing is represented by polymerase chain reaction (PCR)-based assessment of microsatellite alterations using five microsatellite markers including at least BAT-25 and BAT-26 (strong agreement). Next-generation sequencing, coupling MSI and TMB analysis, may represent a decisive tool for selecting patients for immunotherapy, for common or rare cancers not belonging to the spectrum of Lynch syndrome (very strong agreement). The relationships between MSI, TMB and PD-1/PD-L1 expression are complex, and differ according to tumour types. CONCLUSIONS This ESMO initiative is a response to the urgent questions raised by the growing success of immunotherapy and provides also important insights on the relationships between MSI, TMB and PD-1/PD-L1.
Activation of AMP-Activated Protein Kinase by Metformin Improves Left Ventricular Function and Survival in Heart Failure

Clinical studies have reported that the widely used antihyperglycemic drug metformin significantly reduces cardiac risk factors and improves clinical outcomes in patients with heart failure. The mechanisms by which metformin exerts these cardioprotective effects remain unclear and may be independent of antihyperglycemic effects. We tested the hypothesis that chronic activation of AMP-activated protein kinase (AMPK) with low-dose metformin exerts beneficial effects on cardiac function and survival in in vivo murine models of heart failure. Mice were subjected to permanent left coronary artery occlusion or to 60 minutes left coronary artery occlusion followed by reperfusion for 4 weeks. High-resolution, 2D echocardiography was performed at baseline and 4 weeks after myocardial infarction to assess left ventricular dimensions and function. Metformin (125 &mgr;g/kg) administered to mice at ischemia and then daily improved survival by 47% (P<0.05 versus vehicle) at 4 weeks following permanent left coronary artery occlusion. Additionally, metformin given at reperfusion and then daily preserved left ventricular dimensions and left ventricular ejection fraction (P<0.01 versus vehicle) at 4 weeks. The improvement in cardiac structure and function was associated with increases in AMPK and endothelial nitric oxide synthase (eNOS) phosphorylation, as well as increased peroxisome proliferator-activated receptor-&ggr; coactivator (PGC)-1&agr; expression in cardiac myocytes. Furthermore, metformin significantly improved myocardial cell mitochondrial respiration and ATP synthesis compared to vehicle. The cardioprotective effects of metformin were ablated in mice lacking functional AMPK or eNOS. This study demonstrates that metformin significantly improves left ventricular function and survival via activation of AMPK and its downstream mediators, eNOS and PGC-1&agr;, in a murine model of heart failure.
The Neglect of Sodium Restriction in Dialysis Patients: A Short Review

In end‐stage renal failure, natriuresis decreases, sodium accumulates, and extracellular volume (ECV) excess develops. In 1962, Scribner, reporting about the first maintenance hemodialysis (HD) patient, observed that ECV control using a low‐salt diet and ultrafiltration led to blood pressure (BP) normalization. Thus, the concept of dry weight, the ideal postdialysis weight allowing for a stable normal BP, was born. Achieving dry weight requires a combination of negative diffusive sodium balance, adequate ultrafiltration, and a low‐salt diet. Unfortunately, the low‐salt diet is very often neglected today. In the late 1960s, BP control was achieved in 90% of HD patients using low‐sodium dialysis and a low‐salt diet. As time passed and HD duration was reduced, there was a worsening BP control and subsequent increasing in morbidity and mortality.
Gender effects on age-related changes in brain structure.

BACKGROUND AND PURPOSE Previous reports have suggested that brain atrophy is associated with aging and that there are gender differences in brain atrophy with aging. These reports, however, neither exclude silent brain lesions in "healthy subjects" nor divide the brain into subregions. The aim of this study is to clarify the effect of gender on age-related changes in brain subregions by MR imaging. METHODS A computer-assisted system was used to calculate the brain matter area index (BMAI) of various regions of the brain from MR imaging of 331 subjects without brain lesions. RESULTS There was significantly more brain atrophy with aging in the posterior parts of the right frontal lobe in male subjects than there was in female subjects. Age-related atrophy in the middle part of the right temporal lobe, the left basal ganglia, the parietal lobe, and the cerebellum also was found in male subjects, but not in female subjects. In the temporal lobe, thalamus, parieto-occipital lobe, and cerebellum, brain volume in the left hemisphere is significantly smaller than in the right hemisphere; sex and age did not affect the hemisphere differences of brain volume in these regions. CONCLUSION The effect of gender on brain atrophy with aging varied in different subregions of the brain. There was more brain atrophy with aging in male subjects than in female subjects.
Diversity of Extended HLA-DRB1 Haplotypes in the Finnish Population

The Major Histocompatibility Complex (MHC, 6p21) codes for traditional HLA and other host response related genes. The polymorphic HLA-DRB1 gene in MHC Class II has been associated with several complex diseases. In this study we focus on MHC haplotype structures in the Finnish population. We explore the variability of extended HLA-DRB1 haplotypes in relation to the other traditional HLA genes and a selected group of MHC class III genes. A total of 150 healthy Finnish individuals were included in the study. Subjects were genotyped for HLA alleles (HLA-A, -B, -DRB1, -DQB1, and -DPB1). The polymorphism of TNF, LTA, C4, BTNL2 and HLA-DRA genes was studied with 74 SNPs (single nucleotide polymorphism). The C4A and C4B gene copy numbers and a 2-bp silencing insertion at exon 29 in C4A gene were analysed with quantitative genomic realtime-PCR. The allele frequencies for each locus were calculated and haplotypes were constructed using both the traditional HLA alleles and SNP blocks. The most frequent Finnish A∼B∼DR -haplotype, uncommon in elsewhere in Europe, was A*03∼B*35∼DRB1*01∶01. The second most common haplotype was a common European ancestral haplotype AH 8.1 (A*01∼B*08∼DRB1*03∶01). Extended haplotypes containing HLA-B, TNF block, C4 and HLA-DPB1 strongly increased the number of HLA-DRB1 haplotypes showing variability in the extended HLA-DRB1 haplotype structures. On the contrary, BTNL2 block and HLA-DQB1 were more conserved showing linkage with the HLA-DRB1 alleles. We show that the use of HLA-DRB1 haplotypes rather than single HLA-DRB1 alleles is advantageous when studying the polymorphisms and LD patters of the MHC region. For disease association studies the HLA-DRB1 haplotypes with various MHC markers allows us to cluster haplotypes with functionally important gene variants such as C4 deficiency and cytokines TNF and LTA, and provides hypotheses for further assessment. Our study corroborates the importance of studying population-specific MHC haplotypes.
The Medicago truncatula LysM receptor-like kinase LYK9 plays a dual role in immunity and the arbuscular mycorrhizal symbiosis.

Plant -specific lysin-motif receptor-like kinases (LysM-RLKs) are implicated in the perception of N-acetyl glucosamine-containing compounds, some of which are important signal molecules in plant-microbe interactions. Among these, both lipo-chitooligosaccharides (LCOs) and chitooligosaccharides (COs) are proposed as arbuscular mycorrhizal (AM) fungal symbiotic signals. COs can also activate plant defence, although there are scarce data about CO production by pathogens, especially nonfungal pathogens. We tested Medicago truncatula mutants in the LysM-RLK MtLYK9 for their abilities to interact with the AM fungus Rhizophagus irregularis and the oomycete pathogen Aphanomyces euteiches. This prompted us to analyse whether A. euteiches can produce COs. Compared with wild-type plants, Mtlyk9 mutants had fewer infection events and were less colonised by the AM fungus. By contrast, Mtlyk9 mutants were more heavily infected by A. euteiches and showed more disease symptoms. Aphanomyces euteiches was also shown to produce short COs, mainly CO II, but also CO III and CO IV, and traces of CO V, both ex planta and in planta. MtLYK9 thus has a dual role in plant immunity and the AM symbiosis, which raises questions about the functioning and the ancestral origins of such a receptor protein.
Validity and test–retest reliability of the Persian version of the Montgomery–Asberg Depression Rating Scale

Background and aims The Montgomery–Asberg Depression Rating Scale (MADRS) is an expert’s rating tool to assess the severity and symptoms of depression. The aim of the present two studies was to validate the Persian version of the MADRS and determine its test–retest reliability in patients diagnosed with major depressive disorders (MDD). Methods In study 1, the translated MADRS and the Hamilton Depression Rating Scale (HDRS) were applied to 210 patients diagnosed with MDD and 100 healthy adults. In study 2, 200 patients diagnosed with MDD were assessed with the MADRS in face-to-face interviews. Thereafter, 100 patients were assessed 3–14 days later, again via face-to-face-interviews, while the other 100 patients were assessed 3–14 days later via a telephone interview. Results Study 1: The MADRS and HDRS scores between patients with MDD and healthy controls differed significantly. Agreement between scoring of the MADRS and HDRS was high (r=0.95). Study 2: The intraclass correlation coefficient (test–retest reliability) was r=0.944 for the face-to-face interviews, and r=0.959 for the telephone interviews. Conclusion The present data suggest that the Persian MADRS has high validity and excellent test–retest reliability over a time interval of 3–14 days, irrespective of whether the second assessment was carried out face-to-face or via a telephone interview.
Minimum Wage Effects on Labor Market Outcomes under Search, Matching, and Endogenous Contact Rates

Building upon a continuous-time model of search with Nash bargaining in a stationary environment, we analyze the effect of changes in minimum wages on labor market outcomes and welfare. Although minimum wage increases may or may not lead to increases in unemployment in our model, they can be welfare-improving to labor market participants on both the supply and demand sides of the labor market. We discuss identification of the model using Current Population Survey data on accepted wages and unemployment durations, and show that by incorporating a limited amount of information from the demand side of the market it is possible to obtain credible and precise estimates of all primitive parameters. We show that the optimal minimum wage in 1996 depends critically on whether or not contact rates can be considered to be exogenous and we note that the limited variation in minimum wages makes testing this assumption problematic.
Hearing Loss: Stigma Consciousness, Quality of Life and Social Identity

Abstract In the present research, three tests, Pinel’s Stigma Consciousness (1999); Quality of Life by Ruiz and Baca (1993); and the Social Identity by Cameron (2004), were adapted and validated by hearing loss of different ages, educational levels, marital status and occupation in order to make the sample more representative. The content validity was established using a group of experts formed by disabled people and technicians in disability with the purpose of adapting the items of the different tests. The reliability of the three tests was adequate with values higher than . 70. The Stigma Consciousness test presented a unifactorial structure, that of Quality of Life with four factors (General Satisfaction, Free Time, Physical and Psychological Well-being and Social Support) and Social Identity with three factors (Centrality, Ingroup Ties and Ingroup Affect). Goodness-of-fit tests showed adequate values. We also analyzed the convergent and discriminant validity of the scale in order to see which tests presented major and minor associations and the criterion validity relating the scales to the level of studies, the percentage of disability and the work place of the evaluated ones. Finally, we analyzed the similarities between our results and those obtained in the original tests.
Efficacy and safety of triple versus dual combination blood pressure-lowering drug therapy: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND OBJECTIVES Most patients with hypertension need at least two drugs to achieve goal blood pressure. This systematic review assessed efficacy and safety of triple versus dual combination therapy for the management of hypertension. METHODS Publication databases, clinical trial registries and regulatory agency websites were searched until April 2018 for double-blind randomized controlled trials (RCTs) comparing triple with dual therapy of BP-lowering drugs, for at least 3 weeks, among patients with hypertension. Meta-analyses for efficacy and safety outcomes were performed using random-effects model. Regimen efficacy was predicted using the Therapeutic Intensity Score (TIS) and the Law et al. method (which predict dose doubling increases efficacy by 100% and around 20%, respectively), and compared with observed efficacy. RESULTS Fourteen RCTs (11 457 participants) were included. Overall, triple compared with dual therapy reduced BP by 5.4/3.2 mmHg (P < 0.001), and improved BP control by 58 versus 45% [relative risk (RR) 1.33 (95% CI 1.25-1.41)], whereas incidence of withdrawals because of adverse events were 3.3 versus 3.4% [RR 1.24 (95% CI 1.00-1.54), P = 0.05]. Law et al.'s method was superior to TIS in predicting differences in efficacy between triple and dual therapies. For patients uncontrolled on submaximal dose dual therapy, adding a third drug achieved on average approximately four times more BP reduction than doubling the dose of dual therapy component drugs (6.0/3.6 versus 1.5/0.8 mmHg, respectively). CONCLUSION Addition of a third drug is likely to be more efficacious without increasing adverse events, compared with increasing dose of existing dual therapy. Early use of triple therapy can significantly improve hypertension control.
Restoration of p53 acetylation by HDAC inhibition permits the necrosis/apoptosis switch of pancreatic ainar cell during experimental pancreatitis in mice

The severity of acute pancreatitis (AP) is greatly attributed to the pancreatic acinar cell (PAC) death response. It has been established that the apoptosis‐inducing therapy can protect against experimental pancreatitis and have great clinical therapeutic potential. However, current pharmacologic agents that target apoptosis during AP largely lack specificity. Thus, it remains imperative to reveal the specific mechanisms governing acinar cell death. Death responses of PAC are manifested by the progressive necrosis accompanied by apoptosis silencing during AP in mice. In this study, we found that the transcriptional activity of p53 was impaired and the expressions of its proapoptotic targets Puma and CD95 were significantly decreased, which explains the apoptosis silencing during AP. Furthermore, we found that the functional depression of p53 was resulted from histone deacetylase (HDAC)‐mediated deacetylation of p53 C‐terminal in PAC during AP. Treatment of the HDAC inhibitor trichostatin‐A restored p53 apoptosis pathway, resulted in a necrosis/apoptosis switch and protected mice from cerulein‐ or l‐Arg‐induced AP. Our research identified the HDAC‐dependent regulation of p53 activity as a critical mechanism underlying acinar cell death response, which represents a specific target for the treatment of AP.
Evaluation of 2 self‐administered questionnaires to ascertain dermatitis among metal workers and its relation with exposure to metalworking fluids

We performed an exploratory study to evaluate 2 self‐administered questionnaires assessing hand dermatitis and investigate a possible exposure–response relationship between dermal exposure to semi‐synthetic metalworking fluids (SMWF) and dermatitis. In a cross‐sectional survey on dermatitis, a symptom‐based questionnaire and a picture‐based skin screening list were applied in 80 SMWF‐exposed workers and 67 referents. To evaluate the accuracy of the questionnaires, 47 subjects were examined by a dermatologist. Dermal exposure levels to SMWF were assessed on hands, forearms, and face with a observational method that was validated using a fluorescent tracer method. The symptom‐based questionnaire had a relatively high sensitivity (0.86) but moderate specificity (0.64), and the skin screening list had a low sensitivity (0.36) and a relatively high specificity (0.84). The skin screening list seemed to represent the more severe cases of dermatitis and showed a significant relation with exposure for dermatitis on hands, forearms, or face. In epidemiological surveys where workers are not seen by a dermatologist, the skin screening list seems to be more appropriate to detect cases of dermatitis, as its higher specificity results in less false positives. Alternatively, it would be preferable applying the symptom‐based questionnaire; workers with symptoms should be seen by a dermatologist to identify false positives.
Resistance to MEK Inhibitors: Should We Co-Target Upstream?

Amplification of an upstream kinase in a three-kinase module confers resistance to cancer drugs that target a downstream kinase. Aberrant activation of the ERK pathway is common in human tumors. This pathway consists of a three-tiered kinase module [comprising the kinases RAF, mitogen-activated protein kinase (MAPK) kinase (MEK), and extracellular signal–regulated kinase (ERK)] that functions as a negative feedback amplifier to confer robustness and stabilization of pathway output. Because this pathway is frequently dysregulated in human cancers, intense efforts are under way to develop selective inhibitors of the ERK pathway as anticancer drugs. Although promising results have been reported in early trials for inhibitors of RAF or MEK, resistance invariably occurs. Amplification of the upstream oncogenic driver of ERK signaling has been identified as a mechanism for MEK inhibitor resistance in cells with mutant BRAF or KRAS. Increased abundance of the oncogenic driver (either KRAS or BRAF in the appropriate cellular context) in response to prolonged drug treatment results in increased flux through the ERK pathway and restoration of ERK activity above the threshold required for cell growth. For patients with BRAF mutant tumors, the results suggest that the addition of a RAF inhibitor to a MEK inhibitor may delay or overcome drug resistance. The data thus provide a mechanistic basis for ongoing trials testing concurrent treatment with RAF and MEK inhibitors.
Update on Paramutation in Maize Trans-Homolog Interactions Facilitating Paramutation in Maize

Paramutations represent locus-specific trans-homolog interactions affecting the heritable silencing properties of endogenous alleles. Although examples of paramutation are well studied in maize (Zea mays), the responsible mechanisms remain unclear. Genetic analyses indicate roles for plant-specific DNA-dependent RNA polymerases that generate small RNAs, and current working models hypothesize that these small RNAs direct heritable changes at sequences often acting as transcriptional enhancers. Several studies have defined specific sequences that mediate paramutation behaviors, and recent results identify a diversity of DNA-dependent RNA polymerase complexes operating in maize. Other reports ascribe broader roles for some of these complexes in normal genome function. This review highlights recent research to understand the molecular mechanisms of paramutation and examines evidence relevant to small RNA-based modes of transgenerational epigenetic inheritance.
Hormone therapy following surgery in low-grade endometrial stromal sarcoma: Is it related to a decrease in recurrence rate?

Background: Low-grade endometrial stromal sarcoma (LGESS) is, in most cases, a slow-growing malignancy; however, it is related with high recurrence rates. The aim of this study is to determine which factors may be associated with the recurrence rate of LGESS. Methods: The clinicopathological features and treatment options in 37 patients with LGESS were evaluated. Results: All patients underwent the hysterectomy and bilateral salpingo-oophorectomy. Additionally, lymphadenectomy was performed in 56.8% (n = 21) of the patients. Among the patients who underwent lymphadenectomy, 14.3% (n = 3) had lymph node metastasis. The disease was limited to the uterus in 75.7% of patients. Treatment following surgery was radiotherapy in three patients, chemotherapy in seven patients, hormone therapy in 12 patients, and chemotherapy plus hormone therapy in one patient. Megestrol acetate was used in all patients who received hormone therapy. Median follow-up time was 96 months. The 5-year disease-free survival and disease-specific survival were 72% and 97%, respectively. The recurrence rate was 27%. Only hormone therapy following surgery was significantly associated with a lower recurrence rate, even in patients with stage 1 disease. None of the patients treated with hormone therapy following surgery had recurrence, whereas recurrence occurred in 38.5% of the patients who underwent surgery only (p = 0.039). Conclusion: Hormone therapy after surgery should be considered a viable option for decreasing the LGESS recurrence rate, regardless of the disease stage.