Deciphering LAG-3: unveiling molecular mechanisms and clinical advancements.

Treatment based on immune checkpoint blockade has revolutionized cancer therapy. Despite the remarkable success achieved and the preclinical development of multiple checkpoint inhibitors targeting other checkpoints, only antibodies targeting the PD-1/PD-L1 axis and CTLA-4 have been approved for patient treatment, especially in solid tumors. Currently, with the approval of relatlimab, a LAG-3 blocking antibody, a third player, has been used in the fight against cancer. The endorsement of relatlimab marks a significant milestone in cancer immunotherapy, opening new avenues for combination therapies and enhancing treatment outcomes. However, the complex biology of LAG-3 may hinder its full development as a therapeutic alternative. In this review, we provide in-depth insight into the biology of LAG-3 and its current and future development in cancer treatment.

An in-depth analysis of data reduction methods for sustainable deep learning.

In recent years, deep learning has gained popularity for its ability to solve complex classification tasks. It provides increasingly better results thanks to the development of more accurate models, the availability of huge volumes of data and the improved computational capabilities of modern computers. However, these improvements in performance also bring efficiency problems, related to the storage of datasets and models, and to the waste of energy and time involved in both the training and inference processes. In this context, data reduction can help reduce energy consumption when training a deep learning model. In this paper, we present up to eight different methods to reduce the size of a tabular training dataset, and we develop a Python package to apply them. We also introduce a representativeness metric based on topology to measure the similarity between the reduced datasets and the full training dataset. Additionally, we develop a methodology to apply these data reduction methods to image datasets for object detection tasks. Finally, we experimentally compare how these data reduction methods affect the representativeness of the reduced dataset, the energy consumption and the predictive performance of the model.

The gender gap in outpatient care for non-communicable diseases in Mexico between 2006 and 2022.

BACKGROUND: Equitable health service utilization is key to health systems' optimal performance and universal health coverage. The evidence shows that men and women use health services differently. However, current analyses have failed to explore these differences in depth and investigate how such gender disparities vary by service type. This study examined the gender gap in the use of outpatient health services by Mexican adults with non-communicable diseases (NCDs) from 2006 to 2022. METHODS: A cross-sectional population-based analysis of data drawn from National Health and Nutrition Surveys of 2006, 2011-12, 2020, 2021, and 2022 was performed. Information was gathered from 300,878 Mexican adults aged 20 years and older who either had some form of public health insurance or were uninsured. We assessed the use of outpatient health services provided by qualified personnel for adults who reported having experienced an NCD and seeking outpatient care in the 2 weeks before the survey. Outpatient service utilization was disaggregated into four categories: non-use, use of public health services from providers not corresponding to the user's health insurance, use of public health services from providers not corresponding to the user's health insurance, and use of private services. This study reported the mean percentages (with 95% confidence intervals [95% CIs]) for each sociodemographic covariate associated with service utilization, disaggregated by gender. The percentages were reported for each survey year, the entire study period, the types of service use, and the reasons for non-use, according to the type of health problem. The gender gap in health service utilization was calculated using predictive margins by gender, type of disease, and survey year, and adjusted through a multinomial logistic regression model. RESULTS: Overall, we found that women were less likely to fall within the "non-use" category than men during the entire study period (21.8% vs. 27.8%, P < 0.001). However, when taking into account the estimated gender gap measured by incremental probability and comparing health needs caused by NCDs against other conditions, compared with women, men had a 7.4% lower incremental likelihood of falling within the non-use category (P < 0.001), were 10.8% more likely to use services from providers corresponding to their health insurance (P < 0.001), and showed a 12% lower incremental probability of using private services (P < 0.001). Except for the gap in private service utilization, which tended to shrink, the others remained stable throughout the period analyzed. CONCLUSION: Over 16 years of outpatient service utilization by Mexican adults requiring care for NCDs has been characterized by the existence of gender inequalities. Women are more likely either not to receive care or resort to using private outpatient services, often resulting in catastrophic out-of-pocket expenses for them and their families. Such inequalities are exacerbated by the segmented structure of the Mexican health system, which provides health insurance conditional on formal employment participation. These findings should be considered as a key factor in reorienting NCD health policies and programs from a gender perspective.

Persistency of catastrophic out-of-pocket health expenditures: Measurement with evidence from three African countries - Malawi, Tanzania, and Uganda.

Catastrophic out-of-pocket health expenditure (CHE) remain high in Sub-Saharan Africa and may not conform to the sporadic random pattern of acute illnesses that shapes insurance arrangements intended to avoid the risk of financial loss. The persistency of CHE remains a largely unexplored issue due to the lack of relevant methods and scarcity of panel data. This paper addresses the first shortcoming by presenting three different approaches to incorporating the timeframes into the analysis, considering dynamics between two periods, average over time and the recurrence of CHE incidence. Through the application of the complementary approaches, we identify (i) those at risk of persistent CHE in the short-term; (ii) those facing transient versus persistent CHE in the long-term; and (iii) those facing multiple CHE spells. The methods are applied to different definitions of CHE using panel data from three sub-Saharan countries: Malawi (3 waves: 2010, 2013, and 2016) with 4983 observations; Tanzania (3 waves: 2008, 2010, and 2012) with 8715 observations; and Uganda (5 waves: 2009, 2010, 2011, 2013, and 2015) with 6475 observations. All datasets are balanced panels. Additionally, we employ empirical strategies to identify the underlying factors contributing to these persistent and relatively high OOP. Across the three countries, we find that at least 27% of the people facing CHE in one period, because they spent more than 5% of their household budget on health out-of-pocket, will face it again in the next period. The lower-bound risk for those spending more than 10% of their household budget is 9% and for those spending more than 25% of their household capacity to pay is 13%. Between 11% and 45% of the population incurred CHE at least twice during the observation period when using the 5% budget definition of CHE. The double recurrence rate ranges between 7% and 13% when using the 25% capacity-to-pay definition and between 3% and 20% when using the 10% budgetshare definition. Between 22% and 32% of the population experienced chronic CHE at the 5% of the budgetshare definition (6%-10% at the 10% of the budgetshare definition of CHE; 2%-11% at 25% of capacity-to-pay). Our panel regression analysis consistently highlights the susceptibility of certain groups to face persistence CHE, notably those residing in rural areas, individuals with lower levels of education, the elderly, and those who have undergone hospitalizations.

Sex-Related Differences in Life Expectancy Compared to General Population after Surgery for Ascending Aortic Aneurysm.

Background/Objectives: Understanding sex-based differences in cardiovascular outcomes is paramount to improving clinical outcomes. Surgery is an aggressive but effective therapy for ascending aortic aneurysm. We sought to determine if being a woman is a risk factor for long-term mortality after this surgery. We compared their life expectancy with a general population of the same age, sex, year, and region. Methods: We compared men and women undergoing AAA surgery at our institution from 2000 to 2019. After balancing the population with propensity score (PS) matching, we compared long-term mortality control with a Cox regression. We determined the RS using the Ederer II method and compared it to a healthy reference population of the same age, sex, and region. Results: From 2000 to 2019, 232 women and 506 men underwent ascending aortic aneurysm surgery. After a mean follow-up of 51.5 ± 34.5 months, sex was not an independent risk factor for long-term mortality in the multivariable analysis [HR: 0.68 (95% CI 0.43-1.07, p = 0.23)]. Matching by baseline characteristics, 196 pairs were analyzed with no differences regarding mortality in the Cox regression [HR: 1.11 (95% CI 0.65-1.9, p = 0.23)]. Men and women who survived the postoperative period presented a relative survival of 100.3% (95% CI 97.4-101%) and 100.3% (95% CI 98.9-101.1%), respectively, similar to the reference population without the disease. Conclusions: For patients undergoing AAA surgery, sex was not an independent predictor of mortality. Men and women who survived the postoperative period presented a similar life expectancy to that of the reference population (people free from the disease of the same age, sex, year, and region).

Cardiopulmonary Complications after Pulmonary Embolism in COVID-19.

Although pulmonary embolism (PE) is a frequent complication in COVID-19, its consequences remain unknown. We performed pulmonary function tests, echocardiography and computed tomography pulmonary angiography and identified blood biomarkers in a cohort of consecutive hospitalized COVID-19 patients with pneumonia to describe and compare medium-term outcomes according to the presence of PE, as well as to explore their potential predictors. A total of 141 patients (56 with PE) were followed up during a median of 6 months. Post-COVID-19 radiological lung abnormalities (PCRLA) and impaired diffusing capacity for carbon monoxide (DLCOc) were found in 55.2% and 67.6% cases, respectively. A total of 7.3% had PE, and 6.7% presented an intermediate-high probability of pulmonary hypertension. No significant difference was found between PE and non-PE patients. Univariate analysis showed that age > 65, some clinical severity factors, surfactant protein-D, baseline C-reactive protein, and both peak red cell distribution width and Interleukin (IL)-10 were associated with DLCOc < 80%. A score for PCRLA prediction including age > 65, minimum lymphocyte count, and IL-1ß concentration on admission was constructed with excellent overall performance. In conclusion, reduced DLCOc and PCRLA were common in COVID-19 patients after hospital discharge, but PE did not increase the risk. A PCRLA predictive score was developed, which needs further validation.

Plasma levels of complement components C5 and C9 are associated with thrombin generation.

BACKGROUND: The thrombin generation assay (TGA) evaluates the potential of plasma to generate thrombin over time, providing a global picture of an individual's hemostatic balance. OBJECTIVES: This study aimed to identify novel biological determinants of thrombin generation using a multiomics approach. METHODS: Associations between TGA parameters and plasma levels of 377 antibodies targeting 236 candidate proteins for cardiovascular risk were tested using multiple linear regression analysis in 770 individuals with venous thrombosis from the Marseille Thrombosis Association (MARTHA) study. Proteins associated with at least 3 TGA parameters were selected for validation in an independent population of 536 healthy individuals (Etablissement Français du Sang Alpes-Méditerranée [EFS-AM]). Proteins with strongest associations in both groups underwent additional genetic analyses and in vitro experiments. RESULTS: Eighteen proteins were associated (P < 1.33 × 10⁻4) with at least 3 TGA parameters in MARTHA, among which 13 demonstrated a similar pattern of associations in EFS-AM. Complement proteins C5 and C9 had the strongest associations in both groups. Ex vivo supplementation of platelet-poor plasma with purified C9 protein had a significant dose-dependent effect on TGA parameters. No effect was observed with purified C5. Several single nucleotide polymorphisms associated with C5 and C9 plasma levels were identified, with the strongest association for the C5 missense variant rs17611, which was associated with a decrease in C5 levels, endogenous thrombin potential, and peak in MARTHA. No association of this variant with TGA parameters was observed in EFS-AM. CONCLUSION: This study identified complement proteins C5 and C9 as potential determinants of thrombin generation. Further studies are warranted to establish causality and elucidate the underlying mechanisms.

Combined PIK3CA and SOX2 Gene Amplification Predicts Laryngeal Cancer Risk beyond Histopathological Grading.

The PIK3CA and SOX2 genes map at 3q26, a chromosomal region frequently amplified in head and neck cancers, which is associated with poor prognosis. This study explores the clinical significance of PIK3CA and SOX2 gene amplification in early tumorigenesis. Gene copy number was analyzed by real-time PCR in 62 laryngeal precancerous lesions and correlated with histopathological grading and laryngeal cancer risk. Amplification of the SOX2 and PIK3CA genes was frequently detected in 19 (31%) and 32 (52%) laryngeal dysplasias, respectively, and co-amplification in 18 (29%) cases. The PIK3CA and SOX2 amplifications were predominant in high-grade dysplasias and significantly associated with laryngeal cancer risk beyond histological criteria. Multivariable Cox analysis further revealed PIK3CA gene amplification as an independent predictor of laryngeal cancer development. Interestingly, combined PIK3CA and SOX2 amplification allowed us to distinguish three cancer risk subgroups, and PIK3CA and SOX2 co-amplification was found the strongest predictor by ROC analysis. Our data demonstrate the clinical relevance of PIK3CA and SOX2 amplification in early laryngeal tumorigenesis. Remarkably, PIK3CA amplification was found to be an independent cancer predictor. Furthermore, combined PIK3CA and SOX2 amplification is emerging as a valuable and easy-to-implement tool for cancer risk assessment in patients with laryngeal precancerous lesions beyond current WHO histological grading.

Manejo de Alteraciones Neurosensoriales Asociadas a Procedimientos Quirúrgicos Mandibulares, Scoping Review

Las alteraciones neurosensoriales son complicaciones que se pueden presentar posterior a la realización de ciertos procedimientos quirúrgicos orales. Múltiples reportes indican específicamente el territorio inervado por el nervio alveolar inferior y nervio lingual como las regiones mayormente afectadas. Dar a conocer las diferentes alternativas terapéuticas para estas complicaciones, sería de suma relevancia para el clínico, con el propósito de mejorar el pronóstico en cuanto a la recuperación neurosensorial de estos nervios. El objetivo de este trabajo fue describir el manejo terapéutico de las alteraciones neurosensoriales asociadas al daño del nervio alveolar inferior y nervio lingual, en procedimientos quirúrgicos mandibulares. La búsqueda de la literatura científica fue realizada en las bases de datos PubMed, Scopus y Web of Science. Se utilizaron los términos de búsqueda "Trigeminal nerve injuries", "lingual nerve", "mandibular nerve", "oral surgical procedures", "treatment" en conjunto al conector booleano "AND" y "OR". Fueron considerados artículos publicados entre los años 2012 y 2022. En la selección de los artículos primarios se eliminaron los duplicados y se aplicaron los criterios de inclusión y exclusión. Finalmente se realizó el análisis a texto completo con un total de 14 artículos seleccionados. Un total de 14 artículos fueron revisados. Del total de artículos, 6 corresponden a terapia láser de bajo nivel, 2 a medicación y bloqueo del ganglio estrellado, 1 a bloqueo de ganglio estrellado e irradiación con luz xenón y 5 artículos corresponden a tratamiento mediante reparación microquirúrgica. La terapia láser de bajo nivel, el bloqueo del ganglio estrellado, la administración de vitamina B12/ATP y la reparación microquirúrgica son tratamientos efectivos para las alteraciones neurosensoriales ocasionadas por lesiones del nervio alveolar inferior y nervio lingual.

SUMMARY: Neurosensory abnormalities are complications can occur after performing certain oral surgical procedures. Multiple reports specifically indicate the area innervated by the inferior alveolar nerve and the lingual nerve as the most affected regions. Presenting the different therapeutic alternatives for these complications would be extremely relevant for the clinician, in order to improve the prognosis in terms of neurosensory recovery of these nerves. The objective of this study was to describe the therapeutic management of neurosensory abnormalities associated with damage to the inferior alveolar nerve and lingual nerve, in mandibular surgical procedures. The search for scientific literature was carried out in the PubMed, Scopus and Web of Science databases. The search terms "Trigeminal nerve injuries", "lingual nerve", "mandibular nerve", "oral surgical procedures", "treatment" together with the boolean connector "AND" and "OR" were used. Articles published between the years 2012 and 2022 were considered. In the selection of primary articles, duplicates were eliminated and the inclusion and exclusion criteria were applied. Finally, the full text analysis was carried out with a total of 14 selected articles. A total of 14 articles were reviewed. About the articles, 6 correspond to low-level laser therapy, 2 to medication and stellate ganglion block, 1 to stellate ganglion block and xenon light irradiation, and 5 articles correspond to treatment by microsurgical repair. Low-level laser therapy, stellate ganglion block, vitamin B12/ATP administration, and microsurgical repair are effective treatments for neurosensory abnormalities caused by inferior alveolar nerve and lingual nerve injuries.

Equity in out-of-pocket health expenditure: Evidence from a health insurance program reform in Mexico.

Background: The fragmentation of health systems in low- and middle-income countries (LMICs) deepens health inequities and shifts the economic burden of health care to families via out-of-pocket spending (OOPHE). This problem has been addressed by introducing public health insurance programs for poor people; however, there is a lack of knowledge about how equitable these programs are. We aimed to analyse the long-term effects of the Seguro Popular (SP) voluntary health insurance program, recently phased out and replaced by the Health Institute for Welfare (Instituto de Salud para el Bienestar (INSABI)), on OOPHE equity in the poor Mexican population. Methods: We conducted a pooled cross-sectional analysis using eleven waves of the National Household Income and Expenditure Survey (2002-2020). We identified the effect of SP by selecting households without social security (with SP or without health insurance (n = 169 766)) and matched them by propensity score to reduce bias in the decision to enrol in SP. We estimated horizontal and vertical equity metrics and assessed their evolution across subpopulations. Results: The program's entry years (2003-2010) show a positive redistributive effect associated with a focalised stage of the program, while oversaturation could have diluted these effects during 2010-2014, with adverse results in terms of vertical equity and re-ranking among insured families. SP is more horizontally inequitable than for those uninsured. Within SP, the redistributive effect could improve up to 13% if all families with similar expenditures were spending equal OOPHE and horizontal equity was eliminated. Regarding vertical equity, SP outperforms the insured population with middle-range coverage some years after the implementation, but this progress disappears. Conclusions: To achieve universal health coverage, health authorities need to create and execute financial protection mechanisms that effectively address structural inequalities. This involves implementing a more comprehensive risk-pooling mechanism that makes social insurance sustainable in the long-run by increasing the social-economic influx of resources. It is essential to monitor oversaturation and financial sustainability to achieve optimal results. The replacement of the SP with INSABI highlights the complexity of maintaining a social insurance program where the ideology of different governments can influence the program structure, regulation, financing, and even its existence.

Inequitable Financial Protection in Health for Indigenous Populations: the Mexican Case.

BACKGROUND: There is an important gap in the literature concerning the level, inequality, and evolution of financial protection for indigenous (IH) and non-indigenous (NIH) households in low- and middle-income countries. This paper offers an assessment of the level, socioeconomic inequality and middle-term trends of catastrophic (CHE), impoverishing (IHE), and excessive (EHE) health expenditures in Mexican IHs and NIHs during the period 2008-2020. METHODS: We conducted a pooled cross-sectional analysis using the last seven waves of the National Household Income and Expenditure Survey (n = 315,829 households). We assessed socioeconomic inequality in CHE, IHE, and EHE by estimating their Wagstaff concentration indices according to indigenous status. We adjusted the CHE, IHE, and EHE by estimating a maximum-likelihood two-stage probit model with robust standard errors. RESULTS: We observed that, during the period analyzed, CHE, IHE, and EHE were concentrated in the poorest IHs. CHE decreased from 5.4% vs. 4.7% in 2008 to 3.4% vs. 2.9% in 2014 in IHs and NIHs, respectively, and converged at 2008 levels towards 2020. IHE remained unchanged from 2008 to 2014 (1.6% for IHs vs. 1.0% for NIHs) and increased by 40% in IHs and NIHs during 2016-2020. EHE plunged in 2014 (4.6% in IHs vs. 3.8% in NIHs), then rose, and remained unchanged during 2016-2020 (6.7% in IHs and 5.6% in NIHs). CONCLUSION: In pursuit of universal health coverage, health authorities should formulate and implement effective financial protection mechanisms to address structural inequalities, especially forms of discrimination including racialization, that vulnerable social groups such as indigenous peoples have systematically faced. Doing so would contribute to closing the persistent ethnic gaps in health.

Beyond the anti-PD-1/PD-L1 era: promising role of the BTLA/HVEM axis as a future target for cancer immunotherapy.

Recent introduction of monoclonal antibodies targeting immune checkpoints to harness antitumor immunity has revolutionized the cancer treatment landscape. The therapeutic success of immune checkpoint blockade (ICB)-based therapies mainly relies on PD-1/PD-L1 and CTLA-4 blockade. However, the limited overall responses and lack of reliable predictive biomarkers of patient´s response are major pitfalls limiting immunotherapy success. Hence, this reflects the compelling need of unveiling novel targets for immunotherapy that allow to expand the spectrum of ICB-based strategies to achieve optimal therapeutic efficacy and benefit for cancer patients. This review thoroughly dissects current molecular and functional knowledge of BTLA/HVEM axis and the future perspectives to become a target for cancer immunotherapy. BTLA/HVEM dysregulation is commonly found and linked to poor prognosis in solid and hematological malignancies. Moreover, circulating BTLA has been revealed as a blood-based predictive biomarker of immunotherapy response in various cancers. On this basis, BTLA/HVEM axis emerges as a novel promising target for cancer immunotherapy. This prompted rapid development and clinical testing of the anti-BTLA blocking antibody Tifcemalimab/icatolimab as the first BTLA-targeted therapy in various ongoing phase I clinical trials with encouraging results on preliminary efficacy and safety profile as monotherapy and combined with other anti-PD-1/PD-L1 therapies. Nevertheless, it is anticipated that the intricate signaling network constituted by BTLA/HVEM/CD160/LIGHT involved in immune response regulation, tumor development and tumor microenvironment could limit therapeutic success. Therefore, in-depth functional characterization in different cancer settings is highly recommended for adequate design and implementation of BTLA-targeted therapies to guarantee the best clinical outcomes to benefit cancer patients.

First report of Fusarium clavum causing garlic bulb rot in Mexico.

In Mexico, the main states for garlic (Allium sativum L.) production are Zacatecas, Guanajuato, and Puebla. In the 2020 crop season, garlic cultivation encompassed 6,794 ha, yielding 85,505 tons (SIAP, 2021). In February 2020, 35 garlic samples showing basal rot symptoms were collected from the garlic-growing regions in the states of Zacatecas and Aguascalientes in the municipalities of San Antonio Tepezala 22°13'13.5''N, 102°15'55.3''W, Rincón de Romos 22°17'44.9''N, 102°13'06.8''W, and Calera 22°58'39.4''N and 102°41'29.9W, respectively. The sampling carried out was random sampling by conglomerates, dividing each field in groups with plants that showed similar symptoms. The infected plants were stunted in growth, with reddish dying leaves. The stalks and bulbs were soft, and their root system was poorly developed. The collected samples were placed in polyethylene bags and taken to laboratory. The roots and bulbs of 35 plants were cleaned, portions of the diseased tissue was cut into 0.5 cm pieces and disinfected in 1% sodium hypochlorite for 3 minutes. The samples were rinsed twice with sterile distilled water and dried on sterile paper towels. The tissues were cultured on Potato Dextrose Agar (PDA) medium and incubated in the dark at 25°C. Seven days after incubation, pure cultures were obtained using monoconidial cultures technique on Spezieller Nährstoffmmarmer agar (SNA) and subcultured on carnation leaf agar (CLA). Ten isolates were obtained that grew slowly, showing a white coloration, then turning yellow with abundant aerial mycelia. Microscopic traits of 30 characterized spores included slender macroconidia that were curved dorsiventrally, tapering towards both ends, with five to seven thin septa, measuring 36.4-56.6 µm × 4.0-4.9 µm in size and chlamydospores that were abundant, globose to oval, subhyaline and terminal or intercalary in chains measuring 8.8-4.5 µm in diameter. Microconidia, were single-celled, hyaline, nonseptate, and ovoid. The morphological traits matched the description of Fusarium clavum (Xia et al. 2019). To confirm the strain's identity, DNA was extracted from six monoconidial cultures and used as template to amplify translation elongation factor (TEF) gene 1α, RNA polymerase largest subunit (RPB1), and RNA polymerase second largest subunit (RPB2) (O'Donnell et al. 2010). The products were sequenced and deposited in GenBank as ON209360, OM640008 and OM640009, the homology analysis using BLASTn was similar to F. clavum with 99.46%, 99.49% and 98.82% respectively with E VALUE 0.0 in all cases with access numbers OP48709, HM347171 and OP486686. Koch postulate was performed to confirm the pathogenicity of the six isolates. Variegated garlic cloves were planted after being disinfected with sodium hypochlorite at 3% w/v in 2-kg pots under the greenhouse conditions. When the garlic plants developed 4 or 5 true leaves, their basal stalks were inoculated by pouring uniformly with 1 mL of a spore suspension at 108 conidia/mL prepared from 1-week-old colonies (Lai et al. 2020). Twenty-four plants were inoculated with six isolates (four plants per isolate), and four control plants were treated with sterile distilled water. Symptoms appeared 20 days post-inoculation. The leaves were reddish, and the stalks were soft. The leaves eventually developed foliar dieback disease symptoms, their root system showed brown lesions and rot, and all water-inoculated controls remained asymptomatic. Isolations were made on the diseased plants, and the inoculated pathogen was recovered and confirmed morphologically and molecularly by DNA extraction and PCR reactions. Koch's postulate was repeated twice, obtaining the same results. To our best knowledge, this is the first report of F. clavum infecting Allium sativum L. in Mexico. bulb rot caused by F. clavum is a severe threat to garlic cultivation, and identification of this pathogen is important for effective disease management and control.

The TINCR ubiquitin-like microprotein is a tumor suppressor in squamous cell carcinoma.

The TINCR (Terminal differentiation-Induced Non-Coding RNA) gene is selectively expressed in epithelium tissues and is involved in the control of human epidermal differentiation and wound healing. Despite its initial report as a long non-coding RNA, the TINCR locus codes for a highly conserved ubiquitin-like microprotein associated with keratinocyte differentiation. Here we report the identification of TINCR as a tumor suppressor in squamous cell carcinoma (SCC). TINCR is upregulated by UV-induced DNA damage in a TP53-dependent manner in human keratinocytes. Decreased TINCR protein expression is prevalently found in skin and head and neck squamous cell tumors and TINCR expression suppresses the growth of SCC cells in vitro and in vivo. Consistently, Tincr knockout mice show accelerated tumor development following UVB skin carcinogenesis and increased penetrance of invasive SCCs. Finally, genetic analyses identify loss-of-function mutations and deletions encompassing the TINCR gene in SCC clinical samples supporting a tumor suppressor role in human cancer. Altogether, these results demonstrate a role for TINCR as protein coding tumor suppressor gene recurrently lost in squamous cell carcinomas.

Blood Coagulation and Beyond: Position Paper from the Fourth Maastricht Consensus Conference on Thrombosis.

The Fourth Maastricht Consensus Conference on Thrombosis included the following themes. Theme 1: The "coagulome" as a critical driver of cardiovascular disease. Blood coagulation proteins also play divergent roles in biology and pathophysiology, related to specific organs, including brain, heart, bone marrow, and kidney. Four investigators shared their views on these organ-specific topics. Theme 2: Novel mechanisms of thrombosis. Mechanisms linking factor XII to fibrin, including their structural and physical properties, contribute to thrombosis, which is also affected by variation in microbiome status. Virus infection-associated coagulopathies perturb the hemostatic balance resulting in thrombosis and/or bleeding. Theme 3: How to limit bleeding risks: insights from translational studies. This theme included state-of-the-art methodology for exploring the contribution of genetic determinants of a bleeding diathesis; determination of polymorphisms in genes that control the rate of metabolism by the liver of P2Y12 inhibitors, to improve safety of antithrombotic therapy. Novel reversal agents for direct oral anticoagulants are discussed. Theme 4: Hemostasis in extracorporeal systems: the value and limitations of ex vivo models. Perfusion flow chamber and nanotechnology developments are developed for studying bleeding and thrombosis tendencies. Vascularized organoids are utilized for disease modeling and drug development studies. Strategies for tackling extracorporeal membrane oxygenation-associated coagulopathy are discussed. Theme 5: Clinical dilemmas in thrombosis and antithrombotic management. Plenary presentations addressed controversial areas, i.e., thrombophilia testing, thrombosis risk assessment in hemophilia, novel antiplatelet strategies, and clinically tested factor XI(a) inhibitors, both possibly with reduced bleeding risk. Finally, COVID-19-associated coagulopathy is revisited.

Targeting oncogenic functions of miR-301a in head and neck squamous cell carcinoma by PI3K/PTEN and MEK/ERK pathways.

Treatment of head and neck squamous cell carcinomas (HNSCC), the sixth most frequent cancer worldwide, remains challenging. miRNA dysregulation is closely linked to tumorigenesis and tumor progression, thus emerging as suitable targets for cancer treatment. Transcriptomic analysis of TCGA HNSCC dataset revealed that miR-301a expression levels significantly increased in primary tumors, as compared to patient-matched normal tissue. This prompted us to investigate its pathobiological role and potential as new therapeutic target using different preclinical HNSCC models. miR-301a overexpression in HNSCC-derived cell lines led to enhanced proliferation and invasion, whereas miR-301 inhibition reduced these effects. In vivo validation was performed using an orthotopic mouse model. Results concordantly showed that the mitotic counts, the percentage of infiltration depth and Ki67 proliferative index were significantly augmented in the subgroup of mice harboring miR-301a-overexpressing tumors. Further mechanistic characterization revealed PI3K/PTEN/AKT and MEK/ERK pathways as central signaling nodes responsible for mediating the oncogenic activity of miR-301a observed in HNSCC cells. Notably, pharmacological disruption of PI3K and ERK signals with BYL-719 and PD98059, respectively, was effective to completely revert/abolish miR-301a-promoted tumor cell growth and invasion. Altogether, these findings demonstrate that miR-301a dysregulation plays an oncogenic role in HNSCC, thus emerging as a candidate therapeutic target for this disease. Importantly, available PI3K and ERK inhibitors emerge as promising anti-tumor agents to effectively target miR-301a-mediated signal circuit hampering growth-promoting and pro-invasive functions.

The influence of meaningful activities in the quality of life and functional autonomy of adults with intellectual disability: A prospective study during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic might negatively impact the quality of life and functional autonomy of Spanish adults with intellectual disability, and meaningful activities could prevent this negative progression. METHODS: This is a prospective cohort study in Spanish adults with intellectual disability during the COVID-19 pandemic. Quality of life, functional autonomy and functional independence were measured. The meaningful activities studied were structured-leisure, community self-management, and occupational and physical activities. RESULTS: Seventy-three participants were included in the study. Quality of life and functional autonomy significantly deteriorated during the COVID-19 pandemic (all p > .001). Greater participation in community self-management activities before COVID-19 was associated with less detriment to quality of life (ß = -.312; p = .008), while greater participation in occupational and physical activities was associated with less detriment to the performance of instrumental activities (ß = -.317; p = .016; and ß = -.285; p = .030, respectively). CONCLUSION: People with intellectual disability living in residential homes experienced a decrease in their quality of life and functional autonomy during the COVID-19 pandemic. Their involvement in community self-management activities and physical and occupational activities before the pandemic had preventive effects on the detriment to the quality of life and functional autonomy.

Association of the Surgical Technique With the Structural Valve Deterioration of a Bioprosthesis: A Prospective Cohort Study.

The Trifecta aortic valve is a prosthesis with externally mounted leaflets and a stent which may be deformed during implant. Our aim was to know if the use of the holder as a protection device during the knotting has an impact on the incidence of structural valve deterioration (SVD) or endocarditis. Prospective cohort study where all patients who underwent aortic valve replacement with a Trifecta aortic valve between 2013 and 2018 were included. The use of the holder as a protection device was collected in a database. Propensity-score matched methods were used and analyses were based on competing events. Death without SVD or prosthesis replacement not due to SVD was considered competing events. 782 patients were included, 352 pairs after the matching. Rates of SVD at 5 and 8 years were 5.8% (95% CI 3.5-8.7) and 13.6% (95% CI 9.2-18.9) in the group without holder and 2.3% (95% CI 1-4.5) and 7% (95% CI 4.2-10.8) in the group with holder; sHR = 0.49 (95% CI 0.27-0.86; P = 0.015). The risk of endocarditis at 8 years was 4.8% (95% CI 2.8-7.4) in the group without holder and 2.3% (95% CI 1.1-4.3) in the group with holder, sHR = 0.49 (95% CI 0.21-1.15, P = 0.1). The use of holder as a protection device during the knotting of the Trifecta aortic valve is associated with less risk of SVD.

Early and mid-term outcomes of transcatheter tricuspid valve repair: systematic review and meta-analysis of observational studies.

INTRODUCTION AND OBJECTIVES: Severe tricuspid regurgitation (TR) is associated with poor prognosis when left untreated, and a growing number of studies on transcatheter tricuspid valve repair (TTVr) have been published over the last few months. METHODS: We performed a comprehensive systematic review of published literature providing clinical data on TTVr for patients with significant TR. Early and mid-term clinical and echocardiographic outcomes were evaluated. Risk ratios (RR) or mean differences (MD) were obtained when comparing pre- and postprocedural data. A sensitivity analysis was also performed according to the main approach for repair (edge-to-edge vs annuloplasty). RESULTS: A total of 19 studies (all observational or single-arm trials) and 991 patients who underwent isolated TTVr were included. Thirty-day mortality and stroke rates were 2.8% and 0.2%, respectively. Pooled random-effects resulted in a significant reduction of ≥ severe TR (RR, 0.33; 95%CI, 0.26-0.42; P < .001), vena contracta width (MD, 5.9mm; 95%CI, 4-7.9; P <.001), right ventricular end-diastolic diameter (MD, 3.5mm; 95%CI, 2.5-4.5; P <.001), and New York Heart Association (NYHA) class III or IV at last follow-up (RR, 0.32; 95%CI, 0.27-0.37; P <.001). Bleeding complications and residual ≥ severe TR were numerically higher in the annuloplasty-like group compared with edge-to-edge repair (13.3% vs 3.8% for bleeding and 40.4% vs 27.9% for residual severe TR). CONCLUSIONS: Among 991 patients comprising the early experience for several TTVr devices, there was a statistically significant reduction in ≥ severe TR, NYHA class III-IV, vena contracta width and right ventricular end-diastolic diameter after TTVr. Thus far, the edge-to-edge approach seems to be associated with a better safety profile.