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Resistance to platinum-based chemotherapy becomes a major obstacle in non-small-cell lung cancer (NSCLC) treatment. Overexpression of the excision repair cross-complementing 1 (ERCC1) gene is reported to negatively influence the effectiveness of cisplatin-based therapy for NSCLC cells. In this study, we confirm that high ERCC1 expression correlates with cisplatin resistance in NSCLC cells. Importantly, histone deacetylase inhibitors (HDACis) re-sensitize ERCC1-high NSCLC cells to cisplatin both in vitro and in vivo. Mechanistically, the HDACi induces the expression of miR-149 by acetylation and activation of E2F1, which directly targets ERCC1 and inhibits ERCC1 expression. Inhibition of miR-149 reverses the promotion effect of HDACis on cisplatin-induced DNA damage and cell apoptosis in ERCC1-high NSCLC cells. In conclusion, this study reveals a novel mechanism by which HDACis re-sensitizes ERCC1-high NSCLC cells to cisplatin via regulation of the E2F1/miR-149/ERCC1 axis, and we propose that combination of HDACis and cisplatin might hold promise to be a more effective therapeutic paradigm for ERCC1-high NSCLCs.Despite remarkable responses to cancer immunotherapy in a subset of patients, many patients remain resistant to therapies. It is now clear that elevated levels of tumor-infiltrating T cells as well as a systemic anti-tumor immune response are requirements for successful immunotherapies. However, the tumor microenvironment imposes an additional resistance mechanism to immunotherapy. We have developed a practical and improved strategy for cancer immunotherapy using an oncolytic virus and anti-OX40. This strategy takes advantage of a preexisting T cell immune repertoire in vivo, removing the need to know about present tumor antigens. We have shown in this study that the replication-deficient oncolytic Sindbis virus vector expressing interleukin-12 (IL-12) (SV.IL12) activates immune-mediated tumor killing by inducing OX40 expression on CD4 T cells, allowing the full potential of the agonistic anti-OX40 antibody. The combination of SV.IL12 with anti-OX40 markedly changes the transcriptome signature and metabolic program of T cells, driving the development of highly activated terminally differentiated effector T cells. These metabolically reprogrammed T cells demonstrate enhanced tumor infiltration capacity as well as anti-tumor activity capable of overcoming the repressive tumor microenvironment. Our findings identify SV.IL12 in combination with anti-OX40 to be a novel and potent therapeutic strategy that can cure multiple types of low-immunogenic solid tumors.Background Little is known about survival and quality of life (QoL) of patients treated by transcatheter aortic valve implantation (TAVI) compared to the age- and sex-matched general population. In this study we compared subgroups of the National Heart Registration TAVI cohort to the Dutch age- and sex-matched population at the level of survival and QoL. Methods and results From the Netherlands Heart Registration (NHR) the TAVI cohort (5489 patients, period 2013-2017) was extracted. These data were compared to the national Dutch population data collected from the national statistics office, Statistics Netherlands (CBS). Subgroups were defined according to sex and age (80 years) had the same survival as the age-matched general population (46vs43% at 5 years, respectively). Survival in women was better than in men in both the general population and the TAVI cohort. Patients treated by TAVI, aged 65 years and older had a comparable QoL to that of the general population. Conclusions This study shows that TAVI patients aged 80 years and older have a similar long-term survival as an age-matched general population. However, because of lower survival in under 80 TAVI patients, the overall long term survival of all TAVI patients is worse than that of the general population in the Netherlands. This study also suggests that QoL after TAVI treatment is comparable to QoL in the general population.Introduction This study aimed to identify the relationship of sociodemographic variables with older adults participation in an online registry for recruitment and longitudinal assessment in cognitive aging. Methods Using Brain Health Registry (BHR) data, associations between sociodemographic variables (sex, race, ethnicity, education) and registry participation outcomes (task completion, willingness to participate in future studies, referral/enrollment in other studies) were examined in adults aged 55+ (N = 35,919) using logistic regression. All models included sex, race, ethnicity, education, age, and subjective memory concern. Results Non-white race, being Latino, and lower educational attainment were associated with decreased task completion and enrollment in additional studies. Results for sex were mixed. Discussion The findings provide novel information about engagement in online aging-related registries, and highlight a need to develop improved engagement strategies targeting underrepresented sociodemographic groups. Increasing registry diversity will allow researchers to refer more representative populations to Alzheimer's and related dementias prevention and treatment trials.Female Genital Mutilation or Cutting (FGM) and its medicalisation remain a challenge in sub-Sahara African (SSA). Early identification of at-risk women might help in instituting focused counselling against FGM medicalisation. We hypothesised that the risk of medicalised FGM by girls/women is associated with socioeconomic status (SES) their household belongs. We used 2010-2019 Demographic and Health surveys data from 13 countries in SSA. We analysed information on 214,707 women (Level 1) nested within 7299 neighbourhoods (Level 2) from the 13 countries (Level 3). We fitted 5 multivariable binomial multilevel logistic regression models using the MLWin 3.03 module in Stata. The estimation algorithms adopted was the first order marginal quasi-likelihood linearisation using the iterative generalised least squares. The odds of FGM medicalisation increased with the wealth status of the household of the woman, with 29%, 45%- and 75%-times higher odds in the middle, richer and richest household wealth quintiles, respectively than those from the poorest households (p less then 0.05). The more educated a woman and the better a woman's community SES was, the higher her odds of reporting medicalisation of FGM. Rural community was associated with higher odds of medicalised FGM than urban settings. Medicalised FGM is common among women from a high socioeconomic, educational background and rural settings of SSA. We recommend a culturally sensitive policy that will discourage perpetuation of FGM, particularly by healthcare providers. Future studies should focus on identifying drivers of FGM among the high social class families in the society in SSA.Smoke-free legislations aim to protect non-smokers from second-hand smoke (SHS) exposure and improve population health outcomes. The aim of this study was to explore residents' perceptions to understand how people living in distinctive SES neighborhoods are differently affected by comprehensive smoke-free laws in a large city like Madrid, Spain. We conducted a qualitative project with 37 semi-structured interviews and 29 focus group discussions in three different SES neighborhoods within the city of Madrid. Constructivist grounded theory was used to analyze the transcripts. Selleck AZD2811 One core category arose in our analyses Neighborhood inequalities in second-hand smoke (SHS) exposure in outdoor places. The enactment of the comprehensive smoke-free law resulted in unintended consequences that affected neighborhoods differently relocation of smokers to outdoor setting, SHS exposure, noise disturbance and cigarette butt littering. Changes in the urban environment in the three neighborhoods resulted in the denormalization of smoking in outdoor public places, which was more clearly perceived in the high SES neighborhood. Changes in the built environment in outdoor areas of hospitality venues were reported to actually facilitate smoking. Comprehensive smoke-free laws resulted in denormalization of smoking, which might be effective in reducing SHS exposure. Extending smoking bans to outdoor areas like bus stops and hospitality venues is warranted and should include a public health inequalities perspective.We present a case of a complex proximal humerus fracture combined with an articular glenoid fracture, in an elderly patient. This is a rare combination of injuries, and its proper treatment is scarcely described in the current literature. Our selected treatment consisted of reverse shoulder arthroplasty combined with glenoid fracture fixation, which has been reported only once in the current literature. At 18 months follow-up we report a result consisting of great pain control, appropriate mobility and functional score, and absence of signs of glenohumeral instability or implant loosening, which is in line with has been previously described. We conclude that this surgical approach is a great alternative to others such as reverse shoulder arthroplasty combined with glenoid grafting, or shoulder hemiarthroplasty.Background Paper-analytical devices (PADs) have gained popularity as a simple and low-cost alternative for determining a wide range of analytes including proteins. Even though several colorimetric PADs methods for protein estimation are reported in literature, they lack justification for the chosen method and parameters therein. Aim Major aim of this work was to thoroughly evaluate the most commonly used colorimetric protein assays and recommend the most appropriate method for PADs platform. Method We performed following six colorimetric protein assays on PADs biuret, lowry, bicinchoninic acid, bradford, bromocresol green, and tetrabromophenol blue. We obtained assay signal by analyzing images of the PADs and then assessed analytical figures of merit. Result Precision, accuracy, LOD, and LOQ of PADs protein assay methods ranged from 1.2 to 6.4%, 73.3-102.4%, 0.3-3.8 mg/mL, and 1.2-12.8 mg/mL, respectively. Out of six methods, we determined bromocresol green and tetrabromophenol blue as the best methods for serum and urine samples, respectively based on their optimized parameters and analytical figures of merit. The total average serum and urine protein in human samples were found to be 94.6 ± 16.2 mg/mL and 2.1 ± 1.5 mg/mL, respectively using PADs methods. The PADs result on human samples moderately correlated with the results from spectrophotometric determination (r2 > 0.6). link2 Conclusion Paper-based protein assays were easy to perform and were completed with thousand-fold less volume of samples/reagents without a spectrophotometer compared to conventional assay methods. link3 After testing human samples, we found one protein assay method may not be appropriate for all types of samples.Microbacterium are Gram-positive, nonspore-forming, rod-shaped bacteria inhabiting a wide range of environments including soil, water, dairy products, other living organisms, etc. Microbacterium sp. strain Be9, isolated from mill tailings porewaters in France, shows a remarkable behavior in presence of uranium under distinct conditions, which is the main reason for the interest in sequencing its genome. In this work, we describe the draft genome sequence of Be9, comprising 4,046,806 bp, with a G+C content of 68.10% and containing 3,947 protein-coding sequences. The preliminary genome annotation analysis identified some genes encoding for resistance to antibiotics and toxic compounds like heavy metals. This draft genome has been deposited at DDBJ/ENA/GenBank under the accession PRJNA590666.
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