Harnessing nanomaterials for copper-induced cell death.

Copper (Cu), an essential micronutrient with redox properties, plays a pivotal role in a wide array of pathological and physiological processes across virtually all cell types. Maintaining an optimal copper concentration is critical for cellular survival: insufficient copper levels disrupt respiration and metabolism, while excess copper compromises cell viability, potentially leading to cell death. Similarly, in the context of cancer, copper exhibits a dual role: appropriate amount of copper can promote tumor progression and be an accomplice, yet beyond befitting level, copper can bring about multiple types of cell death, including autophagy, apoptosis, ferroptosis, immunogenic cell death, pyroptosis, and cuproptosis. These forms of cell death are beneficial against cancer progression; however, achieving precise copper regulation within tumors remains a significant challenge in the pursuit of effective cancer therapies. The emergence of nanodrug delivery systems, distinguished by their precise targeting, controlled release, high payload capacity, and the ability to co-deliver multiple agents, has revitalized interest in exploiting copper's precise regulatory capabilities. Nevertheless, there remains a dearth of comprehensive review of copper's bidirectional effects on tumorigenesis and the role of copper-based nanomaterials in modulating tumor progression. This paper aims to address this gap by elucidating the complex role in cancer biology and highlighting its potential as a therapeutic target. Through an exploration of copper's dualistic nature and the application of nanotechnology, this review seeks to offer novel insights and guide future research in advancing cancer treatment.

Mild near-infrared laser-triggered photo-immunotherapy potentiates immune checkpoint blockade via an all-in-one theranostic nanoplatform.

One of the primary challenges for immune checkpoint blockade (ICB)-based therapy is the limited infiltration of T lymphocytes (T cells) into tumors, often referred to as immunologically "cold" tumors. A promising strategy to enhance the anti-tumor efficacy of ICB is to increase antigen exposure, thereby enhancing T cell activation and converting "cold" tumors into "hot" ones. Herein, we present an innovative all-in-one therapeutic nanoplatform to realize local mild photothermal- and photodynamic-triggered antigen exposure, thereby improving the anti-tumor efficacy of ICB. This nanoplatform involves conjugating programmed death-ligand 1 antibody (aPD-L1) with gadolinium-doped near-infrared (NIR)-emitting carbon dots (aPD-L1@GdCDs), which displays negligible cytotoxicity in the absence of light. But under controlled NIR laser irradiation, the GdCDs produce combined photothermal and photodynamic effects. This not only results in tumor ablation but also induces immunogenic cell death (ICD), facilitating enhanced infiltration of CD8+ T cells in the tumor area. Importantly, the combination of aPD-L1 with photothermal and photodynamic therapies via aPD-L1@GdCDs significantly boosts CD8+ T cell infiltration, reduces tumor size, and improves anti-metastasis effects compared to either GdCDs-based phototherapy or aPD-L1 alone. In addition, the whole treatment process can be monitored by multi-modal fluorescence/photoacoustic/magnetic resonance imaging (FLI/PAI/MRI). Our study highlights a promising nanoplatform for cancer diagnosis and therapy, as well as paves the way to promote the efficacy of ICB therapy through mild photothermal- and photodynamic-triggered immunotherapy.

Autophagic cell death induced by pH modulation for enhanced iron-based chemodynamic therapy.

Iron-based chemodynamic therapy (CDT) exhibits commendable biocompatibility and selectivity, but its efficacy is constrained by the intracellular pH of tumors. To overcome this obstacle, we constructed a silica delivery platform loaded with autophagy-inducing reagents (rapamycin, RAPA) and iron-based Fenton reagents (Fe3O4). This platform was utilized to explore a novel strategy that leverages autophagy to decrease tumor acidity, consequently boosting the effectiveness of CDT. Both in vitro and in vivo experiments revealed that RAPA prompted the generation of acidic organelles (e.g., autophagic vacuoles and autophagosomes), effectively changing the intracellular pH in the tumor microenvironment. Furthermore, RAPA-induced tumor acidification significantly amplified the efficacy of Fe3O4-based Fenton reactions, consequently increasing the effectiveness of Fe3O4-based CDT. This innovative approach, which leverages the interplay between autophagy induction and iron-based CDT, shows promise in overcoming the limitations posed by tumor pH, thus offering a more efficient approach to tumor treatments.

An Exploratory Study on the Suicidal Behaviours of People With Intellectual Disability or Autism: Examining Their Understanding of Suicide and Death, and the Perceptions of Their Direct Support Staff.

BACKGROUND: Individuals with intellectual disability or autism exhibit suicidal behaviours at an equal or greater rate than the general population, yet little is known about associated risk factors. This study explores suicidality in these populations, focusing on their understanding of suicide and death and perceptions of their direct support staff regarding their suicidality. METHOD: Semi-structured interviews from 23 suicidal and non-suicidal participants and their support staff were analysed qualitatively to extract common themes and compare between groups. RESULTS: A breadth of suicidal behaviours was documented. Generally, suicidal participants demonstrated a more elaborate understanding of suicide and death than non-suicidal participants. While staff often acknowledged never having discussed the topic with their client, most assumed they understood death accurately. CONCLUSION: Results suggest interactions between conceptions of death and suicidal behaviour and a need for discussion around death and suicide in clinical settings. Implications for future research and clinical practice are discussed.

Effectiveness of the frailty index in predicting short-term and long-term mortality risk in patients with chronic heart failure.

OBJECTIVE: This study explored the effectiveness of a newly constructed frailty index (FI) for predicting short-term and long-term mortality in patients with chronic heart failure (HF). MATERIALS AND METHODS: This retrospective study included inpatients aged ≥60 years diagnosed with chronic HF at a teaching hospital in western China. General data on the patients were collected from the electronic medical record system between January 1, 2017, and July 7, 2022, and death information was obtained from follow-up calls made from July 31, 2022, to August 1, 2022. Receiver operating characteristic (ROC) curves were used to analyze the accuracy of the FI in predicting death in patients with chronic HF. Logistic regression (during hospitalization and within 30 days after discharge) and Cox regression (within 180 days after discharge and one year after discharge) analyses were used to assess associations between frailty and mortality risk in elderly patients with chronic HF. RESULTS: A total of 432 patients with chronic HF were included in the study. The non-frail group had FI values <0.3, while the FI values in the frail group were ≥0.3. Overall, 130 patients (30.09 %) were diagnosed with frailty, 66 (15.28 %) died during hospitalization or within 30 days after discharge, 55 (12.73 %) died within 180 days after discharge, and 68 (15.74 %) died within one year after discharge. The in-hospital and 30-day mortality rates, the 180-day mortality rates, and the 1-year mortality rates were higher in frail patients than in non-frail patients (in-hospital and 30-day mortality rates, 37.69 % vs. 5.63 %, P < 0.001; within 180 days, 30.61 % vs. 8.45 %, P < 0.001; within 1 year, 34.69 % vs. 11.49 %, P < 0.001). The area under the curve (AUC) values of FI for predicting in-hospital and 30-day mortality after discharge were 0.804, with values of 0.721 for 180-day mortality after discharge and 0.720 for 1-year mortality after discharge. Logistic regression analysis with adjustment for potential confounders indicated that frail HF patients had a higher risk of death during hospitalization and within 30 days than non-frail patients (odds ratio [OR] = 4.98, 95 % confidence interval [CI]: 2.46-10.09). Cox regression analysis with adjustment for potential confounders showed that frail HF patients had a higher risk of death within 180 days (hazard ratio [HR] = 2.63, 95 %CI: 1.47-4.72) and within 1 year (HR = 2.01, 95 %CI: 1.19-3.38). CONCLUSION: The results of this study showed that the new FI constructed according to the established construction rules could predict the in-hospital mortality and the risk of death within 30 days after discharge, 180 days after discharge, and 1 year after discharge in patients with chronic HF.

Deceased Donor Program in India: Listing and Allocation Practices and the Legal Process With Respect to Liver Transplantation.

India is the country with the third largest transplantation activity in the world but has one of the lowest deceased donation rates. The Transplantation of Human Organs Act was first enacted as law 29 years ago, its implementation has been non-uniform and growth in deceased donation has been slow and heterogenous. This review discusses the concept of brain death, ethics of deceased donation and organ allocation, Indian legislation in this area and the regulatory structure of the National Organ transplantation program. We also discuss current status of deceased donation and deceased donor liver transplantation in the country, identify variation in liver allocation policies across Indian states and identify areas of need and potential solutions.

Experiencias de duelo anticipado en cuidadoras informales de la Región Metropolitana (Chile): cambios ocupacionales

Introducción: La pérdida de un ser querido se construye como una experiencia humana inevitable, que genera una vivencia emocional que impacta tanto al individuo que experimenta la pérdida como a su entorno. Objetivo: Investigar la relación entre los procesos de duelo anticipado y las alteraciones en la participación ocupacional de quienes fueron cuidadoras principales informales de personas con enfermedad terminal en la Región Metropolitana de Chile. Método: Enfoque cualitativo con 7 entrevistas semiestructuradas individuales a cuidadoras adultas en el sur y poniente de la región. Resultados: Fueron categorizadas experiencias y subjetividades que expresan la importancia que las mujeres atribuyen al cuidado de sus familiares, con una escasa demostración emocional durante esta etapa. Además, emergen categorías como rutinas y roles, donde muchas mujeres priorizan el cuidado; redes de apoyo, con relatos frecuentes sobre la falta de ayuda y herramientas más allá de lo económico; y áreas de ocupación afectadas, predominantemente el descanso y sueño, aunque también se menciona el autocuidado y la participación social. Conclusión: Si bien el proceso de duelo anticipado genera dolor y desgaste propio, es el cuidado informal lo que genera cambios en la participación y calidad de vida de las mujeres cuidadoras.

Introdução: A perda de um ente querido é construída como uma experiência humana inevitável, que gera uma vivência emocional que afeta tanto o indivíduo que experimenta a perda quanto seu entorno. Objetivo: investigar a relação entre os processos de luto antecipado e as alterações na participação ocupacional daquelas que foram cuidadoras primárias informais de pessoas com doença terminal na Região Metropolitana do Chile. Método: abordagem qualitativa com 7 entrevistas individuais semiestruturadas com cuidadoras adultas no sul e oeste da região. Resultados: Foram categorizadas experiências e subjetividades que expressam a importância que as mulheres atribuem ao cuidado de seus familiares, com uma escassa demonstração emocional durante essa etapa. Além disso, surgem categorias como rotinas e papéis, em que muitas mulheres priorizam o cuidado; redes de apoio, com relatos frequentes sobre a falta de ajuda e ferramentas além das econômicas; e áreas de ocupação afetadas, predominantemente o descanso e o sono, embora o autocuidado e a participação social também sejam mencionados. Conclusão: Embora o processo de luto antecipado gere dor e desgaste próprio, é o cuidado informal que gera mudanças na participação e na qualidade de vida das mulheres cuidadoras.

Introduction: The loss of a loved one is constructed as an inevitable human experience, which generates an emotional experience that impacts both the individual experiencing the loss and his or her environment. Objective: To investigate the relationship between anticipated grief processes and alterations in the occupational participation of informal primary caregivers of terminally ill persons in the Metropolitan Region of Chile. Method: Qualitative approach with 7 individual semi-structured interviews with adult caregivers in the south and west of the region. Results: Experiences and subjectivities were categorized that express the importance that women attribute to the care of their relatives, with little emotional demonstration during this stage. In addition, categories such as routines and roles emerge, where many women prioritize caregiving; support networks, with frequent reports on the lack of help and tools beyond the economic; and areas of occupation affected, predominantly rest and sleep, although self-care and social participation are also mentioned. Conclusion: Although the process of anticipatory grief generates pain and self-exhaustion, it is informal caregiving that generates changes in the participation and quality of life of women caregivers.

Actitudes ante la muerte en profesionales de enfermería latinoamericanos: una revisión integrativa

Introducción: La muerte es parte de los tabúes sociales existentes y puede fomentar actitudes que distan de su abordaje explícito en relación con los cuidados. Objetivo: Analizar las actitudes ante la muerte en profesionales de enfermería de acuerdo con las publicaciones científicas en el contexto latinoamericano en el período 2018 a 2022. Metodología: Se realizó una revisión de literatura integrativa de las publicaciones científicas latinoamericanas respecto de las actitudes ante la muerte en el contexto de la enfermería, empleando los siguientes términos estandarizados: actitud, muerte, enfermería y cuidados de enfermería. Se incluyeron 8 artículos publicados en el período definido, en idioma español y portugués, en los que se abordó explícitamente la temática de la revisión. La información de los artículos fue analizada tomando como referencia los conceptos de la teoría de las transiciones. Resultados: Se encontraron diseños tanto cuantitativos (50 %) como cualitativos (50 %), elaborados en su totalidad en el ámbito hospitalario. Los principales resultados dan cuenta del predominio de la indiferencia ante la muerte en el contexto de los cuidados. En relación con la teoría de las transiciones, la mayoría de los artículos abordan las condiciones en que estas se dan, además de los conceptos de terapéutica de enfermería y patrones de respuesta. Conclusiones: La producción de investigaciones sobre la actitud ante la muerte en profesionales de enfermería es escasa en Latinoamérica. Las experiencias de pérdidas cercanas, la capacitación y el soporte institucional son la base para contribuir a una mejor actitud hacia la muerte

Introdução: A morte faz parte dos tabus sociais existentes e pode fomentar atitudes que se distanciam de sua abordagem explícita em relação aos cuidados. Objetivo: analisar as atitudes diante da morte em profissionais de enfermagem de acordo com as publicações científicas no contexto latino-americano no período de 2018 a 2022. Metodologia: Foi realizada uma revisão de literatura integrativa de publicações científicas latino-americanas sobre atitudes diante da morte no contexto da enfermagem, utilizando os seguintes termos padronizados: atitude, morte, enfermagem e cuidados de enfermagem. Foram incluídos 8 artigos publicados no período definido, em espanhol e português, nos quais o tema da revisão foi abordado explicitamente. As informações dos artigos foram analisadas tendo como referência os conceitos da teoria das transições. Resultados: Foram identificados desenhos quantitativos (50 %) e qualitativos (50 %), elaborados totalmente no âmbito hospitalar. Os principais resultados mostram a predominância da indiferença diante da morte no contexto do cuidado. Em relação à teoria das transições, a maioria dos artigos aborda as condições em que as transições ocorrem, além dos conceitos de terapêutica de enfermagem e padrões de resposta. Conclusões: A produção de pesquisas sobre atitudes diante da morte em profissionais de enfermagem é escassa na América Latina. As experiências de perdas próximas, a capacitação e o apoio institucional são a base para contribuir para uma melhor atitude em relação à morte

Introduction: Death is part of the existing social taboos and can foster attitudes that are far from its explicit approach in relation to care. Objective: To analyze attitudes towards death in nursing professionals according to scientific publications in the Latin American context in the period 2018 to 2022. Methodology: An integrative literature review was conducted of Latin American scientific publications regarding attitudes towards death in the context of Nursing, using the following standardized terms: attitude, death, nursing and nursing care. Eight articles published in the defined period were included, in Spanish and Portuguese, in which the subject of the review was explicitly addressed. The information in the articles was analyzed using the concepts of the theory of transitions as a reference. Results: Both quantitative (50 %) and qualitative (50 %) designs were found, all of them elaborated in the hospital setting. The main results show the predominance of indifference to death in the context of care. In relation to the theory of transitions, most of the articles address the conditions under which these occur, in addition to the concepts of nursing therapeutics and response patterns. Conclusions: The production of research on the attitude towards death in nursing professionals is scarce in Latin America. Experiences of close losses, training and institutional support are the basis for contributing to a better attitude towards death

Desfechos obstétricos adversos durante a COVID-19: uma série de casos retrospectiva / Adverse obstetric outcomes during COVID-19: a retrospective case series / Resultados obstétricos adversos durante el COVID-19: serie de casos retrospectiva

Objetivo: analisar as características e os desfechos obstétricos adversos em gestantes/puérperas infectadas pelo SARS-CoV-2 em serviço de referência. Método: série de casos retrospectiva entre gestantes com Covid-19 em um hospital universitário em Minas Gerais, Brasil, atendidas no serviço de 2020 a 2021, coletados em abril de 2022, empregando-se estatística descritiva para análise dos dados através do Statistical Package for the Social Science. Resultados: incluídas 26 gestantes, em sua maioria brancas, que tiveram como principais desfechos obstétricos adversos a internação em UTI (43,5%), parto prematuro (34,6%), dado reestratificado de semanas para dias para investigar o encurtamento da gestação, onde constatou-se média de 38,6 dias potenciais de gravidez perdidos dos 280 dias ideais, e ainda 15,4% evoluíram para óbito materno. Conclusão: o estudo proporcionou evidenciar a necessidade de vigilância e atenção às gestantes com foco nos principais desfechos adversos, podendo-se intervir em tempo oportuno para diminuir adversidades.

Objective: to analyze the characteristics and adverse obstetric outcomes in pregnant/puerperal women infected by SARS-CoV-2 at a reference service. Method: a retrospective case series conducted among pregnant women with Covid-19 in a university hospital from Minas Gerais, Brazil, treated at the service from 2020 to 2021. The cases were collected in April 2022 employing descriptive statistics for data analysis in the Statistical Package for the Social Science. Results: a total of 26 pregnant women were included, mostly white-skinned, whose main adverse obstetric outcomes were admission to the ICU (43.5%), premature birth (34.6%) and data restratified from weeks to days to investigate shortening of pregnancy, where a mean of 38.6 potential days of pregnancy were lost out of the ideal 280 days, and 15.4% resulted in maternal death. Conclusion: the study provided evidence of the need for surveillance and care for pregnant women with a focus on the main adverse outcomes, enabling timely intervention to reduce adversities.

Objetivo: analizar las características y resultados obstétricos adversos en gestantes/puérperas infectadas por SARS-CoV-2 en un servicio de referencia. Método: serie de casos retrospectiva entre gestantes con Covid-19 en un hospital universitario de Minas Gerais, Brasil, atendidas en el servicio de 2020 a 2021. Los datos se recolectaron en abril de 2022, se utilizó estadística descriptiva para analizar los datos mediante el Statistical Package for the Social Science. Resultados: se incluyeron 26 gestantes, la mayoría de raza blanca, cuyos principales resultados obstétricos adversos fueron ingreso a UCI (43,5%), parto prematuro (34,6%), dato reestratificado de semanas a días para investigar el acortamiento de la gestación, que arrojó como resultado un promedio de 38,6. Se comprobó que se perdieron en promedio 38,6 días potenciales de embarazo de los 280 días ideales, y muerte materna (15,4%). Conclusión: la evidencia que proporcionó el estudio indica que es necesario vigilar y atender a las gestantes enfocándose en los principales resultados adversos, lo que permite intervenir de forma oportuna para reducir adversidades.

Social, health and lifestyle-related determinants of older adults' preferences for place of death in South Tyrol, Italy - a cross-sectional survey study.

BACKGROUND: As the global aging population expands, understanding older adults' preferences for place of death becomes pivotal in ensuring person-centered end-of-life care. OBJECTIVE: This study aimed to investigate the influence of sociodemographic, health, and lifestyle-related factors on end-of-life care preferences of older adults in South Tyrol, Italy. METHODS: Employing a cross-sectional design, a population-based survey was conducted with a stratified probabilistic sample of adults aged ≥ 75 years in South Tyrol (Autonomous Province of Bolzano/Bozen, Italy). From a randomly selected sample of 3,600 older adults, participants were invited to respond to a questionnaire that included items on older adults' preferences for place of death and socio-demographic and health- and lifestyle-related factors, including frailty (e.g., PRISMA-7). Descriptive and multinomial logistic regression analyses were performed. RESULTS: The majority (55.3%) of the 1,695 older adults (participation rate: 47%) expressed a preference for dying at home and 12.7% indicated a desire for specialized end-of-life care in a healthcare facility. However, 27.9% refrained from disclosing their end-of-life care preferences. The factors influencing these preferences concerning the place of death included age, native language, educational level, living situation, and community. Compared to the preference of dying at own home or home of family or friends, older adults aged ≥ 85 years (OR = 0.57, P = 0.002) and living in an urban area (OR = 0.40, P < 0.001) were less likely to prefer dying at a hospital, palliative care unit, or hospice. Older adults living alone (OR = 1.90, P < 0.001), Italian-speaking (OR = 1.46, P = 0.03), and those with an educational level above high school (OR = 1.69, P = 0.002) were more likely to prefer dying at a hospital, palliative care unit, or hospice. CONCLUSIONS: End-of-life care preferences among older adults in South Tyrol were associated with socio-demographic, yet not health- and lifestyle-related factors. Recognizing and integrating these preferences is essential for developing, implementing, and evaluating interventions to promote advance care planning and provide effective, patient-centered end-of-life care.

Perceived risk of death among patients with advanced cancer: a qualitative directed content analysis.

BACKGROUND: Risk perception with respect to death is a prerequisite for patients with advanced cancer when the time comes to make medical decisions. However, the nature of death risk perception remains unclear. METHOD: In-depth interviews were conducted with 28 patients with advanced cancer who were recruited from two hospitals and one home-based hospice in Fujian, China. Interviews were transcribed and directed content analysis applied. The Tripartite Model of Risk Perception was used as a theoretical framework. RESULTS: Patients with advanced cancer perceived their risk of death in different ways. Professional communication about death risk and data-driven risk perception were common in clinical settings. Affective influences, inherent cognition, and comparisons to others or oneself also contributed to the subjects' self-perceived death risk. CONCLUSION: This theory-informed qualitative study clarifies the nature of the perceived risk of death among patients with advanced cancer. The study findings offer healthcare providers a more nuanced understanding of the perceived risk of death among patients with advanced cancer.

Clinical outcomes of conversion surgery after induction immunochemotherapy for borderline resectable T4 esophageal squamous cell carcinoma.

BACKGROUND: The current treatment strategies for borderline resectable esophageal squamous cell carcinoma remain controversial. This study aimed to evaluate the efficacy and safety of programmed cell death 1 inhibitors combined with chemotherapy, followed by conversion surgery, for borderline resectable esophageal squamous cell carcinoma. METHODS: Patients with borderline resectable esophageal squamous cell carcinoma treated with induction immunochemotherapy from January 1, 2020 to July 1, 2023 at our hospital were retrospectively analyzed. The primary study outcome was the R0 resection rate. Secondary study outcomes included progression-free survival (PFS), overall survival (OS), pathological complete remission (pCR) rate, and safety. RESULTS: Forty patients with borderline resectable esophageal squamous cell carcinoma were included in the analysis. The R0 resection rate was 23/40 (57.5%); the conversion success rate was 27/40 (67.5%), and the pCR rate was 11/40 (27.5%). The median follow-up was 23.6 months (95% CI, 19.1-28.2). One-year OS and PFS rates were 77.7% and 71.8%, respectively. The incidence rate of Grade 3-4 adverse events was 10%. There was a significant difference in PFS between patients who underwent surgery and those who did not (P = 0.008, HR: 0.144 95%CI: 0.034-0.606). However, the difference in OS was not significant (P = 0.128, HR: 0.299 95%CI: 0.063-1.416). Patients who achieved clinical downstaging after induction therapy had significantly better OS (P = 0.004 h: 0.110 95%CI: 0.025-0.495) and PFS (P = 0.0016, HR: 0.106 95%CI: 0.026-0.426) compared to those who did not. CONCLUSIONS: Conversion surgery after induction immunochemotherapy is a promising new strategy with a high conversion rate, inspiring R0 resection rate, significant pathological remission rate, and mild toxicity for borderline resectable esophageal squamous cell carcinoma.

Analysis of early and treatment related deaths among children and adolescents with acute myeloid leukemia in Poland: 2005-2023.

Background: A personalised approach to the treatment of acute myeloid leukemia (AML) in children and adolescents, as well as the development of supportive therapies, has significantly improved survival. Despite this, some patients still die before starting treatment or in an early phase of therapy before achieving remission. The study analysed the frequency, clinical features and risk factors for early deaths (ED) and treatment related deaths (TRD) of children and adolescents with AML. Methods: From January 2005 to November 2023, 646 children with AML treated in the centers of the Polish Pediatric Leukemia and Lymphoma Study Group according to three subsequent therapeutic protocols were evaluated: AML-BFM 2004 Interim (385 children), AML-BFM 2012 Registry (131 children) and AML-BFM 2019 (130 children). Results: Out of 646 children, early death occurred in 30 children, including 15 girls. The median age was 10.7 years (1 day to 18 years). More than half of the patients (53%) were diagnosed with acute myelomonocytic leukemia (M5) and 13% with acute promyelocytic leukemia (M3). The ED rate for the three consecutive AML-BFM protocols was 4.9% vs. 5.3% vs. 3.1%, respectively. In 19 patients, death occurred before the 15th day of treatment, in 11 between the 15th and 42nd day. The most common cause of death before the 15th day (ED15) was leukostasis and bleeding, whereas between the 15th and 42nd day (ED15-42), infections, mainly bacterial sepsis. A significant association was found between ED15 and high leukocyte count (>10 × 109/L), M3 leukemia (p < 0.001), and ED15-42 and age <1 year (p = 0.029). In the univariate analysis only initial high leukocyte count >100 × 109/L, was a significant predictor of early death. The overall TRD for the entire study period was 3.4%. The main cause of death were infections, mainly bacterial sepsis (10 children out of 22, 45.4%). Conclusions: Hyperleukocytosis remains significant factor of early mortality in patients with AML, despite the introduction of various cytoreductive methods. Infections are still the main cause of treatment related deaths. A more individualized approach by using new targeted drugs may be the therapeutic option of choice in the future.

Regulated Cell Death Pathways in Pathological Cardiac Hypertrophy.

Cardiac hypertrophy is characterized by an increased volume of individual cardiomyocytes rather than an increase in their number. Myocardial hypertrophy due to pathological stimuli encountered by the heart, which reduces pressure on the ventricular walls to maintain cardiac function, is known as pathological hypertrophy. This eventually progresses to heart failure. Certain varieties of regulated cell death (RCD) pathways, including apoptosis, pyroptosis, ferroptosis, necroptosis, and autophagy, are crucial in the development of pathological cardiac hypertrophy. This review summarizes the molecular mechanisms and signaling pathways underlying these RCD pathways, focusing on their mechanism of action findings for pathological cardiac hypertrophy. It intends to provide new ideas for developing therapeutic approaches targeted at the cellular level to prevent or reverse pathological cardiac hypertrophy.

Women undergoing primary total hip arthroplasty (THA) for hip fracture have lower in-hospital mortality compared to men.

INTRODUCTION: We evaluated the association of patient sex with in-patient mortality and discharge disposition after primary total hip arthroplasty (THA) for hip fracture in the U.S. METHODS: Using the 2016-2019 U.S. National Inpatient Sample (NIS), we calculated adjusted odds ratios (aOR) and 95% confidence intervals (CI) of the association of sex with post-procedural complications and in-hospital mortality after primary THA for hip fracture, adjusting for demographics, social determinants of health, medical comorbidity, hospital characteristics, and post-procedural complications. RESULTS: There were 400,930 primary THA procedure hospitalizations for hip fracture in the 2016-2019 NIS data. In multivariable-adjusted analysis, compared to males, female sex was associated with lower in-hospital mortality following THA for hip fracture (aOR 0.65, 95 % CI 0.58 - 0.74; p < 0.001). Multivariable-adjusted analysis showed that female sex was associated with higher odds of discharge to a non-home destination after a THA for hip fracture (aOR 1.14, 95 % CI 1.07 - 1.22; p < 0.001). CONCLUSIONS: Female sex was associated with lower in-hospital mortality after a THA for hip fracture. Further insights into the protective mechanisms that mediate this lower mortality in women undergoing a THA for hip fracture are needed to achieve better outcomes for men in the future.

The mode of action of sorafenib in MDA-MB-231 breast carcinoma cells involves components of apoptotic, necroptotic and autophagy-dependent cell death pathways.

We report the identification of an interesting mode of action by sorafenib (SF) (Nexavar), in triple-negative breast adenocarcinoma MDA-MB-231 cells. The dying cells presented features of apoptosis, such as externalization of phosphatidylserine and cleaved caspase-3, and autophagy-mediated cell death, such as formation of autophagosomes and autolysosomes, the overexpression of LC3-II, and the presence of LAMP1-positive vacuoles, while displaying insufficient autophagic flux. Components of endoplasmic reticulum stress (ER stress; PERK and CHOP) and of necroptosis (p-MLKL) were also elevated considerably. Investigating potential target proteins that could regulate this form of cell death, we next investigated the role of tubulin disruption, which is known to induce necroptosis, apoptosis, and autophagy-dependent cell death. Interactions of SF with purified tubulin were investigated in detail using a combination of cellular and biophysical assays, transmission electron microscopy, and computer simulations. A marked reduction in the intrinsic tryptophan fluorescence of tubulin, a concentration-dependent elevation of anilinonaphthalene sulfonate-tubulin complex fluorescence, electron micrographs of deformed in vitro-assembled microtubules, and disrupted and hyper-stabilized cellular microtubules evinced the ability of SF to target tubulin and disrupt cellular microtubules at its IC50 for cell viability. Molecular docking and molecular dynamic simulations positioned the drug between the α and ß subunits of tubulin with considerable stability (ΔGbind, -31.43 kcal/mol), suggesting that drug-induced perturbation of tubulin could contribute to this mode of cell death.

Variants that get straight to your heart - Cardiogenetic secondary findings in exome sequencing.

BACKGROUND: Exome sequencing has been established as a fundamental tool in genetic diagnostics. It may also provide information about variants in genes unrelated to the primary purpose, so-called secondary findings. Especially, diagnoses of unnoticed inborn cardiac diseases are of high clinical relevance due to therapeutic options in context of prevention of sudden cardiac death. METHODS: Exome data of 9962 individuals was analysed for relevant cardiogenetic findings. Genes were selected according to ACMG recommendations for secondary findings (v.3.1). First, a filter for (likely) pathogenic variants, published in the ClinVar database, was used. Second, exome data was screened for loss of function (LoF) variants in genes in which LoF is a known disease pathomechanism. All variants were evaluated by geneticists regarding their pathogenicity. RESULTS: Pathogenic or likely pathogenic variants were identified in 136 different individuals (136/9962, 1.4%), with the Low-Density Lipoprotein Receptor gene (LDLR, 24/136, 17.6%) and the Titin gene (TTN, 24/136, 17.6%), being the most frequently affected ones. 31.6% (43/136) of the identified variants had been reported beforehand, while 47.1% (64/136) had not been reported. The remaining cases (29/136, 21.3%) were part of research projects with no written reports. In 26.5% (36/136), the finding would have been missed, if only index patients and not their parents had been screened for secondary findings in case of trio ES. CONCLUSION: As demonstrated in our study, at least one or two out of one hundred people are likely to carry a pathogenic cardiogenetic variant. Counselling geneticist and clinicians need to be aware of these findings in exome and genome sequencing. Informed consent of the patient regarding the report of secondary findings should absolutely be obtained beforehand.

Multi-omics revealed that ELAVL3 regulates MYCN in neuroblastoma via immunogenic cell death: Risk stratification and experimental research.

Neuroblastoma (NB), a common and highly lethal malignant disease in pediatrics, still lacks an effective therapeutic approach that addresses all conditions. Immunogenic Cell Death (ICD) plays a crucial role in tumor cell death and triggers a potent anti-tumor immune response. In this study, we report an ICD-related index (ICDR-Index) in NB through various machine learning methodologies, utilizing bulk transcriptome data from 1244 NB samples and 16 scRNA-seq datasets. Our results showed that the ICDR-Index could accurately identify different risk subtypes of patients with NB and provide predictive value for prognosis. Importantly, we found that high-risk patients with NB exhibited significantly poor overall survival (OS) rates, adverse clinical phenotypes, poor immune cell infiltration, and low sensitivity to immunotherapy. Furthermore, we identified ELAVL3 as a key gene within the ICDR-Index, where high expression levels were associated with malignancy and poor OS in NB. Additionally, targeted silencing of ELAVL3 down-regulated MYCN gene expression and reduced the malignancy of NB cells. Notably, the si-ELAVL3-transfected NB cells enhanced the anti-tumor activity of NK cells. Collectively, this study offers avenues for predicting the risk stratification of patients with NB and reveals a potential mechanism by which ELAVL3 regulates NB cell death.

Advancements in programmed cell death research in antitumor therapy: a comprehensive overview.

Cell death is a normal physiological process within cells that involves multiple pathways, such as normal DNA damage, cell cycle arrest, and programmed cell death (PCD). Cell death has been a hot spot of research in tumor-related fields, especially programmed cell death, which is a key form of cell death and is classified into different types according to the mechanism of occurrence, such as apoptosis, autophagy, necroptosis, pyroptosis, ferroptosis, and disulfidptosis. Given the important role of PCD in maintaining tissue homeostasis and inhibiting tumorigenesis and development, more and more basic and clinical studies are devoted to revealing its potential application in anti-tumor strategies. The purpose of this review is to systematically review the regulatory mechanisms of PCD and to summarize the latest research progress of anti-tumor treatment strategies based on PCD.

Adam Omelianchuk, Alexander Morgan Capron, Lainie Friedman Ross, Arthur R. Derse, James L. Bernat, and David Magnus reply.

This letter responds to letters by Garson Leder and by Harrison Lee in the same issue, September-October 2024, of the Hastings Center Report.