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Rationale: Despite evidence demonstrating a prognostic role for computed tomography (CT) scans in idiopathic pulmonary fibrosis (IPF), image-based biomarkers are not routinely used in clinical practice or trials. Objectives: To develop automated imaging biomarkers using deep learning–based segmentation of CT scans. Methods: We developed segmentation processes for four anatomical biomarkers, which were applied to a unique cohort of treatment-naive patients with IPF enrolled in the PROFILE (Prospective Observation of Fibrosis in the Lung Clinical Endpoints) study and tested against a further United Kingdom cohort. The relationships among CT biomarkers, lung function, disease progression, and mortality were assessed. Measurements and Main Results: Data from 446 PROFILE patients were analyzed. Median follow-up duration was 39.1 months (interquartile range, 18.1–66.4 mo), with a cumulative incidence of death of 277 (62.1%) over 5 years. Segmentation was successful on 97.8% of all scans, across multiple imaging vendors, at slice thicknesses of 0.5–5 mm. Of four segmentations, lung volume showed the strongest correlation with FVC (r = 0.82; P < 0.001). Lung, vascular, and fibrosis volumes were consistently associated across cohorts with differential 5-year survival, which persisted after adjustment for baseline gender, age, and physiology score. Lower lung volume (hazard ratio [HR], 0.98 [95% confidence interval (CI), 0.96–0.99]; P = 0.001), increased vascular volume (HR, 1.30 [95% CI, 1.12–1.51]; P = 0.001), and increased fibrosis volume (HR, 1.17 [95% CI, 1.12–1.22]; P < 0.001) were associated with reduced 2-year progression-free survival in the pooled PROFILE cohort. Longitudinally, decreasing lung volume (HR, 3.41 [95% CI, 1.36–8.54]; P = 0.009) and increasing fibrosis volume (HR, 2.23 [95% CI, 1.22–4.08]; P = 0.009) were associated with differential survival. Conclusions: Automated models can rapidly segment IPF CT scans, providing prognostic near and long-term information, which could be used in routine clinical practice or as key trial endpoints. [ABSTRACT FROM AUTHOR]

This article explores the significance of analyzing historical mortality data to gain insights into current health disparities. It highlights the shift in causes of death from infectious diseases to non-communicable diseases over the past century and a half. The article emphasizes the need to contextualize recent events, such as the COVID-19 pandemic, within long-term historical trends. It also recognizes the persistence of socio-demographic inequalities in health and the importance of comprehensive population-based studies to address these disparities. The text discusses international initiatives, like the EU COST Action "The Great Leap," which aim to understand the drivers of health inequalities through historical analysis. However, the authors note that additional long-term population-based studies are necessary to tackle the public health challenges of the 21st century. The authors express gratitude to their collaborators and acknowledge financial support from the Swiss National Science Foundation. [Extracted from the article]

Aims: One half of Norwegians die in nursing homes, where death certificates (DCs) are completed by two types of physicians: in-house physicians or physicians on call. The aims of this study were to examine differences in the quality of DCs due to type of physician and to uncover possible implications of errors for the public statistics. Methods: DCs from the year 2013 from nursing homes in the catchment area of Akershus University Hospital were examined with regard to logical deficiencies, garbage code diagnoses and type of certifying physician. In one third of cases, the registered causes of death were compared to information in the medical records. Results: A total of 873 DCs from 24 nursing homes were evaluated. Physicians on call certified 46% of all deaths. Logical deficiencies were found in 34% of all DCs and were more common in DCs from physicians on call. Garbage code diagnoses were used in every third DC, with 'sudden death' or 'cause of death unknown' preferred by physicians on call and 'unspecified pneumonia' preferred by in-house physicians. Comparisons against medical records uncovered missing information in 49% and 35% of DCs from physicians on call and in-house physicians, respectively. A dementia diagnosis was frequently overlooked by both physician types. Garbage code diagnoses were more common in DCs with missing information from medical records. Conclusions: Error rates in DCs in nursing homes in Norway are high. The results raise concerns about the validity of public cause of death statistics. [ABSTRACT FROM AUTHOR]

The leading cause of cancer‐related death is lung cancer, with metastasis being the most common cause of death. To elucidate the role of macrophages in lung cancer and angiogenesis processes, we established an in vitro co‐culture model of A549 or HUVEC with THP‐1 cells that polarized to M2c macrophages with hydrocortisone. The proteasome inhibitors bortezomib and ixazomib were investigated for their effects on proliferation, invasion, migration, metastasis, and angiogenesis pathways. The effects of bortezomib and ixazomib on gene expression in gene panels, including crucial genes related to angiogenesis and proteasomes, were investigated after the co‐culture model to determine these effects at the molecular level. In conclusion, bortezomib and ixazomib showed antiproliferative effects in both cells, as well as in M2c macrophage co‐culture. M2c macrophages also increased invasion in A549 cells and both invasion and migration in HUVEC. mRNA expression upregulation, specifically in the NFKB and VEGF genes, supported the metastatic and angiogenic effects found in A549 and HUVEC with M2c macrophage co‐culture. Additionally, bortezomib inhibited the VEGFB pathway in HUVEC and NFKB1 in A549 cells. The significant findings obtained as a result of this study will provide information regarding angiogenesis induced by M2 macrophages. [ABSTRACT FROM AUTHOR]

Despite the paucity of information on the relative frequency of cancers around the world and their socio-economic consequences in different regions, relatively little is known about the global burden of cancer and associated drug resistance. Although there is no reliable data on its incidence and evolution, with estimates varying according to the development index of the countries concerned, cancer is one of the main causes of death and disability in the world. Several treatments are available, but many treatment methods are ineffective because of resistance to anticancer drugs. Although previously thought to be rare in some communities, cancer, and drug-resistant cancer have recently been found to be common, and the situation has worsened since the HIV-AIDS pandemic about three decades ago. Drug resistance may be due to the activation of intrinsic (pre-existing) or acquired (drug-induced) mechanisms, and favors therapeutic failure, hence the need to understand the mechanisms underlying the development of drug resistance. The advanced stage of diagnosis and the unavailability/high cost of therapeutic agents result in a significant economic burden for the patient, his or her family, the community, and the country. This chapter of the book describes the incidence and burden of cancer, as well as global concerns about cancer drug resistance and resistance mechanisms, and finally provides updates on the global burden. [ABSTRACT FROM AUTHOR]

The incidence and mortality of cancer are increasing, making it a leading cause of death worldwide. Conventional treatments such as surgery, radiotherapy, and chemotherapy face significant limitations due to therapeutic resistance. Autophagy, a cellular self-degradation mechanism, plays a crucial role in cancer development, drug resistance, and treatment. This review investigates the potential of autophagy inhibition as a therapeutic strategy for cancer. A systematic search was conducted on Embase, PubMed, and Google Scholar databases from 1967 to 2024 to identify studies on autophagy inhibitors and their mechanisms in cancer therapy. The review includes original articles utilizing in vitro and in vivo experimental methods, literature reviews, and clinical trials. Key terms used were "Autophagy", "Inhibitors", "Molecular mechanism", "Cancer therapy", and "Clinical trials". Autophagy inhibitors such as chloroquine (CQ) and hydroxychloroquine (HCQ) have shown promise in preclinical studies by inhibiting lysosomal acidification and preventing autophagosome degradation. Other inhibitors like wortmannin and SAR405 target specific components of the autophagy pathway. Combining these inhibitors with chemotherapy has demonstrated enhanced efficacy, making cancer cells more susceptible to cytotoxic agents. Clinical trials involving CQ and HCQ have shown encouraging results, although further investigation is needed to optimize their use in cancer therapy. Autophagy exhibits a dual role in cancer, functioning as both a survival mechanism and a cell death pathway. Targeting autophagy presents a viable strategy for cancer therapy, particularly when integrated with existing treatments. However, the complexity of autophagy regulation and the potential side effects necessitate further research to develop precise and context-specific therapeutic approaches. [ABSTRACT FROM AUTHOR]

UNLABELLED: Medical aid in dying (MAID) is a highly controversial ethical issue in the global medical community. Unfortunately, the International Classification of Diseases (ICD) of the World Health Organization (WHO) lacks coding for MAID. Therefore, no robust data adequately monitors worldwide trends that include information on diseases and conditions underlying the patients request for assisted dying (MAID gap). Countries with legalised MAID observe substantial increases in cases, and likely additional countries will allow MAID in the near future. Hence, we encourage the WHO to create specific ICD codes for MAID. According to internationally established practices, a revised classification would require separate MAID-codes for (1) assisted suicide and (2) voluntary active euthanasia including supplemental codings of diseases, clusters of symptoms and function-oriented categories. By addressing these concerns, the WHO could close the MAID gap with new codes providing urgently necessary insights to society, public health decision-makers and regulators on this comparatively new social and medical ethical phenomenon. SEARCH STRATEGY AND SELECTION CRITERIA: Data for this Viewpoint were identified by searches of MEDLINE, PubMed, and references from relevant articles using the search terms Medical Aid in Dying, Assisted Dying, Assisted suicide, Voluntary active euthanasia, End of life decisions and Cause of death statistics. Only articles and sources published in English between 1997 and 2023 were included.

Clinical reasoning has been characterized as being an essential aspect of being a physician. Despite this, clinical reasoning has a variety of definitions and medical error, which is often attributed to clinical reasoning, has been reported to be a leading cause of death in the United States and abroad. Further, instructors struggle with teaching this essential ability which often does not play a significant role in the curriculum. In this article, we begin with defining clinical reasoning and then discuss four principles from the literature as well as a variety of techniques for teaching these principles to help ground an instructors’ understanding in clinical reasoning. We also tackle contemporary challenges in teaching clinical reasoning such as the integration of artificial intelligence and strategies to help with transitions in instruction (e.g., from the classroom to the clinic or from medical school to residency/registrar training) and suggest next steps for research and innovation in clinical reasoning. [ABSTRACT FROM AUTHOR]

One of the significant causes of death globally is cancer (http://www.who.org/). Another critical problem is obesity, which is associated with an increased cancer threat. This work provides insight into how obesity contributes to cancer progression and metastasis. We developed a diffusive obesity-cancer model consisting of cancer cells, normal cells, fat cells, macrophages, and an extracellular matrix (ECM) for this aim. We have directed the formed model's global existence and non-negativity. Equilibrium points for the related ODE are calculated, and its existence and stability study is also done. We present a traveling wave analysis of the obesity-cancer model and have calculated the minimum wave speed. Using a combination of analytic and numerical results of traveling waves, we conjecture that the minimal wave speed depends on fat cells' diffusive rate and haptotaxis coefficient. We followed the theory of the Partial Rank Correlation Coefficient (PRCC) to carry out a global sensitivity analysis to evaluate the most sensitive parameters reliable for cancer progression. We delivered a comprehensive numerical analysis of our deterministic and diffusive models (in 1D and 2D) and analogized the result. Numerical simulation of corresponding spatially explicit systems conveys complex spatio-temporal dynamics, resulting in the appearance of patterns. It also discloses that cancer spread increases with increased haptotaxis coefficient and growth rate of obese cells. Our simulation confirms that the degradation of the ECM increases cancer spread and density. [ABSTRACT FROM AUTHOR]

A time-series analysis of serum Cancer Antigen 125 (CA-125)levels was performed in 791 patients with high-grade serous ovarian cancer (HGSOC) from the Australian Ovarian Cancer Study to evaluate the development of chemoresistance and response to therapy. To investigate chemoresistance and better predict the treatment effectiveness, we examined two traits: resistance (defined as the rate of CA-125 change when patients were treated with therapy) and aggressiveness (defined as the rate of CA-125 change when patients were not treated). We found that as the number of treatment lines increases, the data-based resistance increases (a decreased rate of CA-125 decay). We use mathematical models of two distinct cancer cell types, treatment-sensitive cells and treatment-resistant cells, to estimate the values and evolution of the two traits in individual patients. By fitting to individual patient HGSOC data, our models successfully capture the dynamics of the CA-125 level. The parameters estimated from the mathematical models show that patients with inferred low growth rates of treatment-sensitive cells and treatment-resistant cells (low model-estimated aggressiveness) and a high death rate of treatment-resistant cells (low model-estimated resistance) have longer survival time after completing their second-line of therapy. These findings show that mathematical models can characterize the degree of resistance and aggressiveness in individual patients, which improves our understanding of chemoresistance development and could predict treatment effectiveness in HGSOC patients. Author summary: Ovarian cancer is a major cause of death in women worldwide due to the emergence of treatment resistance and eventual treatment failure. Serum levels of the biomarker Cancer Antigen-125 (CA-125) can be used to monitor treatment response in patients with epithelial ovarian cancer. We used time series of CA-125 in 791 patients with high-grade serous ovarian cancer (HGSOC) from the Australian Ovarian Cancer Study to quantify the evolution of resistance and aggressiveness as a response to therapy in individual patients to predict the dynamics of CA-125 and the survival outcomes. We present two mathematical models that include treatment-resistant cells and treatment-sensitive cells. These models accurately fit the data and characterize patients with the best outcomes as those with the least model-estimated aggressively growing cells and the least model-estimated resistant cells. Models with only a single cell type provide poor fits to the data. These minimal models with just two cell types could provide a valuable tool for rapidly and robustly understanding the dynamics of individual patients and pointing the way to identifying specific mechanisms. [ABSTRACT FROM AUTHOR]

Background: Acute Coronary Syndrome is the most common heart disease and the most significant cause of death and disability-adjusted life years worldwide. Teaching a healthy eating style is one preventive measure to prevent the disease's recurrence. This study aimed to determine the effect of healthy nutrition education with the help of traffic light labels on food selection, preference, and consumption in patients with acute coronary syndrome. Methods: This randomized, single-blinded clinical trial was conducted with 139 participants (66 in the intervention group and 73 in the control group) from January 2021 to August 2021 in Shaheed Rajaie Hospital, Tehran, Iran. The control group received standard training. The intervention group, besides this, received additional bedside training with an educational poster on traffic light labels from the research team during their final hospitalization days. Data were collected using a researcher-made questionnaire on food selection, preference, and consumption. Results: The Brunner-Munzel test showed no significant difference between the two groups in terms of selection (P = 0.127), preference (P = 0.852), and food consumption (P = 0.846) in the baseline, while after the intervention, there were significant differences in selection (P > 0.001), preference (P > 0.001), and consumption (p < 0.004). Comparing the difference between the two groups in the difference between the before and after scores for selection (p < 0.001), preference (p < 0.001), and food consumption (p = 0.011) with the Brunner-Munzel test indicated a significant difference in all outcome variables. Conclusions: Teaching healthy eating styles with the help of traffic light labels affected food selection, preference, and consumption and led to healthier diets in these patients. Clinical trial registration number: Clinical trial registration: It was prospectively registered in the Iran Clinical Trials Registration Center on this date 30/10/2020 (IRCT20200927048857N1). [ABSTRACT FROM AUTHOR]

Cancer is a disease that encompasses multiple and different malignant conditions and is among the leading causes of death in the world. Therefore, the search for new pharmacotherapeutic options and potential candidates that can be used as treatments or adjuvants to control this disease is urgent. Natural products, especially those obtained from plants, have played an important role as a source of specialized metabolites with recognized pharmacological properties against cancer, therefore, they are an excellent alternative to be used. The objective of this research was to evaluate the action of the monoterpene isoespintanol (ISO) against the human tumor cell lines MDA-MB-231, A549, DU145, A2780, A2780-cis and the non-tumor line MRC-5. Experiments with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and fluorescence with propidium iodide (PI), 4′,6-diamidino-2-phenylindole dilactate (DAPI) and green plasma revealed the cytotoxicity of ISO against these cells; furthermore, morphological and chromogenic studies revealed the action of ISO on cell morphology and the inhibitory capacity on reproductive viability to form colonies in MDA-MB-231 cells. Likewise, 3D experiments validated the damage in these cells caused by this monoterpene. These results serve as a basis for progress in studies of the mechanisms of action of these compounds and the development of derivatives or synthetic analogues with a better antitumor profile. [ABSTRACT FROM AUTHOR]

• We propose and parameterize a mathematical model of healthy blood cell formation and acute myeloid leukemia. • The model accounts for symmetric and asymmetric stem cell divisions and various impacts of nonlinear feedback regulation. • We studied different clinically relevant scenarios including bone marrow transplantation and expansion of malignant cells. • Slight change in the cell fate probabilities is sufficient to observe onset of leukemia within the human lifespan. • Feedback regulation of symmetric and asymmetric division probabilities impacts on healthy cell recovery and cancer growth. Acute myeloid leukemia (AML) is a paradigmatic example of a stem cell-driven cancer. AML belongs to the most aggressive malignancies and has a poor prognosis. A hallmark of AML is the expansion of malignant cells in the bone marrow and the out-competition of healthy blood-forming (hematopoietic) cells. In the present study, we develop a nonlinear ordinary differential equation model to study the impact of feedback configurations and kinetic cell properties such as symmetric self-renewal probability, symmetric differentiation probability, asymmetric division probability, proliferation rate, or death rate on leukemic cell population dynamics. The model accounts for two healthy cell types (mature and immature) and for two leukemic cell types (cells that can divide and cells that have lost the ability to divide). The model considered here is a generalization of previous models and contains them as a special case. We consider multiple feedback configurations that differ in their impact on symmetric self-renewal, symmetric differentiation, and asymmetric division probabilities. Linearized stability analysis is performed to derive necessary and sufficient conditions for the expansion or extinction of leukemic cells. In our analysis, we distinguish three types of steady states, namely purely leukemic steady states (presence of leukemic and absence of healthy cells), healthy steady states (presence of healthy cells and absence of leukemic cells), and composite steady states where healthy and leukemic cells coexist. Steady-state analysis reveals that under biologically plausible assumptions the healthy and the purely leukemic steady states are unique. If composite steady states exist, they are non-unique and form a one-dimensional manifold. The purely leukemic steady state is locally asymptotically stable if and only if the steady state of healthy cells is unstable. The analytical results are illustrated by numerical simulations. Our models suggest that a slight increase of the symmetric self-renewal probability or a slight decrease of the symmetric differentiation probability in leukemic compared to healthy cells results in a destabilization of the homeostatic equilibrium and expansion of malignant cells. This finding is in line with the differentiation arrest observed in leukemic cells. Changes of these parameters in the opposite direction can re-establish the healthy population. Our model furthermore suggests that the configuration of the feedback loops impacts on healthy cell regeneration, the growth rate of malignant cells, the malignant cell burden in late stage leukemias and the decline of healthy cells in leukemic patients. [ABSTRACT FROM AUTHOR]

Cancer is a leading cause of death worldwide. Several targeted anticancer drugs entered clinical practice and improved survival of cancer patients with selected tumor types, but therapy resistance and metastatic disease remains a challenge. A major class of targeted anticancer drugs are therapeutic antibodies, but their use is limited to extracellular targets. Hence, alternative binding scaffolds have been investigated for intracellular use and better tumor tissue penetration. Among those, monobodies are small synthetic protein binders that were engineered to bind with high affinity and selectivity to central intracellular oncoproteins and inhibit their signaling. Despite their use as basic research tools, the potential of monobodies as protein therapeutics remains to be explored. In particular, the pharmacological properties of monobodies, including plasma stability, toxicity and pharmacokinetics have not been investigated. Here, we show that monobodies have high plasma stability, are well-tolerated in mice, but have a short half-life in vivo due to rapid renal clearance. Therefore, we engineered monobody fusions with an albumin-binding domain (ABD), which showed enhanced pharmacological properties without affecting their target binding: We found that ABD-monobody fusions display increased stability in mouse plasma. Most importantly, ABD-monobodies have a dramatically prolonged in vivo half-life and are not rapidly excreted by renal clearance, remaining in the blood significantly longer, while not accumulating in specific internal organs. Our results demonstrate the promise and versatility of monobodies to be developed into future therapeutics for cancer treatment. We anticipate that monobodies may be able to extend the spectrum of intracellular targets, resulting in a significant benefit to patient outcome. [ABSTRACT FROM AUTHOR]

Ovarian cancer is a leading cause of death among gynecologic tumors, often detected at advanced stages. Metabolic reprogramming and increased lipid biosynthesis are key factors driving cancer cell growth. Stearoyl-CoA desaturase 1 (SCD1) is a crucial enzyme involved in de novo lipid synthesis, producing mono-unsaturated fatty acids (MUFAs). Here, we aimed to investigate the expression and significance of SCD1 in epithelial ovarian cancer (EOC). Comparative analysis of normal ovarian surface epithelial (NOSE) tissues and cell lines revealed elevated SCD1 expression in EOC tissues and cells. Inhibition of SCD1 significantly reduced the proliferation of EOC cells and patient-derived organoids and induced apoptotic cell death. Interestingly, SCD1 inhibition did not affect the viability of non-cancer cells, indicating selective cytotoxicity against EOC cells. SCD1 inhibition on EOC cells induced endoplasmic reticulum (ER) stress by activating the unfolded protein response (UPR) sensors and resulted in apoptosis. The addition of exogenous oleic acid, a product of SCD1, rescued EOC cells from ER stress-mediated apoptosis induced by SCD1 inhibition, underscoring the importance of lipid desaturation for cancer cell survival. Taken together, our findings suggest that the inhibition of SCD1 is a promising biomarker as well as a novel therapeutic target for ovarian cancer by regulating ER stress and inducing cancer cell apoptosis. [ABSTRACT FROM AUTHOR]

Both cancer and cardio-metabolic disease disparities exist among specific populations in the US. For example, African Americans experience the highest rates of breast and prostate cancer mortality and the highest incidence of obesity. Native and Hispanic Americans experience the highest rates of liver cancer mortality. At the same time, Pacific Islanders have the highest death rate attributed to type 2 diabetes (T2D), and Asian Americans experience the highest incidence of non-alcoholic fatty liver disease (NAFLD) and cancers induced by infectious agents. Notably, the pathologic progression of both cancer and cardio-metabolic diseases involves innate immunity and mechanisms of inflammation. Innate immunity in individuals is established through genetic inheritance and external stimuli to respond to environmental threats and stresses such as pathogen exposure. Further, individual genomes contain characteristic genetic markers associated with one or more geographic ancestries (ethnic groups), including protective innate immune genetic programming optimized for survival in their corresponding ancestral environment(s). This perspective explores evidence related to our working hypothesis that genetic variations in innate immune genes, particularly those that are commonly found but unevenly distributed between populations, are associated with disparities between populations in both cancer and cardiometabolic diseases. Identifying conventional and unconventional innate immune genes that fit this profile may provide critical insights into the underlying mechanisms that connect these two families of complex diseases and offer novel targets for precision-based treatment of cancer and/or cardiometabolic disease. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a major life-threatening disease, being the third most common cancer and a leading cause of death worldwide. Enhanced adiposity, particularly visceral fat, is a major risk factor for CRC, and obesity-associated alterations in metabolic, inflammatory and immune profiles in visceral adipose tissue (VAT) strongly contribute to promoting or sustaining intestinal carcinogenesis. The role of diet and nutrition in obesity and CRC has been extensively demonstrated, and AT represents the main place where diet-induced signals are integrated. Among the factors introduced with diet and processed or enriched in AT, ω3/ω6 polyunsaturated fatty acids (PUFAs) are endowed with pro- or anti-inflammatory properties and have been shown to exert either promoting or protective roles in CRC. In this study, we investigated the impact of ex vivo exposure to the ω3 and ω6 PUFAs docosahexaenoic and arachidonic acids on VAT adipocyte whole transcription in healthy lean, obese and CRC-affected individuals. High-throughput sequencing of protein-coding and long non-coding RNAs allowed us to identify specific pathways and regulatory circuits controlled by PUFAs and highlighted an impaired responsiveness of obese and CRC-affected individuals as compared to the strong response observed in healthy lean subjects. This further supports the role of healthy diets and balanced ω3/ω6 PUFA intake in the primary prevention of obesity and cancer. [ABSTRACT FROM AUTHOR]

Despite advances in their diagnosis and treatment, pediatric cancers remain among the leading causes of death in childhood. The development of immunotherapies and other forms of targeted therapies has significantly changed the prognosis of some previously incurable cancers in the adult population. However, so far, the results in pediatric cohorts are disappointing, which is mainly due to differences in tumor biology, including extreme heterogeneity and a generally low tumor mutational burden. A central role in the limited efficacy of immunotherapeutic approaches is played by the peculiar characteristics of the tumor microenvironment (TME) in pediatric cancer, with the scarcity of tumor infiltration by T cells and the abundance of stromal cells endowed with lymphocyte suppressor and tumor-growth-promoting activity. Thus, progress in the treatment of pediatric solid tumors will likely be influenced by the ability to modify the TME while delivering novel, more effective therapeutic agents. In this review, we will describe the TME composition in pediatric solid tumors and illustrate recent advances in treatment for the modulation of immune cells belonging to the TME. [ABSTRACT FROM AUTHOR]

Background: In Japan, difference in birth rates depending on educational attainment has not been investigated. This study aimed to reveal birth rates in Japan depending on the highest level of educational attainment and their trends over the years using nationwide government statistics data. Methods: Individual-level data from Vital Statistics and the Census from 2000, 2010, and 2020 were used for birth and population data, respectively. Data linkage was conducted for males and females in the Census and fathers and mothers in the Vital Statistics using information about gender, household, nationality, marital status, birth year, birth month, prefecture, and municipality for individuals. The birth rate was calculated by gender, a five-year age group, the highest level of educational attainment achieved, and year. In addition, the slope index of inequality (SII) and relative index of inequality (RII) were calculated to evaluate the degree of inequality in birth rates, depending on the educational attainment. Results: Birth rates were higher in persons with lower educational attainment compared to those with a higher educational attainment among males and females in their twenties, while they tended to be higher in persons with higher educational attainment among those in their thirties and forties. Additionally, an increase in the birth rate from 2000 to 2020 was the largest in university graduates among males aged 25–49 years and women aged 30–49 years, and a decrease in the birth rate was the smallest in university graduates among males and females aged 20–24 years. As a result, SII and RII increased from 2000 to 2020 among males and females in their thirties and forties. Conclusions: In conclusion, persons with higher educational attainment tended to have a relatively favorable trend in the birth rate compared with persons with lower educational attainment in recent decades. It suggested that enhanced administrative support for individuals with lower educational attainment or lower socioeconomic status may be required to ameliorate the declining birth rate in Japan. [ABSTRACT FROM AUTHOR]

Background: Mosaic loss of chromosome Y (LOY) in leukocytes is the most prevalent somatic aneuploidy in aging humans. Men with LOY have increased risks of all-cause mortality and the major causes of death, including many forms of cancer. It has been suggested that the association between LOY and disease risk depends on what type of leukocyte is affected with Y loss, with prostate cancer patients showing higher levels of LOY in CD4 + T lymphocytes. In previous studies, Y loss has however been observed at relatively low levels in this cell type. This motivated us to investigate whether specific subsets of CD4 + T lymphocytes are particularly affected by LOY. Publicly available, T lymphocyte enriched, single-cell RNA sequencing datasets from patients with liver, lung or colorectal cancer were used to study how LOY affects different subtypes of T lymphocyte. To validate the observations from the public data, we also generated a single-cell RNA sequencing dataset comprised of 23 PBMC samples and 32 CD4 + T lymphocytes enriched samples. Results: Regulatory T cells had significantly more LOY than any other studied T lymphocytes subtype. Furthermore, LOY in regulatory T cells increased the ratio of regulatory T cells compared with other T lymphocyte subtypes, indicating an effect of Y loss on lymphocyte differentiation. This was supported by developmental trajectory analysis of CD4 + T lymphocytes culminating in the regulatory T cells cluster most heavily affected by LOY. Finally, we identify dysregulation of 465 genes in regulatory T cells with Y loss, many involved in the immunosuppressive functions and development of regulatory T cells. Conclusions: Here, we show that regulatory T cells are particularly affected by Y loss, resulting in an increased fraction of regulatory T cells and dysregulated immune functions. Considering that regulatory T cells plays a critical role in the process of immunosuppression; this enrichment for regulatory T cells with LOY might contribute to the increased risk for cancer observed among men with Y loss in leukocytes. [ABSTRACT FROM AUTHOR]

Cancer is one of the major causes of death worldwide and the development of multidrug resistance (MDR) in cancer cells is the principal cause of chemotherapy failure. To gain insights into the specific mechanisms of MDR in cancer cell lines, we developed a novel method for the combined analysis of recently published datasets on drug sensitivity and CRISPR loss-of-function screens for the same set of cancer cell lines. For our analysis, we first selected cell lines that consistently exhibit drug resistance across several classes of compounds. We then identified putative resistance genes for each class of compound and used inferred gene regulatory networks (GRNs) to study possible mechanisms underlying the development of MDR in the identified cancer cell lines. We show that the same method of analysis can also be used to identify cell lines that consistently exhibit resistance to the gene knockout effect of the CRISPR-Cas9 technique and to study the possible underlying mechanisms. In the GRN associated to the drug resistant cell lines, we identify genes previously associated with resistance (UHMK1, RALYL, MGST3, USP9X, and ESRG), genes for which an indirect association can be identified (SPINK13, LINC00664, MRPL38, and EMILIN3), and genes that are found to be overexpressed in non-resistant cancer cell lines (MRPL38, EMILIN3 and RALYL). In the GRNs associated to the CRISPR-Cas9 resistance mechanism, none of the identified genes has been previously reported in the admittedly sparse literature on the subject. However, some of these genes have a common role: APBB2, RUNX1T1, ZBTB7C, and ISX regulate transcription, while APBB2, BTG3, ZBTB7C, SZRD1 and LEF1 have a function in regulating proliferation, suggesting a role for these two pathways. While our results are specific for the lung cancer cell lines we selected for this work, our method of analysis can be applied to cell lines from other tissues and for which the required data is available. [ABSTRACT FROM AUTHOR]

Colorectal cancer is the third leading cause of death from neoplasia worldwide. Thanks to new screening programs, we are now seeing an increase in Early Onset of ColoRectal Cancer (EOCRC) in patients below the age of 50. Herein, we report a clinical case of a woman affected by EOCRC. This case illustrates the importance of genetic predisposition testing also in tumor patients. Indeed, for our patient, we used a combined approach of multiple molecular and cellular biology technologies that revealed the presence of an interesting novel variant in the SMARCA4 gene. The latter gene is implicated in damage repair processes and related, if mutated, to the onset of various tumor types. In addition, we stabilized Patient-Derived Organoids from the tumor tissue of the same patient and the result confirmed the presence of this novel pathogenic variant that has never been found before even in early onset cancer. In conclusion, with this clinical case, we want to underscore the importance of including patients even those below the age of 50 years in appropriate screening programs which should also include genetic tests for predisposition to early onset cancers. [ABSTRACT FROM AUTHOR]

Cancer in dogs has increased in recent years and is a leading cause of death. We have developed a retroviral replicating vector (RRV) that specifically targets cancer cells for infection and replication. RRV carrying a suicide gene induced synchronized killing of cancer cells when administered with a prodrug after infection. In this study, we evaluated two distinct RRVs derived from amphotropic murine leukemia virus (AMLV) and gibbon ape leukemia virus (GALV) in canine tumor models both in vitro and in vivo. Despite low infection rates in normal canine cells, both RRVs efficiently infected and replicated within all the canine tumor cells tested. The efficient intratumoral spread of the RRVs after their intratumoral injection was also demonstrated in nude mouse models of subcutaneous canine tumor xenografts. When both RRVs encoded a yeast cytosine deaminase suicide gene, which converts the prodrug 5-fluorocytosine (5-FC) to the active drug 5-fluorouracil, they caused tumor-cell-specific 5-FC-induced killing of the canine tumor cells in vitro. Furthermore, in the AZACF- and AZACH-cell subcutaneous tumor xenograft models, both RRVs exerted significant antitumor effects. These results suggest that RRV-mediated suicide gene therapy is a novel therapeutic approach to canine cancers. [ABSTRACT FROM AUTHOR]

Background and Aims: To systematically review the literature for reports on Wolcott‐Rallison syndrome, focusing on the spectrum and natural history, genotype‐phenotype correlations, patient and native liver survival, and long‐term outcomes. Methods: PubMed, Livio, Google Scholar, Scopus and Web of Science databases were searched. Data on genotype, phenotype, therapy, cause of death and follow‐up were extracted. Survival and correlation analyses were performed. Results: Sixty‐two studies with 159 patients met the inclusion criteria and additional 30 WRS individuals were collected by personal contact. The median age of presentation was 2.5 months (IQR 2) and of death was 36 months (IQR 50.75). The most frequent clinical feature was neonatal diabetes in all patients, followed by liver impairment in 73%, impaired growth in 72%, skeletal abnormalities in 59.8%, the nervous system in 37.6%, the kidney in 35.4%, insufficient haematopoiesis in 34.4%, hypothyroidism in 14.8% and exocrine pancreas insufficiency in 10.6%. Episodes of acute liver failure were frequently reported. Liver transplantation was performed in six, combined liver‐pancreas in one and combined liver‐pancreas‐kidney transplantation in two individuals. Patient survival was significantly better in the transplant cohort (p =.0057). One‐, five‐ and ten‐year patient survival rates were 89.4%, 65.5% and 53.1%, respectively. Liver failure was reported as the leading cause of death in 17.9% of cases. Overall survival was better in individuals with missense mutations (p =.013). Conclusion: Wolcott‐Rallison syndrome has variable clinical courses. Overall survival is better in individuals with missense mutations. Liver‐ or multi‐organ transplantation is a feasible treatment option to improve survival. [ABSTRACT FROM AUTHOR]

Diabetes mellitus type 1 (T1D) and type 2 (T2D) develop due to dysfunction of the Langerhans islet β-cells in the pancreas, and this dysfunction is mediated by oxidative, endoplasmic reticulum (ER), and mitochondrial stresses. Although the two types of diabetes are significantly different, β-cell failure and death play a key role in the pathogenesis of both diseases, resulting in hyperglycemia due to a reduced ability to produce insulin. In T1D, β-cell apoptosis is the main event leading to hyperglycemia, while in T2D, insulin resistance results in an inability to meet insulin requirements. It has been suggested that autophagy promotes β-cell survival by delaying apoptosis and providing adaptive responses to mitigate the detrimental effects of ER stress and DNA damage, which is directly related to oxidative stress. As people with diabetes are now living longer, they are more susceptible to a different set of complications. There has been a diversification in causes of death, whereby a larger proportion of deaths among individuals with diabetes is attributable to nonvascular conditions; on the other hand, the proportion of cancer-related deaths has remained stable or even increased in some countries. Due to the increasing cases of both T1D and T2D, these diseases become even more socially significant. Hence, we believe that search for any opportunities for control of this disease is an overwhelmingly important target for the modern science. We focus on two differences that are characteristic of the development of diabetes’s last periods. One of them shows that all-cause death rates have declined in several diabetes populations, driven in part by large declines in vascular disease mortality but large increases in oncological diseases. Another hypothesis is that some T2D medications could be repurposed to control glycemia in patients with T1D. [ABSTRACT FROM AUTHOR]

Every year millions of people are burned and many of them are transported to specialized burn centers. One of the most important challenges in the face of burn patients in urban areas is deciding about referring patients to specialized burn centers. In this study, correlation between referral distance and mortality rate is investigated. Our cross-sectional analytic study included admission data of 7248 burn patients from Imam Reza Burn Center (Mashhad, Iran) over 9 years. The outcomes of interest were mortality, length of hospital stay, and the Abbreviated Burn Severity Index (ABSI). Also, we measured the distance between the patient referral location to Mashhad. SPSS version 16 was used for data analysis. Overall, 52.7% of admitted patients were referred from hospitals in other cities. The referred group had more severe burn injury (P <.001), higher mortality rate (P <.001), and longer length of hospital stay (P <.001). The referred distance was associated with an increased risk of death (Odds ratio = 1.68, 95% CI, 1.47–1.92), but after controlling the severity of burns, only ABSI was the statistically significant predictor of mortality (Odds ration = 2.17, 95% CI, 2.05–2.28). Therefore, increasing the distance from urban areas to specialized burn center did not increase the mortality rate. After adjusting for ABSI, the mortality rate in referred patients was not related to referral distance. By observing referral points based on available guidelines, distance from a referral burn center does not affect mortality rate independently. Therefore, equipping the existing burn centers instead of building new ones and focusing on improving referral system can be a good strategy in low- and middle-income countries with limited resources. [ABSTRACT FROM AUTHOR]

Background and Aim: The relationship between socioeconomic status (SES), asthma and mortality is complex and multifaceted, and it is not established if educational level modifies the association between asthma and mortality. The aim was to study the association between asthma and mortality in Sweden and Norway and to what extent educational level modifies this association. Participants and Methods: Within the Nordic EpiLung Study, > 56,000 individuals aged 30– 69 years participated in population-based surveys on asthma and associated risk factors in Sweden and Norway during 2005– 2007. Data on educational level and 10-year all-cause mortality were linked by national authorities. The fraction of mortality risk attributable to asthma was calculated, and Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for mortality related to asthma, stratified by educational level. Results: In total, 5.5% of all deaths was attributed to asthma. When adjusted for potential confounders, the HR for mortality related to asthma was 1.71 (95% CI 1.52– 1.93). Those with primary level of education had higher hazard of all-cause death related to asthma than those with tertiary level (HR 1.80, 95% CI 1.48– 2.18, vs HR 1.39, 95% CI 0.99– 1.95). Conclusion: Asthma was associated with an overall 71% increased all-cause mortality and 5.5% of deaths can be attributed to asthma. Educational levels modified the risk of mortality associated with asthma, with the highest risk among those with primary education. [ABSTRACT FROM AUTHOR]

Background: Globally as well as in Sweden, diseases that are caused by unhealthy lifestyle habits are the most common causes of death and disability. Even though there are guidelines that oblige all health-care professionals to counsel patients about lifestyle, studies have shown that it is not prioritized within healthcare. One reason for this among nurses has been shown to be lack of confidence in knowledge and counselling skills. This study aimed to develop, and quality assess the psychometric properties of an instrument to measure self-efficacy in lifestyle counselling. Methods: An instrument inspired by an American instrument, following Bandura's recommendations for development of self-efficacy measures, was developed according to Swedish national guidelines for disease-prevention. The instrument was revised after cognitive interviews with nursing students, university teachers within health sciences, and clinical experts, then administrated to 310 nursing students at different levels in their education. The instrument was tested with Rasch Measurement Theory, with focus on dimensionality, local dependency, targeting, reliability, response category functioning, Rasch model fit, and differential item functioning by age, gender, educational level and previous health care education. Results: The development of the instrument resulted in 20 + 20 items, 20 items about self-efficacy in knowledge, and 20 items about self-efficacy in ability to counsel persons about their lifestyle. The analyses showed that knowledge and ability are two different, but related, constructs, where ability is more demanding than knowledge. The findings provide support (considering dimensionality and local dependency) for that all 20 items within the knowledge construct as well as the 20 items within the ability construct can be summed, achieving two separate but related total scores, where knowledge (reliability 0.81) is a prerequisite for ability (reliability 0.84). Items represented lower self-efficacy than reported by the respondents. Response categories functioned as expected, Rasch model fit was acceptable, and there was no differential item functioning. Conclusions: The SELC 20 + 20 was found to be easy to understand with an acceptable respondent burden and the instrument showed good measurement properties. [ABSTRACT FROM AUTHOR]

Cancer is a leading cause of death globally. The majority of cancer cases are only diagnosed in the late stages of cancer due to the use of conventional methods. This reduces the chance of survival for cancer patients. Therefore, early detection consequently followed by early diagnoses are important tasks in cancer research. Gene expression microarray technology has been applied to detect and diagnose most types of cancers in their early stages and has gained encouraging results. In this paper, we address the problem of classifying cancer based on gene expression for handling the class imbalance problem and the curse of dimensionality. The oversampling technique is utilized to overcome this problem by adding synthetic samples. Another common issue related to the gene expression dataset addressed in this paper is the curse of dimensionality. This problem is addressed by applying chi-square and information gain feature selection techniques. After applying these techniques individually, we proposed a method to select the most significant genes by combining those two techniques (CHiS and IG). We investigated the effect of these techniques individually and in combination. Four benchmarking biomedical datasets (Leukemia-subtypes, Leukemia-ALLAML, Colon, and CuMiDa) were used. The experimental results reveal that the oversampling techniques improve the results in most cases. Additionally, the performance of the proposed feature selection technique outperforms individual techniques in nearly all cases. In addition, this study provides an empirical study for evaluating several oversampling techniques along with ensemble-based learning. The experimental results also reveal that SVM-SMOTE, along with the random forests classifier, achieved the highest results, with a reporting accuracy of 100%. The obtained results surpass the findings in the existing literature as well. [ABSTRACT FROM AUTHOR]

Background: The quality of the statistics on causes of death (CoD) does not present consolidated indicators in literature further than the coding group of ill-defined conditions of the International Classification of Diseases. Our objective was to assess the territorial quality of CoD by reliability of the official mortality statistics in Spain over the years 1980–2019. Methods: A descriptive epidemiological design of four decades (1980-, 1990-, 2000-, and 2010–2019) by region (18) and sex was implemented. The CoD cases, age-adjusted rates and ratios (to all-cause) were assigned by reliability to unspecific and ill-defined quality categories. The regional mortality rates were contrasted to the Spanish median by decade and sex by the Comparative Mortality Ratio (CMR) in a Bayesian perspective. Statistical significance was considered when the CMR did not contain the value 1 in the 95% credible intervals. Results: Unspecific, ill-defined, and all-cause rates by region and sex decreased over 1980–2019, although they scored higher in men than in women. The ratio of ill-defined CoD decreased in both sexes over these decades, but was still prominent in 4 regions. CMR of ill-defined CoD in both sexes exceeded the Spanish median in 3 regions in all decades. In the last decade, women's CMR significantly exceeded in 5 regions for ill-defined and in 6 regions for unspecific CoD, while men's CMR exceeded in 4 and 2 of the 18 regions, respectively on quality categories. Conclusions: The quality of mortality statistics of causes of death has increased over the 40 years in Spain in both sexes. Quality gaps still remain mostly in Southern regions. Authorities involved might consider to take action and upgrading regional and national death statistics, and developing a systematic medical post-grade training on death certification. [ABSTRACT FROM AUTHOR]

This article highlights the need to consider multiple causes of death during the COVID-19 pandemic. While the focus has been on COVID-19, other causes of death, such as cardiovascular diseases, have received less attention. The pandemic has had both direct and indirect effects on non-COVID-19 mortality, including long-term complications, strain on hospital resources, and reduced disease screening. The World Health Organization has provided guidelines for coding COVID-19 deaths on death certificates, prioritizing it as the underlying cause of death. However, this approach may alter mortality trends for other causes and lead to a misleading perception of their severity. Ongoing research is being conducted to evaluate the impact of the pandemic on other causes of death, and the use of multiple causes of death analysis is recommended for a more comprehensive understanding. [Extracted from the article]

Simple Summary: Mammary tumors are the most prevalent type of tumor in the canine population. C6 ceramide has been identified as an essential factor in various functions in cancer; however, the role of C6 ceramide in canine mammary cancer remains unknown. Therefore, we investigated the role of C6 ceramide in the progress of canine mammary cancer and explored its potential mechanism. The findings show that C6 ceramide inhibited cell growth, migration, and invasion in vitro. C6 ceramide decreased tumor growth and metastasis in the lungs without side effects in xenograft models. Further exploring found that EGR3 is a target agent of C6 ceramide, promoting canine mammary cancer cell proliferation and migration by activating the pJAK1/pSTAT3 signaling pathway. This study revealed the anti-tumor activity of C6 ceramide in canine mammary cancer both in vivo and in vitro and revealed that EGR3 is a potential biomarker in canine mammary cancer prognosis and treatment. Cancer is the leading cause of death in both humans and companion animals. Canine mammary tumor is an important disease with a high incidence and metastasis rate, and its poor prognosis remains a serious clinical challenge. C6 ceramide is a short-chain sphingolipid metabolite with powerful potential as a tumor suppressor. However, the specific impact of C6 ceramide on canine mammary cancer remains unclear. However, the effects of C6 ceramide in canine mammary cancer are still unclear. Therefore, we investigated the role of C6 ceramide in the progress of canine mammary cancer and explored its potential mechanism. C6 ceramide inhibited cell growth by regulating the cell cycle without involving apoptosis. Additionally, C6 ceramide inhibited the migration and invasion of CHMp cells. In vivo, C6 ceramide decreased tumor growth and metastasis in the lungs without side effects. Further investigation found that the knockdown of EGR3 expression led to a noticeable increase in proliferation and migration by upregulating the expressions of pJAK1 and pSTAT3, thus activating the JAK1/STAT3 signaling pathway. In conclusion, C6 ceramide inhibits canine mammary cancer growth and metastasis by targeting EGR3 through the regulation of the JAK1/STAT3 signaling pathway. This study implicates the mechanisms underlying the anti-tumor activity of C6 ceramide and demonstrates the potential of EGR3 as a novel target for treating canine mammary cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Canine mammary cancer (CMC) is the most prevalent neoplasm in intact female dogs, with approximately 50% of these cases diagnosed as malignant. Various chemotherapeutic agents have been applied in CMC treatment, but these agents come with notable disadvantages and limited information on efficacy. The benzo[6,7]oxepino[3,2-b] pyridine (BZOP) derivative, 2-((2-methylpyridin-3-yl)oxy)benzaldehyde (MPOBA), exhibited potent anticancer activity against a human colorectal cancer cell line. However, the anticancer effects and molecular mechanisms of MPOBA on CMC have not been elucidated. This study investigated the effects of MPOBA on proliferation, migration, and apoptosis and investigated its potential mechanism in two CMC cell lines, REM134 canine mammary carcinoma and CMGT071020 canine mammary tubulopapillary carcinoma. Furthermore, an in vitro cytotoxicity test was also evaluated in the Madin–Darby canine kidney (MDCK) cell line. The results revealed that MPOBA significantly inhibited proliferation and migration and induced apoptosis in CMC cell lines. In addition, MPOBA showed lower cytotoxicity in MDCK cells. According to the gene expression analysis, the mRNA expression levels of TP53 tumor suppressor (TP53), Bcl-2 associated X (BAX), and B-cell lymphoma-2 (BCL-2) in both CMC cells were significantly altered in the treatment groups compared to the control. These results suggested that MPOBA may have induced apoptosis in both CMC cell lines. This effect may be mediated through the downregulation of BCL-2 and upregulation of BAX gene expressions. These findings indicated that MPOBA may serve as an emerging candidate agent for CMC treatment. However, mRNA expression levels may not be directly proportional to protein expression levels. Therefore, additional studies, including apoptosis-related protein analysis and apoptosis marker assays, are required to confirm the major apoptosis signaling pathway regulated by MPOBA. CMC is the most frequently diagnosed cancer and one of the leading causes of death in non-spayed female dogs. Exploring novel therapeutic agents is necessary to increase the survival rate of dogs with CMC. MPOBA is a BZOP derivative that has a significant anticancer effect in a human cell line. The main goal of this study was to investigate the anticancer properties of MPOBA against two CMC cell lines (REM134 and CMGT071020) using a 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, a wound healing assay, a transwell migration assay, an Annexin V-FITC apoptosis assay with a flow cytometry analysis, a mRNA expression analysis using quantitative real-time PCR (qRT-PCR), and an immunohistochemistry (IHC). According to the accumulated studies, MPOBA caused significant concentration- and time-dependent reductions in cell proliferation and cell migration and induced apoptosis in both CMC cell lines. In gene expression analysis, nine canine genes, including TP53, BCL-2, BAX, epidermal growth factor receptor (EGFR), snail transcription factor (SNAIL), snail-related zinc-finger transcription factor (SLUG), TWIST, E-cadherin, and N-cadherin, were investigated. The mRNA expression results revealed that MPOBA induced upregulation of TP53 and overexpression of the pro-apoptotic gene BAX, together with an inhibition of BCL-2. Moreover, MPOBA also suppressed the mRNA expression levels of SNAIL, EGFR, and N-cadherin and induced upregulation of E-cadherin, crucial genes related to the epithelial-to-mesenchymal transition (EMT). However, there was no significant difference in the IHC results of the expression patterns of vimentin (VT) and cytokeratin (CK) between MPOBA-treated and control CMC cells. In conclusion, the results of the present study suggested that MPOBA exhibited significant anticancer activity by inducing apoptosis in both CMCs via upregulation of TP53 and BAX and downregulation of BCL-2 relative mRNA expression. MPOBA may prove to be a potential candidate drug to be further investigated as a therapeutic agent for CMC. [ABSTRACT FROM AUTHOR]

Background and Objectives: Colorectal cancer (CRC) is a common type of cancer that has a high death rate and is becoming more common in developed countries. Currently, there are several treatment options available for CRC patients, and clinical trials are being conducted to improve conventional therapies. This study investigates the combined impact of Bacillus coagulans (B.C) and Newcastle disease virus (NDV) on the growth of human colorectal adenocarcinoma cells (HT29 cell line). Materials and Methods: The HT29 cell line was cultured under controlled laboratory conditions. They were treated with Fluorouracil (5-FU), NDV, and B.C., after which various assessments were conducted to determine the effects of these treatments. These assessments included MTT assay for cytotoxicity, evaluation of cell viability, and measurement of caspase 8 and 9 activity levels. The significance of the data was determined at a threshold of P<0.05 following analysis. Results: The usage of NDV and B.C significantly increased cell death and reduced cell growth in the HT29 cell line, when compared to the control group. Moreover, the combined application of NDV and B.C along with 5-FU exhibited a synergistic effect in decreasing the proliferation of HT29 cells. Additionally, the results indicated that intrinsic apoptosis pathway was activated by B.C and NDV. Conclusion: It appears that utilizing oncolytic viruses (OV) and bacteria in conjunction with chemotherapy drugs could potentially aid in reducing the growth of colorectal cancer cells. However, further research is necessary, including animal studies, to confirm the efficacy of this treatment method. [ABSTRACT FROM AUTHOR]

Background: Differences in treatment outcomes between community or academic centers are incompletely understood. Methods: Retrospective review of head and neck cancer patients between 2010 and 2020 in a rural health region. Kaplan–Meier curves and log‐rank tests were used to evaluate survival outcomes, along with bivariate and multivariable Cox proportional hazards models. Linear regression was used for functional outcomes of tracheotomy and gastrostomy tube dependence. Results: Two hundred and forty‐eight patients treated at an academic center were compared with 94 patients treated in community centers. In multivariable analysis, the risk of death (HR = 0.60, p = 0.019), and risk of recurrence were lower (HR = 0.29, p < 0.001) for patients treated in academic centers. Patients treated in community centers had longer gastrostomy tube dependence (p = 0.002). Conclusion: Our findings suggest that treatment at an academic center was associated with a lower risk of recurrence and shorter gastrostomy tube dependence compared to treatment in the community. [ABSTRACT FROM AUTHOR]

Cancer is known as one of the most significant causes of death worldwide, and, in spite of novel therapeutic methods, continues to cause a considerable number of deaths. Targeted molecular diagnosis and therapy using aptamers with high affinity have become popular techniques for pathological angiogenesis and cancer therapy scientists. In this paper, several aptamer-based diagnostic and therapeutic techniques such as aptamer–nanomaterial conjugation, aptamer–drug conjugation (physically or covalently), and biosensors, which have been successfully designed for biomarkers, were critically reviewed. The results demonstrated that aptamers can potentially be incorporated with targeted delivery systems and biosensors for the detection of biomarkers expressed by cancer cells. Aptamer-based therapeutic and diagnostic methods, representing the main field of medical sciences, possess high potential for use in cancer therapy, pathological angiogenesis, and improvement of community health. The clinical use of aptamers is limited due to target impurities, inaccuracy in the systematic evolution of ligands via exponential enrichment (SELEX)stage process, and in vitro synthesis, making them unreliable and leading to lower selectivity for in vivo targets. Moreover, size, behavior, probable toxicity, low distribution, and the unpredictable behavior of nanomaterials in in vivo media make their usage in clinical assays critical. This review is helpful for the implementation of aptamer-based therapies which are effective and applicable for clinical use and the design of future studies. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is the leading cause of death by cancer in women worldwide. Triple-negative (TN) BC constitutes aggressive and highly metastatic tumors associated with shorter overall survival of patients compared to other BC subtypes. The Tn antigen, a glycoconjugated structure resulting from an incomplete O-glycosylation process, is highly expressed in different adenocarcinomas, including BC. It also favors cancer growth, immunoregulation, and metastasis in TNBC. This work describes the differentially expressed genes (DEGs) associated with BC aggressiveness and metastasis in an incomplete O-glycosylated TNBC cell model. We studied the transcriptome of a TNBC model constituted by the metastatic murine 4T1 cell line that overexpresses the Tn antigen due to a mutation in one of the steps of the O-glycosylation pathway. We analyzed and compared the results with the parental wild-type cell line and with a Tn-negative cell clone that was poorly metastatic and less aggressive than the 4T1 parental cell line. To gain insight into the generated expression data, we performed a gene set analysis. Biological processes associated with cancer development and metastasis, immune evasion, and leukocyte recruitment were highly enriched among functional terms of DEGs. Furthermore, different highly O-glycosylated protein-coding genes, such as mmp9, ecm1 and ankyrin-2, were upregulated in 4T1/Tn+ tumor cells. The altered biological processes and DEGs that promote tumor growth, invasion and immunomodulation might explain the aggressive properties of 4T1/Tn+ tumor cells. These results support the hypothesis that incomplete O-glycosylation that leads to the expression of the Tn antigen, which might regulate activity or interaction of different molecules, promotes cancer development and immunoregulation. [ABSTRACT FROM AUTHOR]

Objectives: Rituximab is frequently used off-label for the treatment of frequentrelapsing/steroid-dependent nephrotic syndrome (FRNS/SDNS). However, the optimal dosing schedules remain undetermined. The objective of this study was to establish a population pharmacokinetic-pharmacodynamic (PK-PD) model in pediatric patients with FRNS/SDNS, and to investigate dosing regimens that provide adequate suppression of B lymphocytes. Methods: A prospective, open-label, single-center study was conducted in Nephrology Department at Children's Hospital of Fudan University, and a twocompartment PK model of rituximab in pediatric FRNS/SDNS has been developed previously by our group. CD19+ lymphocyte count profiles were obtained from these patients. The presence of anti-rituximab antibodies was assessed prior to medication in children who had previously received rituximab or during followup at the last sampling point for PK analysis. PK-PD analyses were performed to describe the changes of CD19+ lymphocytes, with rituximab assumed to increase their death rate. Monte Carlo simulation was conducted to evaluate different dosing regimens. Results: In total, 102 measurements of CD19+ lymphocyte counts were available for PK-PD analysis. No detectable levels of anti-rituximab antibodies were observed during the PK follow-up period. A turnover model with saturable stimulatory action of rituximab on the removal of lymphocytes best characterized the relationship between rituximab concentration and CD19+ lymphocyte counts, where the Emax and EC50 were estimated to be 99.6*106/L and 5.87 μg/mL, respectively. Simulations indicated that a single infusion of 750 mg/m² and 2 infusions of 375 mg/m² both yielded a 10-week suppression of CD19+ lymphocytes. Conclusion: This study represents a first attempt to quantitatively describe the PKPD relationship of rituximab in pediatric patients with FRNS/SDNS, and provide a potential pathway for future precision dosing strategy for rituximab therapy. Further clinical studies are warranted to evaluate the efficacy and safety of different dosing schemes. [ABSTRACT FROM AUTHOR]

Objective: Cancer is the third leading cause of death in the world with increasing trends in Iran. The study of epidemiology, trend, and geospatial distribution of pediatric cancers provides important information for screening as well as early detection of cancer and policy making. We aimed to assess the spatio-temporal disparity of childhood and adolescence cancer risk among provinces of Iran. Methods: In this retrospective study, we estimated geospatial relative risk (RR) of childhood cancer in provinces of Iran using data from 29198 cases. We used BYM and its extended spatiotemporal model in Bayesian setting. This hierarchical model takes spatial and temporal effects into account in the incidence rate estimation simultaneously. Results: The relative risk of cancer was > 1 for 45% of the provinces, where 27% of provinces had significantly ascending trend. North Khorasan, Yazd and Qazvin provinces had the highest risk rates while Sistan-Baluchistan province showed the lowest risk of cancer. However, the differential trends was highest in Sistan-Baluchistan, Bushehr, Hormozgan, and Kohgilouyeh-Boyerahmad. Both the point estimate and the trend of risk was high in Tehran. Conclusion: The geographic pattern and trend of cancer in children seems to be different from that in adults that urges further studies. This could lead to increased health system capacity and facilitate the access to effective detection, research, care and treatment of childhood cancer. [ABSTRACT FROM AUTHOR]

Cancer is still the leading cause of death in the world despite the developing research and treatment opportunities. Failure of these treatments is generally associated with cancer stem cells (CSCs), which cause metastasis and are defined by their resistance to radio- and chemotherapy. Although known stem cell isolation methods are not sufficient for CSC isolation, they also bring a burden in terms of cost. The aim of this study is to develop a high-efficiency, low-cost, specific method for cancer stem cell isolation with magnetic functional nanoparticles. This study, unlike the stem cell isolation techniques (MACS, FACS) used today, was aimed to isolate cancer stem cells (separation of CD133+ cells) with nanoparticles with specific affinity and modification properties. For this purpose, affinity-based magnetic nanoparticles were synthesized and characterized by providing surface activity and chemical reactivity, as well as making surface modifications necessary for both lectin affinity and metal affinity interactions. In the other part of the study, synthesized and characterized functional polymeric magnetic nanoparticles were used for the isolation of CSC from the human osteosarcoma cancer cell line (SAOS-2) with a cancer stem cell subpopulation bearing the CD133 surface marker. The success and efficiency of separation after stem cell isolation were evaluated via the MACS and FACS methods. As a result, when the His-graft-mg-p(HEMA) nanoparticle was used at a concentration of 0.1 µg/mL for 106 and 108 cells, superior separation efficiency to commercial microbeads was obtained. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the third most common cancer diagnosed today and the third leading cause of death among cancer types. CRC is one of the gastrointestinal tumors with obesity as the main extrinsic risk factor, since, according to authors, the meta-inflammation sustained by the excess adipose tissue can provide abundant circulating lipids, as well as hormones and metabolites crucial to tumor development and aggressiveness. The gut microbiota can protect the colon from meta-inflammation and endocrine changes caused by obesity. The present study aimed to investigate the antitumor activity of a commercial probiotic in intestinal tumor cells under two adiposity conditions. Experimental assays were performed on the Caco2 cell line (colon adenocarcinoma) supplemented with differentiated adipocyte's secretomes of the 3T3-L1 cell line (mouse pre-adipocytes) in two adiposity conditions: (i) differentiation without the use of Pioglitazone (noPGZ) and (ii) differentiation using Pioglitazone (PGZ). The Caco2 cells were first exposed to both secretomes for 24 h and evaluated and subsequently exposed to probiotic extract followed by secretome and evaluated. The effects of these treatments were evaluated using cytotoxicity assays by MTT, cell migration by injury, and antioxidant activity by glutathione assay. The use of secretomes showed a statistically significant increase in cell viability in Caco2 cells, either in noPGZ (p < 0.01) or PGZ (p < 0.05), and the probiotic was not able to reduce this effect. In the injury assay, secretome increased cell migration by more than 199% in both adiposity conditions (p < 0.001 in noPGZ and p < 0.01 in PGZ). In the probiotic treatment, there was a reduction in cell migration compared to the control in adiposity conditions. The antioxidant response of Caco2 cells was increased in both adiposity conditions previously exposed to the probiotic supernatant. This pilot work brings to light some findings that may answer why the modulation of the intestinal microbiota using probiotics is an alternative strategy leading to improvements in the condition and stage of the colon tumor. Additional studies are needed to clarify the role of Pioglitazone in this type of tumor and the metabolites of obesity that are attenuated by the use of probiotics. [ABSTRACT FROM AUTHOR]

Cancer is the second leading cause of death worldwide, despite recent advances in its identification and management. To improve cancer patient diagnosis and care, it is necessary to identify new biomarkers and molecular targets. In recent years, long non-coding RNAs (lncRNAs) have surfaced as important contributors to various cellular activities, with growing proof indicating their substantial role in the genesis, development, and spread of cancer. Their unique expression profiles within specific tissues and their wide-ranging functionalities make lncRNAs excellent candidates for potential therapeutic intervention in cancer management. They are implicated in multiple hallmarks of cancer, such as uncontrolled proliferation, angiogenesis, and immune evasion. This review article explores the innovative application of CRISPR-Cas9 technology in targeting lncRNAs as a cancer therapeutic strategy. The CRISPR-Cas9 system has been widely applied in functional genomics, gene therapy, and cancer research, offering a versatile platform for lncRNA targeting. CRISPR-Cas9-mediated targeting of lncRNAs can be achieved through CRISPR interference, activation or the complete knockout of lncRNA loci. Combining CRISPR-Cas9 technology with high-throughput functional genomics makes it possible to identify lncRNAs critical for the survival of specific cancer subtypes, opening the door for tailored treatments and personalised cancer therapies. CRISPR-Cas9-mediated lncRNA targeting with other cutting-edge cancer therapies, such as immunotherapy and targeted molecular therapeutics can be used to overcome the drug resistance in cancer. The synergy of lncRNA research and CRISPR-Cas9 technology presents immense potential for individualized cancer treatment, offering renewed hope in the battle against this disease. • LncRNAs contribute to cellular activities and play a role in genesis, development, and spread of cancer. • Their unique expression profiles within specific tissues make them excellent candidates for cancer therapy. • CRISPR-Cas9 system is versatile and can target lncRNAs. • CRISPR-Cas9 technology with high-throughput functional genomics can identify lncRNAs critical for specific cancer subtypes. [ABSTRACT FROM AUTHOR]

BACKGROUND: Conventional decomposition analysis identifies contributions from differences in covariates in total between-population difference, but does not address the question of the historical roots of the differences. To close this gap, the contour decomposition method was proposed. Since 2017, when it was published, this method has been successfully applied in several papers. Nevertheless, it has an important limitation: causes of death cannot be included in the analyses. OBJECTIVE: Conventional decomposition analysis provides insight into the reasons for a difference in an aggregate index. It can be either the difference between two populations at a given time or a temporal change for one population. However, it does not consider the origin of this difference. Contour decomposition is the only method that does. We extend the contour decomposition method by adding one more dimension that can be used to estimate the contribution of an additional component; e.g., causes of death or educational structure. METHODS: We use a step-wise replacement algorithm. CONTRIBUTION: The proposed discrete method for decomposition is an extension of the earlier general algorithm of stepwise replacement and contour decomposition and permits a difference in an aggregate measure at a final time point to be split into cause-specific additive components that correspond to the initial differences in the event-rates of the measure and differences in trends in these underlying event-rates. [ABSTRACT FROM AUTHOR]

The world faced a crisis called the coronavirus pandemic, a disease that has been able to disrupt a large proportion of the power and activities of the whole world and has evolved all economic and social decisions. These decisions are primarily related to restrictions such as widespread lockdowns and social distancing. Different countries have taken various approaches and decisions to deal with this situation, each of which has positive and negative sides. Apart from this issue, the rapid spread of this pandemic has affected researchers' knowledge and viewpoints about this disease. Without any doubt, to expand our scientific knowledge and reduce the side effects of this challenge, it is essential to evaluate the behavior of COVID-19. Moreover, developing an effective vaccine in the short term was challenging. Regarding this issue, systematic thinking not only helps to find various ways to prevent this illness from spreading throughout the world but also reduces the mortality rate of this viral disease. From a systematic thinking perspective, governments and individuals play pivotal roles. They take care of vulnerable groups, support health employees, provide general education, identify new patients, and control specific situations in their countries. In such a situation where experts have not discovered any vaccine, governments and the people of society can be considered essential parameters to intensify or reduce the outbreak of this viral disease throughout the country. This paper's main objective and motivation are to utilize causal loop diagrams (CLDs) to evaluate and determine various affecting factors created by governments and members of societies that have direct impacts on deteriorating or decreasing the outbreak of COVID-19 in Iran from a system dynamics perspective. Hence, the statistics on the incidence and deaths caused by the coronavirus in Iran were extracted during some periods. Using the cause and effect diagrams, the behavior of the people and the government in increasing or decreasing the number of patients is discussed. [ABSTRACT FROM AUTHOR]

The number of people affected by cancer and antibiotic-resistant bacterial infections has increased, such that both diseases are already seen as current and future leading causes of death globally. To address this issue, based on a combined in silico and in vitro approach, we explored the anticancer potential of known antibacterials with a thiazolidinedione–thiosemicarbazone (TZD–TSC) core structure. A cytotoxicity assessment showed encouraging results for compounds 2–4, with IC50 values against T98G and HepG2 cells in the low micromolar range. TZD–TSC 3 proved to be most toxic to cancer cell lines, with IC50 values of 2.97 ± 0.39 µM against human hepatoma HepG2 cells and IC50 values of 28.34 ± 2.21 µM against human glioblastoma T98G cells. Additionally, compound 3 induced apoptosis and showed no specific hemolytic activity. Furthermore, treatment using 3 on cancer cell lines alters these cells' morphology and further suppresses migratory activity. Molecular docking, in turn, suggests that 3 would have the capacity to simultaneously target HDACs and PPARγ, by the activation of PPARγ and the inhibition of both HDAC4 and HDAC8. Thus, the promising preliminary results obtained with TZD–TSC 3 represent an encouraging starting point for the rational design of novel chemotherapeutics with dual antibacterial and anticancer activities. [ABSTRACT FROM AUTHOR]

As cancer is the second-leading cause of death globally, this study strives to find efficient medications for colon cancer that cause minimal side effects. The computational approach through QSAR methods, molecular docking, simulation of Molecular Dynamics, and ADME-Tox studies has shown great importance in this area. In this context, several curcumin analogues have been investigated against the human colon cancer HCT-116. The best-established QSAR models in this study have the following statistical parameters: Rtrain2 = 0.971, Qcv2 = 0.544, and Rpred2 = 0.653 for the CoMFA model, and Rtrain2 = 0.940, Qcv2 = 0.619, and Rpred2 = 0.871 for the CoMSIA model. These results show the predictive quality of these models and confirm their robustness, which allowed the proposal of five new molecules: P1–P5. Molecular docking showed that most new compounds bind well to the PARP-1 receptor and have important interactions. According to work predictions, compounds P1, P2, P4, and P5 significantly inhibit cancerous colon cell growth through apoptosis. Molecular dynamics simulations confirmed previous findings, indicating that the P1 and P2 ligands remain stable at the PARP-1 receptor site. As a result, a synthesis method for the promoter compound P2 was suggested using retrosynthesis techniques. ADME-Tox studies confirm the proposed molecules' potential for colon cancer treatments. The current study offers new perspectives for investigating safer, new curcumin-analogue-based drugs. [ABSTRACT FROM AUTHOR]

Death certificates provide incomplete information on the specific drug categories involved in fatal overdoses. The accuracy of previously developed corrections for this and modifications to them was examined. Uncorrected mortality rates were compared with rates from the preferred correction models. Data were obtained for the universe of 932,364 drug overdoses in the U.S. between 1999 and 2020, including 769,982 (82.6%) with a drug classification and 162,382 (17.4%) without, from the National Center for Health Statistics Multiple Cause of Death files. Opioid and cocaine involvement for unclassified overdoses were estimated using multiple approaches. Prediction accuracy was assessed as the mean absolute deviation between actual and estimated involvement for a test sample with known drug involvement. Corrected death rates from preferred models were compared with uncorrected rates. Analyses were conducted in 2022–2023. Previous regression-based corrections that controlled for decedent characteristics can be improved upon by adding state-fixed effects as covariates. Once this is done, supplementary controls for county characteristics or contributory causes of death do not materially improve prediction accuracy. Properly designed naïve models, which distribute unspecified drug deaths proportionately to specified deaths, often provide similar results and, for county-level analyses, supply the most accurate predictions. Uncorrected results substantially understate the levels of opioid and cocaine involvement and can either understate or overstate changes over time. Failing to correct for incomplete information on death certificates leads to inaccurate counts of deaths from specific categories of drugs, such as opioids. However, relatively simple corrections are available that substantially improve accuracy. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with long-lasting metabolic syndrome (MS) are at high risk for cancer and complications of cardiovascular diseases, which remain the leading cause of death globally. Despite the development of many novel therapies for MS, a huge unmet need persists. Currently, there is considerable evidence that exosomes are strongly associated with the occurrence and progression of MS. Thus, this article reviews the composition, biogenesis, biological functions and potential applications of exosomes, particularly focusing on current advances about the potential role of exosomes in the development of MS. Comprehensively understanding the effects of exosome on MS could have the significant potential to identify safe and effective diagnostic and therapeutic approaches to MS. Exosomes are a subtype of extracellular vesicles (EVs) with a diameter of 30~150 nm (averaging ~100 nm) that are primarily produced through the endosomal pathway, and carry various components such as lipids, proteins, RNA, and other small molecular substances. Exosomes can mediate intercellular communication through the bioactive substances they carry, thus participating in different physiological activities. Metabolic syndrome (MS) is a disease caused by disturbances in the body's metabolism, mainly including insulin resistance (IR), diabetes, obesity, non-alcoholic fatty liver disease (NAFLD), hyperlipidemia, and atherosclerosis (AS). Recent studies have shown that exosomes are closely related to the occurrence and development of MS. Exosomes can act as messengers to mediate signaling transductions between metabolic cells in the organism and play a bidirectional regulatory role in the MS process. This paper mainly reviews the components, biogenesis, biological functions and potential applications of exosomes, and exosomes involved in the pathogenesis of MS as well as their clinical significance in MS diagnosis. [ABSTRACT FROM AUTHOR]

Our objective was to explore evolving trends in US drug overdose mortality, overall and by age, sex, race, urbanization, and geography from 1999-2020. This is a descriptive epidemiologic study. We used the US Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research and Multiple Cause of Death files from the National Center for Health Statistics. We used crude and age-adjusted cause of death and mortality rate ratios as measures of effects and 95% confidence limits to test for significance. From 1999-2020, drug overdoses caused 1,013,852 deaths and 4.3-fold increase in mortality rate ratios. Subgroup findings were sex (4.5 men, 4.0 women), race (4.6 White, 3.9 Black or African American, 4.0 Asian or Pacific Islanders, 5.1 Native Americans or Alaskan Natives), age (highest 5.6 in 25-34 years, lowest 1.1 in 75-84, and 0.77 in 85+), geography (highest 6.0 in Midwest, lowest 2.6 in West), and urbanization (highest 6.2 in non-metro, lowest 3.7 in metro). Drug overdoses in the United States from 1999-2020 increased 4.3-fold, with the highest increase in White and Native American or Alaskan Native populations, and Midwest and non-metro areas. The data create preventive and therapeutic challenges, including restrictions on pharmaceutical industries and enhanced efforts by health care providers in safer prescribing. Addiction care should be integrated into all clinical practices, regardless of specialty, and into undergraduate, graduate, and continuing medical education. Targeted interventions are needed to adequately assess patients and provide care. Analytic studies designed a priori are necessary to test hypotheses formulated from these data. [ABSTRACT FROM AUTHOR]

Cancer, one of the leading causes of death, usually commences and progresses as a result of a series of gene mutations and dysregulation of expression. With the development of clustered regularly interspaced palindromic repeat (CRISPR)/Cas9 gene‐editing technology, it is possible to edit and then decode the functions of cancer‐related gene mutations, markedly advance the research of biological mechanisms and treatment of cancer. This review summarizes the mechanism and development of CRISPR/Cas9 gene‐editing technology in recent years and describes its potential application in cancer‐related research, such as the establishment of human tumor disease models, gene therapy and immunotherapy. The challenges and future development directions are highlighted to provide a reference for exploring pathological mechanisms and potential treatment protocols of cancer. [ABSTRACT FROM AUTHOR]