An ultrasound-activated nanoplatform remodels tumor microenvironment through diverse cell death induction for improved immunotherapy.

Although nanomaterial-based nanomedicine provides many powerful tools to treat cancer, most focus on the "immunosilent" apoptosis process. In contrast, ferroptosis and immunogenic cell death, two non-apoptotic forms of programmed cell death (PCD), have been shown to enhance or alter the activity of the immune system. Therefore, there is a need to design and develop nanoplatforms that can induce multiple modes of cell death other than apoptosis to stimulate antitumor immunity and remodel the immunosuppressive tumor microenvironment for cancer therapy. In this study, a new type of multifunctional nanocomposite mainly consisting of HMME, Fe3+ and Tannic acid, denoted HFT NPs, was designed and synthesized to induce multiple modes of cell death and prime the tumor microenvironment (TME). The HFT NPs consolidate two functions into one nano-system: HMME as a sonosensitizer for the generation of reactive oxygen species (ROS) 1O2 upon ultrasound irradiation, and Fe3+ as a GSH scavenger for the induction of ferroptosis and the production of ROS ·OH through inorganic catalytic reactions. The administration of HFT NPs and subsequent ultrasound treatment caused cell death through the consumption of GSH, the generation of ROS, ultimately inducing apoptosis, ferroptosis, and immunogenic cell death (ICD). More importantly, the combination of HFT NPs and ultrasound irradiation could reshape the TME and recruit more T cell infiltration, and its combination with immune checkpoint blockade anti-PD-1 antibody could eradicate tumors with low immunogenicity and a cold TME. This new nano-system integrates sonodynamic and chemodynamic properties to achieve outstanding therapeutic outcomes when combined with immunotherapy. Collectively, this study demonstrates that it is possible to potentiate cancer immunotherapy through the rational and innovative design of relatively simple materials.

Erratum: 'I am afraid the news is not good' - Breaking bad news in the time of COVID: Experiences from a field hospital.

No abstract available.

Enhancing multiple myeloma staging: a novel cell death risk model approach.

The prognostication of survival trajectories in multiple myeloma (MM) patients presents a substantial clinical challenge. Leveraging transcriptomic and clinical profiles from an expansive cohort of 2,088 MM patients, sourced from the Gene Expression Omnibus and The Cancer Genome Atlas repositories, we applied a sophisticated nested lasso regression technique to construct a prognostic model predicated on 28 gene pairings intrinsic to cell death pathways, thereby deriving a quantifiable risk stratification metric. Employing a threshold of 0.15, we dichotomized the MM samples into discrete high-risk and low-risk categories. Notably, the delineated high-risk cohort exhibited a statistically significant diminution in survival duration, a finding which consistently replicated across both training and external validation datasets. The prognostic acumen of our cell death signature was further corroborated by TIME ROC analyses, with the model demonstrating robust performance, evidenced by AUC metrics consistently surpassing the 0.6 benchmark across the evaluated arrays. Further analytical rigor was applied through multivariate COX regression analyses, which ratified the cell death risk model as an independent prognostic determinant. In an innovative stratagem, we amalgamated this risk stratification with the established International Staging System (ISS), culminating in the genesis of a novel, refined ISS categorization. This tripartite classification system was subjected to comparative analysis against extant prognostic models, whereupon it manifested superior predictive precision, as reflected by an elevated C-index. In summation, our endeavors have yielded a clinically viable gene pairing model predicated on cellular mortality, which, when synthesized with the ISS, engenders an augmented prognostic tool that exhibits pronounced predictive prowess in the context of multiple myeloma.

Estimation of cause-specific mortality in Rakai, Uganda, using verbal autopsy 1999-2019.

BACKGROUND: There are scant data on the causes of adult deaths in sub-Saharan Africa. We estimated the level and trends in adult mortality, overall and by different causes, in rural Rakai, Uganda, by age, sex, and HIV status. OBJECTIVES: To estimate and analyse adult cause-specific mortality trends in Rakai, Uganda. METHODOLOGY: Mortality information by cause, age, sex, and HIV status was recorded in the Rakai Community Cohort study using verbal autopsy interviews, HIV serosurveys, and residency data. We estimated the average number of years lived in adulthood. Using demographic decomposition methods, we estimated the contribution of each cause of death to adult mortality based on the average number of years lived in adulthood. RESULTS: Between 1999 and 2019, 63082 adults (15-60 years) were censused, with 1670 deaths registered. Of these, 1656 (99.2%) had completed cause of death data from verbal autopsy. The crude adult death rate was 5.60 (95% confidence interval (CI): 5.33-5.87) per 1000 person-years of observation (pyo). The crude death rate decreased from 11.41 (95% CI: 10.61-12.28) to 3.27 (95% CI: 2.89-3.68) per 1000 pyo between 1999-2004 and 2015-2019. The average number of years lived in adulthood increased in people living with HIV and decreased in HIV-negative individuals between 2000 and 2019. Communicable diseases, primarily HIV and Malaria, had the biggest decreases, which improved the average number of years lived by approximately extra 12 years of life in females and 6 years in males. There were increases in deaths due to non-communicable diseases and external causes, which reduced the average number of years lived in adulthood by 2.0 years and 1.5 years in females and males, respectively. CONCLUSION: There has been a significant decline in overall mortality from 1999 to 2019, with the greatest decline seen in people living with HIV since the availability of antiretroviral therapy in 2004. By 2020, the predominant causes of death among females were non-communicable diseases, with external causes of death dominating in males.

Main findings: There are significant declines in mortality in people living with HIV. However, mortality in HIV-negative people increased due to non-communicable diseases in females, and injuries and external causes of death among males.Added knowledge: In this HIV-endemic area, decreasing adult mortality has been documented over the last 20 years. This paper benchmarks the changes in cause-specific mortality in this area.Global health impact for policy action: As in many African countries, more effort is needed to reduce mortality for non-communicable diseases, injuries, and external causes of death as these seem to have been neglected.

Tumor-derived nanovesicles enhance cancer synergistic chemo-immunotherapy by promoting cGAS/STING pathway activation and immunogenetic cell death.

AIMS: Checkpoint blockade immunotherapy is a promising therapeutic modality that has revolutionized cancer treatment; however, the therapy is only effective on a fraction of patients due to the tumor environment. In tumor immunotherapy, the cGAS-STING pathway is a crucial intracellular immune response pathway. Therefore, this study aimed to develop an immunotherapy strategy based on the cGAS-STING pathway. MATERIALS AND METHODS: The physicochemical properties of the nanoparticles EM@REV@DOX were characterized by TEM, DLS, and WB. Subcutaneous LLC xenograft tumors were used to determine the biodistribution, antitumor efficacy, and immune response. Blood samples and tissues of interest were harvested for hematological analysis and H&E staining. SIGNIFICANCE: Overall, our designed nanovesicles provide a new perspective on tumor immunotherapy by ICD and cGAS-STING pathway, promoting DCs maturation, macrophage polarization, and activating T cells, offering a meaningful strategy for accelerating the clinical development of immunotherapy. KEY FINDINGS: EM@REV@DOX accumulated in the tumor site through EPR and homing targeting effect to release REV and DOX, resulting in DNA damage and finally activating the cGAS-STING pathway, thereby promoting DCs maturation, macrophage polarization, and activating T cells. Additionally, EM@REV@DOX increased the production of pro-inflammatory cytokines (e.g., TNF-α and IFN-ß). As a result, EM@REV@DOX was effective in treating tumor-bearing mice and prolonged their lifespans. When combined with αPD-L1, EM@REV@DOX significantly inhibited distant tumor growth, extended the survival of mice, and prevented long-term postoperative tumor metastasis, exhibiting great potential in antitumor immunotherapy.

Cold resistance of mammalian hibernators ∼ a matter of ferroptosis?

Most mammals adapt thermal physiology around 37°C and large deviations from their range, as observed in severe hypothermia and hyperthermia, resulting in organ dysfunction and individual death. A prominent exception is mammalian hibernation. Mammalian hibernators resist the long-term duration of severe low body temperature that is lethal to non-hibernators, including humans and mice. This cold resistance is supported, at least in part, by intrinsic cellular properties, since primary or immortalized cells from several hibernator species can survive longer than those from non-hibernators when cultured at cold temperatures. Recent studies have suggested that cold-induced cell death fulfills the hallmarks of ferroptosis, a type of necrotic cell death that accompanies extensive lipid peroxidation by iron-ion-mediated reactions. In this review, we summarize the current knowledge of cold resistance of mammalian hibernators at the cellular and molecular levels to organ and systemic levels and discuss key pathways that confer cold resistance in mammals.

Revealing prognostic insights of programmed cell death (PCD)-associated genes in advanced non-small cell lung cancer.

The management of patients with advanced non-small cell lung cancer (NSCLC) presents significant challenges due to cancer cells' intricate and heterogeneous nature. Programmed cell death (PCD) pathways are crucial in diverse biological processes. Nevertheless, the prognostic significance of cell death in NSCLC remains incompletely understood. Our study aims to investigate the prognostic importance of PCD genes and their ability to precisely stratify and evaluate the survival outcomes of patients with advanced NSCLC. We employed Weighted Gene Co-expression Network Analysis (WGCNA), Least Absolute Shrinkage and Selection Operator (LASSO), univariate and multivariate Cox regression analyses for prognostic gene screening. Ultimately, we identified seven PCD-related genes to establish the PCD-related risk score for the advanced NSCLC model (PRAN), effectively stratifying overall survival (OS) in patients with advanced NSCLC. Multivariate Cox regression analysis revealed that the PRAN was the independent prognostic factor than clinical baseline factors. It was positively related to specific metabolic pathways, including hexosamine biosynthesis pathways, which play crucial roles in reprogramming cancer cell metabolism. Furthermore, drug prediction for different PRAN risk groups identified several sensitive drugs explicitly targeting the cell death pathway. Molecular docking analysis suggested the potential therapeutic efficacy of navitoclax in NSCLC, as it demonstrated strong binding with the amino acid residues of C-C motif chemokine ligand 14 (CCL14), carboxypeptidase A3 (CPA3), and C-X3-C motif chemokine receptor 1 (CX3CR1) proteins. The PRAN provides a robust personalized treatment and survival assessment tool in advanced NSCLC patients. Furthermore, identifying sensitive drugs for distinct PRAN risk groups holds promise for advancing targeted therapies in NSCLC.

Targeting Integrin α3 Blocks ß1 Maturation, Triggers Endoplasmic Reticulum Stress, and Sensitizes Glioblastoma Cells to TRAIL-Mediated Apoptosis.

Glioblastoma (GBM) is a devastating brain cancer for which new effective therapies are urgently needed. GBM, after an initial response to current treatment regimens, develops therapeutic resistance, leading to rapid patient demise. Cancer cells exhibit an inherent elevation of endoplasmic reticulum (ER) stress due to uncontrolled growth and an unfavorable microenvironment, including hypoxia and nutrient deprivation. Cancer cells utilize the unfolded protein response (UPR) to maintain ER homeostasis, and failure of this response promotes cell death. In this study, as integrins are upregulated in cancer, we have evaluated the therapeutic potential of individually targeting all αß1 integrin subunits using RNA interference. We found that GBM cells are uniquely susceptible to silencing of integrin α3. Knockdown of α3-induced proapoptotic markers such as PARP cleavage and caspase 3 and 8 activation. Remarkably, we discovered a non-canonical function for α3 in mediating the maturation of integrin ß1. In its absence, generation of full length ß1 was reduced, immature ß1 accumulated, and the cells underwent elevated ER stress with upregulation of death receptor 5 (DR5) expression. Targeting α3 sensitized TRAIL-resistant GBM cancer cells to TRAIL-mediated apoptosis and led to growth inhibition. Our findings offer key new insights into integrin α3's role in GBM survival via the regulation of ER homeostasis and its value as a therapeutic target.

Autopsy-based all-cause unnatural mortality during pre-pandemic and pandemic of COVID-19 in Varanasi, India: a retrospective analysis.

The COVID-19 pandemic has led to significant disruptions in healthcare systems worldwide, with Varanasi, India, experiencing profound challenges in managing mortality rates. In order to inform public health initiatives, it is important to comprehend how the pandemic has affected all-cause unnatural death in comparison to pre-pandemic patterns. This retrospective study intended to investigate patterns of all-cause unnatural mortality employing autopsy records of cases from Varanasi's Institute of Medical Sciences, Banaras Hindu University during the pre-pandemic and pandemic period (First and Second wave) of COVID-19. The analysis included 2694 cases of unnatural mortality, such as road traffic accident (RTA), poisoning, hanging and other causes. Demographic, clinical, and circumstantial data were collected and compared between the two time periods, that revealed significant as well as non-significant shifts in all-cause unnatural mortality rates. Whilst certain types of unnatural deaths, such as RTAs, witnessed a non-significant 2.03% (p = 0.34722) decrease, others like hanging exhibited an unexpected significant 3.17% (p = 0.01732) rise, burning and poisoning witnessed a significant 4.18% (p = 0.00026) and 2.37% (p = 0.0271) decline respectively. RTA was the leading cause of mortality both during and before pandemic. Male deaths (79.18%) outweighed female deaths (20.82%) by a more substantial amount throughout research periods. Additionally, variations in demographic characteristics, circumstances surrounding deaths, and healthcare utilization were observed during the pandemic period. The majority of unnatural fatalities occur in the age group of 21-30 years old in both pre-pandemic (22.62%) and pandemic conditions (26.65%). This study provides important insights into the secondary effects of the pandemic on unnatural mortality and emphasizes the need for individualized public health. Furthermore, research is warranted to explore the long-term implications and address the associated challenges for healthcare systems and public health initiatives.

Hsp90α and cell death in cancers: a review.

Heat shock protein 90α (Hsp90α), an important molecular chaperone, plays a crucial role in regulating the activity of various intracellular signaling pathways and maintaining the stability of various signaling transduction proteins. In cancer, the expression level of Hsp90α is often significantly upregulated and is recognized as one of the key factors in cancer cell survival and proliferation. Cell death can help achieve numerous purposes, such as preventing aging, removing damaged or infected cells, facilitating embryonic development and tissue repair, and modulating immune response. The expression of Hsp90α is closely associated with specific modes of cell death including apoptosis, necrotic apoptosis, and autophagy-dependent cell death, etc. This review discusses the new results on the relationship between expression of Hsp90α and cell death in cancer. Hsp90α is frequently overexpressed in cancer and promotes cancer cell growth, survival, and resistance to treatment by regulating cell death, rendering it a promising target for cancer therapy.

Contributions of elevated CRP, hyperglycaemia, and type 2 diabetes to cardiovascular risk in the general population: observational and Mendelian randomization studies.

OBJECTIVE: To investigate the contributions of low-grade inflammation measured by C-reactive protein (CRP), hyperglycaemia, and type 2 diabetes to risk of ischemic heart disease (IHD) and cardiovascular disease (CVD) death in the general population, and whether hyperglycaemia and high CRP are causally related. RESEARCH DESIGN AND METHODS: Observational and bidirectional, one-sample Mendelian randomization (MR) analyses in 112,815 individuals from the Copenhagen General Population Study and the Copenhagen City Heart Study, and bidirectional, two-sample MR with summary level data from two publicly available consortia, CHARGE and MAGIC. RESULTS: Observationally, higher plasma CRP was associated with stepwise higher risk of IHD and CVD death, with hazard ratios and 95% confidence intervals (95%CI) of 1.50 (1.38, 1.62) and 2.44 (1.93, 3.10) in individuals with the 20% highest CRP concentrations. The corresponding hazard ratios for elevated plasma glucose were 1.10 (1.02, 1.18) and 1.22 (1.01, 1.49), respectively. Cumulative incidences of IHD and CVD death were 365% and 592% higher, respectively, in individuals with both type 2 diabetes and plasma CRP ≥ 2 mg/L compared to individuals without either. Plasma CRP and glucose were observationally associated (ß-coefficient: 0.02 (0.02, 0.03), p = 3 × 10- 20); however, one- and two-sample MR did not support a causal effect of CRP on glucose (-0.04 (-0.12, 0.32) and - 0.03 (-0.13, 0.06)), nor of glucose on CRP (-0.01 (-0.08, 0.07) and - 0.00 (-0.14, 0.13)). CONCLUSIONS: Elevated concentrations of plasma CRP and glucose are predictors of IHD and CVD death in the general population. We found no genetic association between CRP and glucose, or vice versa, suggesting that lowering glucose pharmacologically does not have a direct effect on low-grade inflammation.

Real-World Treatment Patterns and Survival Outcomes for Patients with Non-Metastatic Non-Small-Cell Lung Cancer in Sweden: A Nationwide Registry Analysis from the I-O Optimise Initiative.

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide, with ~40-50% of patients diagnosed with non-metastatic disease (stages IA-IIIC). The treatment landscape is evolving rapidly as immunotherapies and targeted therapy are introduced in the non-metastatic setting, creating a need to assess patient outcomes prior to their introduction. This real-world study using Swedish National Lung Cancer Registry data examined outcomes (overall survival (OS) and time to next treatment or death (TTNTD)) and treatment patterns for adults diagnosed with non-metastatic NSCLC. Baseline characteristics and OS from diagnosis were described for all patients; OS, treatment patterns, and TTNTD from treatment start were described for the treatment subgroup (patients diagnosed from 2014 onwards), stratified by disease stage and initial treatment. OS and TTNTD were described using the Kaplan-Meier estimator. The overall population (2008-2019) included 17,433 patients; the treatment subgroup included 5147 patients. Median OS (interquartile range) overall ranged from 83.3 (31.6-165.3) months (stage I patients) to 10.4 (4.3-24.2) months (stage IIIB patients). Among the treatment subgroup, median OS and TTNTD were longest among patients receiving surgery versus other anticancer treatments. These findings provide a baseline upon which to evaluate the epidemiology of non-metastatic NSCLC as newer treatments are introduced.

Deregulation of New Cell Death Mechanisms in Leukemia.

Hematological malignancies are among the top five most frequent forms of cancer in developed countries worldwide. Although the new therapeutic approaches have improved the quality and the life expectancy of patients, the high rate of recurrence and drug resistance are the main issues for counteracting blood disorders. Chemotherapy-resistant leukemic clones activate molecular processes for biological survival, preventing the activation of regulated cell death pathways, leading to cancer progression. In the past decade, leukemia research has predominantly centered around modulating the well-established processes of apoptosis (type I cell death) and autophagy (type II cell death). However, the development of therapy resistance and the adaptive nature of leukemic clones have rendered targeting these cell death pathways ineffective. The identification of novel cell death mechanisms, as categorized by the Nomenclature Committee on Cell Death (NCCD), has provided researchers with new tools to overcome survival mechanisms and activate alternative molecular pathways. This review aims to synthesize information on these recently discovered RCD mechanisms in the major types of leukemia, providing researchers with a comprehensive overview of cell death and its modulation.

Programmed Death Ligand 1 Expression in Circulating Tumor Cells as a Predictor and Monitor of Response to Atezolizumab plus Bevacizumab Treatment in Patients with Hepatocellular Carcinoma.

There remains no reliable biomarker of therapeutic efficacy in hepatocellular carcinoma (HCC) for the PD-L1 inhibitor atezolizumab and bevacizumab (Atezo/Bev). Circulating tumor cells (CTCs) enable the serial collection of living tumor cells. Pre-treatment and serial CTC gene expression changes and tumor histology were evaluated to identify predictors of response to Atezo/Bev. Peripheral blood from 22 patients with HCC treated with Atezo/Bev and 24 patients treated with lenvatinib was serially collected. The RNA expression in CTCs was analyzed using qRT-PCR. Higher PD-L1 expression in pre-treatment CTCs was associated with response and improved prognosis with Atezo/Bev treatment, but not with lenvatinib. There was no correlation between PD-L1 expression in CTCs and that in liver tumor biopsy specimens scored using imaging software. Furthermore, PD-L1 RNA expression in CTCs was dynamically altered by Atezo/Bev, decreasing during effective response and increasing upon progression. CTC-derived RNA collected during Atezo/Bev indicates that patients with higher PD-L1 expression in CTCs at baseline were 3.9 times more responsive to treatment. Therefore, PD-L1 RNA levels in CTCs are an accurate response predictor and may be a monitorable biomarker that changes dynamically to reflect the response during Atezo/Bev treatment.

Current Perspectives of Mitochondria in Sepsis-Induced Cardiomyopathy.

Sepsis-induced cardiomyopathy (SICM) is one of the leading indicators for poor prognosis associated with sepsis. Despite its reversibility, prognosis varies widely among patients. Mitochondria play a key role in cellular energy production by generating adenosine triphosphate (ATP), which is vital for myocardial energy metabolism. Over recent years, mounting evidence suggests that severe sepsis not only triggers mitochondrial structural abnormalities such as apoptosis, incomplete autophagy, and mitophagy in cardiomyocytes but also compromises their function, leading to ATP depletion. This metabolic disruption is recognized as a significant contributor to SICM, yet effective treatment options remain elusive. Sepsis cannot be effectively treated with inotropic drugs in failing myocardium due to excessive inflammatory factors that blunt ß-adrenergic receptors. This review will share the recent knowledge on myocardial cell death in sepsis and its molecular mechanisms, focusing on the role of mitochondria as an important metabolic regulator of SICM, and discuss the potential for developing therapies for sepsis-induced myocardial injury.

Influence of Human Bone Marrow Mesenchymal Stem Cells Secretome from Acute Myeloid Leukemia Patients on the Proliferation and Death of K562 and K562-Lucena Leukemia Cell Lineages.

Leukemias are among the most prevalent types of cancer worldwide. Bone marrow mesenchymal stem cells (MSCs) participate in the development of a suitable niche for hematopoietic stem cells, and are involved in the development of diseases such as leukemias, to a yet unknown extent. Here we described the effect of secretome of bone marrow MSCs obtained from healthy donors and from patients with acute myeloid leukemia (AML) on leukemic cell lineages, sensitive (K562) or resistant (K562-Lucena) to chemotherapy drugs. Cell proliferation, viability and death were evaluated, together with cell cycle, cytokine production and gene expression of ABC transporters and cyclins. The secretome of healthy MSCs decreased proliferation and viability of both K562 and K562-Lucena cells; moreover, an increase in apoptosis and necrosis rates was observed, together with the activation of caspase 3/7, cell cycle arrest in G0/G1 phase and changes in expression of several ABC proteins and cyclins D1 and D2. These effects were not observed using the secretome of MSCs derived from AML patients. In conclusion, the secretome of healthy MSCs have the capacity to inhibit the development of leukemia cells, at least in the studied conditions. However, MSCs from AML patients seem to have lost this capacity, and could therefore contribute to the development of leukemia.

Development and validation of the Ex-Care BR model: a multicentre initiative for identifying Brazilian surgical patients at risk of 30-day in-hospital mortality.

BACKGROUND: Surgical risk stratification is crucial for enhancing perioperative assistance and allocating resources efficiently. However, existing models may not capture the complexity of surgical care in Brazil. Using data from various healthcare settings nationwide, we developed a new risk model for 30-day in-hospital mortality (the Ex-Care BR model). METHODS: A retrospective cohort study was conducted in 10 hospitals from different geographic regions in Brazil. Data were analysed using multilevel logistic regression models. Model performance was assessed using the area under the receiver operating characteristic curve (AUROC), Brier score, and calibration plots. Derivation and validation cohorts were randomly assigned. RESULTS: A total of 107,372 patients were included, and 30-day in-hospital mortality was 2.1% (n=2261). The final risk model comprised four predictors related to the patient and surgery (age, ASA physical status classification, surgical urgency, and surgical size), and the random effect related to hospitals. The model showed excellent discrimination (AUROC=0.93, 95% confidence interval [CI], 0.93-0.94), calibration, and overall performance (Brier score=0.017) in the derivation cohort (n=75,094). Similar results were observed in the validation cohort (n=32,278) (AUROC=0.93, 95% CI, 0.92-0.93). CONCLUSIONS: The Ex-Care BR is the first model to consider regional and organisational peculiarities of the Brazilian surgical scene, in addition to patient and surgical factors. It is particularly useful for identifying high-risk surgical patients in situations demanding efficient allocation of limited resources. However, a thorough exploration of mortality variations among hospitals is essential for a comprehensive understanding of risk. CLINICAL TRIAL REGISTRATION: NCT05796024.

Incorporation of stromal tumor-infiltrating lymphocytes into an early death prediction model significantly improves net reclassification for outcome estimation in advanced buccal cancer.

We explored the impact of stromal tumor-infiltrating lymphocytes (sTILs) on the prognostic value of an early death model for advanced buccal cancer. We assessed 121 patients with advanced buccal cancer who underwent primary tumor resection at a medical center. Predictors of early death and 5-year overall survival (OS) were analyzed using Cox regression models. Performance of models was evaluated with the Harrell C and Akaike information criterion. The net reclassification improvement of the early death model was also calculated relative to the 5-year OS model for one-year all-cause mortality. A total of 121 patients with advanced buccal cancer were recruited. Mean age was 56.1 ± 9.8 years; 117 (96.7%) patients were male. sTILs ≤30%, clinical nodal disease, pathological nodal disease, poor differentiation, lymphovascular invasion, perineural invasion, WPOI 5, and no adjuvant radiotherapy were risk factors for early death in univariate analysis. In multivariate analysis, clinical TNM, sTILs, clinical nodal disease, poor differentiation, lymphovascular invasion, and no adjuvant RT were independent factors for early death. sTILs, pathological nodal disease, poor differentiation, lymphovascular invasion, and no adjuvant RT were independent factors for early death in the multivariate model with pathological TNM. The discriminatory ability was better for early death model for 1-year all-cause mortality. Finally, incorporation of sTILs into the early death model increased net reclassification by 21% for the clinical TNM model and 28% for the pathological TNM model. Addition of sTILs improved the early death model, which may help physicians to identify high-risk patients for more intensive treatment and follow-up.

Exposure to low-concentration fipronil impairs survival, behavior, midgut morphology and physiology of Aedes aegypti larvae.

The Aedes aegypti mosquito is a vector for various arboviruses, including dengue and yellow fever. Insecticides, such as pyrethroids and organophosphates, are widely used to manage and control these insects. However, mosquitoes have developed resistance to these chemicals. Therefore, this study aimed to investigate the effects of the commercial formulation of fipronil (Tuit® Florestal; 80% purity) on the survival, behavior, morphology, and proteins related to signaling pathways of the midgut in A. aegypti larvae under controlled laboratory conditions. Significant reductions in immature survival were observed in all concentrations of fipronil tested. Low insecticide concentration (0.5 ppb) led to decreased locomotor activity in the larvae and caused disorganization of the epithelial tissue in the midgut. Moreover, exposure to the insecticide decreased the activity of detoxifying enzymes such as catalase, superoxide dismutase, and glutathione-S-transferase. On the other hand, the insecticide increased protein oxidation and nitric oxide levels. The detection of LC3, caspase-3, and JNK proteins, related to autophagy and apoptosis, increased after exposure. However, there was a decrease in the positive cells for ERK 1/2. Furthermore, the treatment with fipronil decreased the number of positive cells for the proteins FMRF, Prospero, PH3, Wg, Armadillo, Notch, and Delta, which are related to cell proliferation and differentiation. These findings demonstrate that even at low concentrations, fipronil exerts larvicidal effects on A. aegypti by affecting behavior and enzymatic detoxification, inducing protein oxidation, free radical generation, midgut damage and cell death, and inhibiting cell proliferation and differentiation. Thus, this insecticide may represent a viable alternative for controlling the spread of this vector.

Causes and attributable fraction of death from ARDS in inflammatory phenotypes of sepsis.

BACKGROUND: Hypoinflammatory and hyperinflammatory phenotypes have been identified in both Acute Respiratory Distress Syndrome (ARDS) and sepsis. Attributable mortality of ARDS in each phenotype of sepsis is yet to be determined. We aimed to estimate the population attributable fraction of death from ARDS (PAFARDS) in hypoinflammatory and hyperinflammatory sepsis, and to determine the primary cause of death within each phenotype. METHODS: We studied 1737 patients with sepsis from two prospective cohorts. Patients were previously assigned to the hyperinflammatory or hypoinflammatory phenotype using latent class analysis. The PAFARDS in patients with sepsis was estimated separately in the hypo and hyperinflammatory phenotypes. Organ dysfunction, severe comorbidities, and withdrawal of life support were abstracted from the medical record in a subset of patients from the EARLI cohort who died (n = 130/179). Primary cause of death was defined as the organ system that most directly contributed to death or withdrawal of life support. RESULTS: The PAFARDS was 19% (95%CI 10,28%) in hypoinflammatory sepsis and, 14% (95%CI 6,20%) in hyperinflammatory sepsis. Cause of death differed between the two phenotypes (p < 0.001). Respiratory failure was the most common cause of death in hypoinflammatory sepsis, whereas circulatory shock was the most common cause in hyperinflammatory sepsis. Death with severe underlying comorbidities was more frequent in hypoinflammatory sepsis (81% vs. 67%, p = 0.004). CONCLUSIONS: The PAFARDS is modest in both phenotypes whereas primary cause of death among patients with sepsis differed substantially by phenotype. This study identifies challenges in powering future clinical trials to detect changes in mortality outcomes among patients with sepsis and ARDS.