Cause Of Death Research Articles

PELP1 is a novel therapeutic target in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths in the United States, with a median survival period of approximately 10 months. There is an urgent need for the development of effective targeted therapies for the treatment of HCC. Proline-, glutamic acid- and leucine-rich protein 1 (PELP1) signaling is implicated in the progression of many cancers, although its specific contribution to the progression of HCC is not yet well understood. Analysis of TCGA HCC gene expression data sets and immunohistochemistry analysis of HCC tissue microarray revealed that HCC tumors had elevated expression of PELP1 compared to normal tissues, and high expression of PELP1 is associated with unfavorable survival outcomes. Suppression of PELP1 expression using shRNA significantly reduced the cell viability, clonogenicity, and invasion of HCC cells. Importantly, SMIP34, a first-in-class small molecule inhibitor targeting PELP1, effectively decreased the cell viability, clonogenic survival and invasiveness of HCC cells. Gene expression analysis using RNA-seq revealed that PELP1-knockdown (KD) cells exhibited a decrease in c-Myc, E2F, and other oncogenic pathways related to HCC. Mechanistic studies showed that SMIP34 treatment impaired the Rix complex, a critical component of ribosomal biogenesis, in HCC cells. Further, the knockdown or pharmacological inhibition of PELP1 significantly decelerated the HCC tumor growth in xenograft models. In summary, our study findings indicate that PELP1 could serve as a promising target for therapeutic intervention in HCC.

A Bruton tyrosine kinase inhibitor-resistance gene signature predicts prognosis and identifies TRIP13 as a potential therapeutic target in diffuse large B-cell lymphoma

Bruton tyrosine kinase inhibitor (BTKi) combined with rituximab-based chemotherapy benefits diffuse large B-cell lymphoma (DLBCL) patients. However, drug resistance is the major cause of relapse and death of DLBCL. In this study, we conducted a comprehensive analysis BTKi-resistance related genes (BRRGs) and established a 10-gene (CARD16, TRIP13, PSRC1, CASP1, PLBD1, CARD6, CAPG, CACNA1A, CDH15, and NDUFA4) signature for early identifying high-risk DLBCL patients. The resistance scores based on the BRRGs signature were associated with prognosis. Furthermore, we developed a nomogram incorporating the BRRGs signature, which demonstrated excellent performance in predicting the prognosis of DLBCL patients. Notably, tumor immune microenvironment, biological pathways, and chemotherapy sensitivity were different between high- and low-resistance score groups. Additionally, we identified TRIP13 as a key gene in our model. TRIP13 was found to be overexpressed in DLBCL and BTKi-resistant DLBCL cell lines, knocking down TRIP13 suppresses cell proliferation, promotes cell apoptosis, and enhances the apoptosis effect of BTKi on DLBCL cells by regulating the Wnt/β-catenin pathway. In conclusion, our study presents a novel BRRGs signature that could serve as a promising prognostic marker in DLBCL, and TRIP13 might be a potential therapeutic target for resistant DLBCL.

Exploring Text Classification Systems for Automatically Coding Historical Occupations and Causes of Death

ObjectivesText classification models can be used to automatically categorize occupations and causes of death within historical documents. It is important to classify/code these categories as different words or textual descriptions could refer to the same occupation or cause of death. Given the many historical documents that are becoming available for research, accurate classification systems can be valuable resources. ApproachWe explore different text classification techniques, from traditional machine learning to deep learning, and investigate methodologies that transform occupations and causes of death into a vectorial space and use these representations as features to train text classification systems. Our data come from IPUMS USA/International, and SCADR. ResultsHistorians have coded occupations and causes of death for some census collections (e.g., US, Canada), but not yet for others (e.g., Scotland). We train and evaluate our classification systems using data from the US and Canada and then deploy it on data from Scotland. We quantitatively measure the performance of the classification systems for historical documents that have codes available. Additionally, once we deploy the model to data that does not yet have codes, we qualitatively evaluate our results by engaging with historians working on those data. We report and discuss these results to understand where the models are performing well and where the models are underperforming. ConclusionsResults suggest that there is value in building and deploying these classification models. We recommend the use of such models in conjunction with engaging with domain experts.

Increased mortality among mothers involved in family court care proceedings compared with their peers in England

ObjectiveResearch has called for Family Courts (FC) and social care services involved in removing children from parental care to consider and address the health of the mother. ApproachWe linked England FC and healthcare data to compare the 10-year mortality risk and cause of death after a first live birth (FLB) for mothers who were involved or not in FC proceedings in England. Results3,072,946 mothers (15-39 years) with a FLB between 2007 and 2019 were followed for up to 10 years (median:8.7 years, IQR: 5.4-10), during which 33,759 were involved in FC. Ten-year cumulative mortality was higher among the FC mothers (1.7 vs 0.3%) and the age-adjusted mortality rate ratio was 7.8 (95%CI: 7.00-8.6). The majority of maternal deaths in both groups met criteria for avoidable death (FC 82.9% vs no-FC 66.8%). Injury was the leading cause of death (204/420; 48.5%) in mothers involved in FCs and cancer (2,823/6,208; 45.5%) in mothers in the no-FC group. Compared with no-FC mothers, more deaths were related to drug use (35.0% vs 6.0%), suicide (14.5% vs 8.4%) or alcohol (9.8% vs 3.5%). Among mothers involved in FCs, maternal mortality was higher in cases when children were placed into out-of-home care (1.65%, 463/28143), than when placed at home (0.94%, 53/5563) at first FC proceeding. Conclusions and ImplicationsAddressing high rates of avoidable mortality among mothers involved in FCs is important for children and parents and could be monitored using routinely linked healthcare, social care and family court data.

Rates and causes of death after release from incarceration: an individual participant data meta-analysis from 1,471,526 people in eight high- and middle-income countries

BackgroundFormerly incarcerated people have exceptionally poor health profiles and are at increased risk of preventable mortality when compared to their general population peers. However, not enough is known about the epidemiology of mortality in this population – specifically the rates, causes, and timing in specific subgroups and regions – to inform the development of targeted, evidence-based responses. MethodsWe examined mortality outcomes for 1,471,526 people released from incarceration in eight countries from 1980-2018, across 10,534,441 person-years of follow-up (range: 0-24 years per person). We combined data from 18 cohort studies using two-step individual participant data meta-analyses to estimate pooled all-cause and cause-specific crude mortality rates (CMRs) per 100,000 person-years, with 95% confidence intervals (95%CI), for specific time periods after release, overall and stratified by age, sex, and region. Findings75,427 deaths were recorded. The all-cause CMR was highest during the first week. The highest cause-specific rates of death during the first week were due to alcohol and other drug poisoning, suicide, and cardiovascular disease. We observed considerable variation in cause-specific CMRs over time since release and across regions. Pooled all-cause CMRs were similar between males and females, and were higher in older age groups. InterpretationThe markedly elevated rate of death in the first week post-release underscores an urgent need for investment in evidence-based, coordinated transitional healthcare, including treatment for mental illness and substance use disorders. Variations in both rates and causes of death over time highlight the need for routine monitoring of post-release mortality.

Progress and developments towards making historic administrative data research ready

ObjectivesTo make research ready data from transcribed historic civil registration records: birth, marriage and death (from mid-19th century onwards). To use historic records effectively for large-scale research they must not only be made machine-readable, but also coded in a suitable format – along with classification of transcribed information. Included on the digitised historic records are textual descriptions of occupations and causes of death. Thus, to code transcribed occupations to HISCO and causes of death to ICD. ApproachIt is impractical to hand-code the records manually (34 million occupations and 8 million causes of death), especially for deaths where more than one cause can be given. As such, coding is viewed as a text classification task and the process is automated. To facilitate auto-coding, a proportion of records were hand-coded as training data (90,000 occupations and 102,000 deaths). Ahead of the auto-coding, initial pre-processing, cleaning and standardising is done on both the occupations and deaths. ResultsPreliminary experiments undertaken obtained reasonable results from a combination of exact matching and statistical classification. Experiments using a larger pilot uncovered that since some occupations are very common, the training data set covers a very large proportion of the records (ie exact match). This proportion is not as high for deaths given the different ways causes are written. ConclusionThis is work in progress to create the research ready data, and the poster will include the results from experiments using the full training data (90,000 occupations and 102,000 deaths).

Association of hepatitis delta virus infection and hepatocellular carcinoma, hepatic decompensation, all-cause and liver-related death in a national cohort.

Hepatitis Delta Virus (HDV) infection is the most severe form of chronic hepatitis. However, studies on outcomes and causes of death in a United States-born population, with primarily horizontal transmission of HDV, are lacking. The aim of this study was to conduct a national study of patients with hepatitis D to understand the natural history and outcomes compared to patients with hepatitis B virus (HBV). infection. In a national cohort of 4,817 HBV infected veterans tested for HDV (99.6% US-born, 3.3% HDV positive) over a 23-year period, we used multivariable models to identify the factors associated with a composite outcome of hepatocellular carcinoma (HCC), decompensation, and liver-related mortality (LRM), as well as all-cause mortality of patients with HDV compared to HBV mono-infection. HDV coinfection (vs. HBV monoinfection) was associated with a significantly higher incidence of composite liver-related outcomes at both 5 (23.84 vs. 7.98, p<0.001), and 10 years (19.14 vs. 10.18, p<0.001) respectively. The most common cause of death was liver-related (33.8% for HDV vs. 24.7% for HBV), followed by non-hepatic malignancies, (15.6 vs. 14.8%),cardiac (11.7 vs. 15.2%), and lung disease (5.2 vs. 3.7%). In multivariable models, HDV was associated with an increased risk of composite liver outcomes (aHR 2.57, 95% CI 1.87-3.52, p<0.001), and all-cause mortality (aHR 1.52, 95% CI 1.20-1.93, p<0.001). In a predominantly U.S born cohort of Veterans, HDV co-infection was associated with an increased risk of liver-related outcomes and all-cause mortality. Our findings support widespread testing for early identification of HDV.

Theranostics: aptamer-assisted carbon nanotubes as MRI contrast and photothermal agent for breast cancer therapy

Breast cancer is one of the leading causes of death among women globally, making its diagnosis and treatment challenging. The use of nanotechnology for cancer diagnosis and treatment is an emerging area of research. To address this issue, multiwalled carbon nanotubes (MWCNTs) were ligand exchanged with butyric acid (BA) to gain hydrophilic character. The successful functionalization was confirmed by FTIR spectroscopy. Surface morphology changes were observed using SEM, while TEM confirmed the structural integrity of the MWCNTs after functionalization. Particle size, zeta potential, and UV spectroscopy were also performed to further characterize the nanoparticles. The breast cancer aptamer specific to Mucin-1 (MUC-1) was then conjugated with the functionalized MWCNTs. These MWCNTs successfully targeted breast cancer cells (MDA-MB-231) as examined by cellular uptake studies and exhibited a reduction in cancer-induced inflammation, as evidenced by gene transcription (qPCR) and protein expression (immunoblotting) levels. Immunoblot and confocal-based immunofluorescence assay (IFA) indicated the ability of CNTs to induce photothermal cell death of MDA-MB-231 cells. Upon imaging, cancer cells were effectively visualized due to the MWCNTs’ ability to act as magnetic resonance imaging (MRI) contrast agents. Additionally, MWCNTs demonstrated photothermal capabilities to eliminate bound cancer cells. Collectively, our findings pave the way for developing aptamer-labeled MWCNTs as viable “theranostic alternatives” for breast cancer treatment.Graphical abstract

CAR expression in invasive breast carcinoma and its effect on adenovirus transduction efficiency

BackgroundBreast cancer is the second leading cause of death in women, with invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) as the two most common forms of invasive breast cancer. While estrogen receptor positive (ER+) IDC and ILC are treated similarly, the multifocality of ILC presents challenges in detection and treatment, worsening long-term clinical outcomes in patients. With increasing documentation of chemoresistance in ILC, additional treatment options are needed. Oncolytic adenoviral therapy may be a promising option, but cancer cells must express the coxsackievirus & adenovirus receptor (CAR) for adenoviral therapy to be effective. The present study aims to evaluate the extent to which CAR expression is observed in ILC in comparison to IDC, and how the levels of CAR expression correlate with adenovirus transduction efficiency. The effect of liposome encapsulation on transduction efficiency is also assessed.MethodsTo characterize CAR expression in invasive breast carcinoma, 36 formalin-fixed paraffin-embedded (FFPE) human breast tumor samples were assayed by CAR immunohistochemistry (IHC). Localization of CAR in comparison to other junctional proteins was performed using a multiplex immunofluorescence panel consisting of CAR, p120-catenin, and E-cadherin. ILC and IDC primary tumors and cell lines were transduced with E1- and E3-deleted adenovirus type 5 inserted with a GFP transgene (Ad-GFP) and DOTAP liposome encapsulated Ad-GFP (DfAd-GFP) at various multiplicities of infection (MOIs). Transduction efficiency was measured using a fluorescence plate reader. CAR expression in the human primary breast carcinomas and cell lines was also evaluated by IHC.ResultsWe observed membranous CAR, p120-catenin and E-cadherin expression in IDC. In ILC, we observed cytoplasmic expression of CAR and p120-catenin, with absent E-cadherin. Adenovirus effectively transduced high-CAR IDC cell lines, at MOIs as low as 12.5. Ad-GFP showed similar transduction as DfAd-GFP in high-CAR IDC cell lines. Conversely, Ad-GFP transduction of ILC cell lines was observed only at MOIs of 50 and 100. Furthermore, Ad-GFP did not transduce CAR-negative IDC cell lines even at MOIs greater than 100. Liposome encapsulation (DfAd-GFP) improved transduction efficiency 4-fold in ILC and 17-fold in CAR-negative IDC cell lines.ConclusionThe present study demonstrates that oncolytic adenoviral therapy is less effective in ILC than IDC due to differences in spatial CAR expression. Liposome-enhanced delivery may be beneficial for patients with ILC and tumors with low or negative CAR expression to improve adenoviral therapeutic effectiveness.

The distribution of cardiovascular diseases in Tanzania: a spatio-temporal investigation.

Cardiovascular Disease (CVD) is currently the major challenge to people's health and the world's top cause of death. In Tanzania, deaths due to CVD account for about 13% of the total deaths caused by the non-communicable diseases. This study examined the spatio-temporal clustering of CVDs from 2010 to 2019 in Tanzania for retrospective spatio-temporal analysis using the Bernoulli probability model on data sampled from four selected hospitals. Spatial scan statistics was performed to identify CVD clusters and the effect of covariates on the CVD incidences was examined using multiple logistic regression. It was found that there was a comparatively high risk of CVD during 2011-2015 followed by a decline during 2015-2019. The spatio-temporal analysis detected two high-risk disease clusters in the coastal and lake zones from 2012 to 2016 (p<0.001), with similar results produced by purely spatial analysis. The multiple logistic model showed that sex, age, blood pressure, body mass index (BMI), alcohol intake and smoking were significant predictors of CVD incidence.

Impact of the COVID-19 pandemic on cancer mortality in Brazil

BackgroundIn the first year of the COVID-19 pandemic, data projections indicated an increase in cancer mortality for the following years due to the overload of health services and the replacement of health priorities. The first studies published with data from mortality records have not confirmed these projections. However, cancer mortality is not an outcome that occurs immediately, and analyses with more extended follow-up periods are necessary. This study aims to analyze the impact of the COVID-19 pandemic on the mortality from all types and the five most common types of cancer in Brazil and investigate the relationship between the density of hospital beds and mortality from COVID-19 in cancer patients in Brazil’s Intermediate Geographic Regions (RGIs).MethodsThe Brazilian Mortality Information System provided data on the deaths from trachea, bronchus, and lung, colorectal, stomach, female breast, and prostate cancer and all types of cancer, and from COVID-19 in individuals who had cancer as a contributing cause of death. Predicted rates for 2020–2022 were compared with the observed ones, through a rate ratio (RR). An association analysis, through multivariate linear regression, was carried out between mortality from COVID-19 in cancer patients, the rate of hospital beds per 100,000 inhabitants, and the Human Development Index of the 133 RGIs of Brazil.ResultsIn 2020, 2021, and 2022, mortality from all cancers in Brazil was lower than expected, with an RR of 0.95, 0.94, and 0.95, respectively, between the observed and predicted rates. Stomach cancer showed the largest difference between observed and expected rates: RR = 0.89 in 2020 and 2021; RR = 0.88 in 2022. Mortality from COVID-19 in cancer patients, which reached its peak in 2021 (6.0/100,000), was negatively associated with the density of hospital beds in the public health system.ConclusionsThe lower-than-expected cancer mortality during 2020–2022 seems to be partly explained by mortality from COVID-19 in cancer patients, which was probably underestimated in Brazil. The findings suggested a protective role of the availability of hospital care concerning deaths due to COVID-19 in this population. More extensive follow-up is needed to understand the impact of the COVID-19 pandemic on cancer mortality.

A 25-Year Retrospective of the Use of AI for Diagnosing Acute Stroke: Systematic Review.

Stroke is a leading cause of death and disability worldwide. Rapid and accurate diagnosis is crucial for minimizing brain damage and optimizing treatment plans. This review aims to summarize the methods of artificial intelligence (AI)-assisted stroke diagnosis over the past 25 years, providing an overview of performance metrics and algorithm development trends. It also delves into existing issues and future prospects, intending to offer a comprehensive reference for clinical practice. A total of 50 representative articles published between 1999 and 2024 on using AI technology for stroke prevention and diagnosis were systematically selected and analyzed in detail. AI-assisted stroke diagnosis has made significant advances in stroke lesion segmentation and classification, stroke risk prediction, and stroke prognosis. Before 2012, research mainly focused on segmentation using traditional thresholding and heuristic techniques. From 2012 to 2016, the focus shifted to machine learning (ML)-based approaches. After 2016, the emphasis moved to deep learning (DL), which brought significant improvements in accuracy. In stroke lesion segmentation and classification as well as stroke risk prediction, DL has shown superiority over ML. In stroke prognosis, both DL and ML have shown good performance. Over the past 25 years, AI technology has shown promising performance in stroke diagnosis.

All-cause and cause-specific mortality amongst individuals with substance misuse: A population-based linked data study in Wales

ObjectiveSubstance misuse has a detrimental impact on an individual’s health and the wider society, as well as elevated mortality. Here, we analysed the association between substance misuse events across several healthcare service providers and risk of mortality. ApproachIn this retrospective population-based cohort study, we identified substance misuse amongst a cohort in Wales, aged ≥10 years old between 2010 and 2019 using the Secure Anonymised Linkage (SAIL) Databank. Cox regression and Kaplan-Meier survival curves were used to calculate risk for all-cause and cause-specific mortality. ResultsDuring the study period 16,229 (9.7%) individuals with a substance misuse event died. A high proportion of these individuals died prematurely (&lt;75 years, 66.7%), and nearly half were from the most deprived areas at time of death (46.8%). Alongside alcoholic liver disease and alcohol hepatic failure, cardiovascular and respiratory diseases were the most common underlying causes of death. Those in receipt of specialist substance misuse treatment for alcohol-use were at greatest risk of suicide (hazard ratio: 1.83) and drug-related deaths (hazard ratio: 1.98). Risk of suicide was also higher for those with a drug-use health event recorded during a hospital admission (hazard ratio: 1.89). ConclusionsSubstance misuse was associated with elevated mortality risk, in particular, amongst those with substance misuse recorded during inpatient hospital admissions. These findings highlight the need for early interventions such as increased screening and monitoring of substance use to prevent premature mortality. ImplicationsOur results provide a clear indication of service needs to support planning and provisioning of health services.

Potentially burdensome care at the end-of-life for people who had a death from cancer: A retrospective population-level cohort study

ObjectivesTo examine factors associated with indicators of potentially burdensome care provided in hospital, and use of hospital services in the last 12 months of life for people who had a death from cancer. ApproachA population-based retrospective cohort study of people aged ≥20 years with a cancer-related cause of death during 2014-2019 in New South Wales, Australia using linked hospital, cancer registry and mortality records. Ten indicators of potentially burdensome care were examined. Multinominal logistic regression examined predictors of a composite measure of potentially burdensome care, derived by summing 4 indicators: &gt;1 ED presentation; &gt;1 hospital admission; ≥1 ICU admission within 30 days of death; died in acute care (scored as 0, 1 ≥2). ResultsOf the 80,005 cancer-related deaths, 69.1% had none, 20.0% had 1 indicator, and 10.9% had ≥2 indicators of potentially burdensome care. Compared to having no indicators of potentially burdensome care, people who smoked, lived in rural areas, were most socially economically disadvantaged, and had their last admission in a private hospital were more likely to experience potentially burdensome care. Older people (≥55 years), females, people with 1 or ≥2 Charlson comorbidities, people with neurological cancers, and people who died in 2018-2019 were less likely to experience potentially burdensome care. Conclusions and implicationsThis study shows the challenge of delivering health services at end-of-life. Opportunities to address potentially burdensome EOLC could involve taking a person-centric approach to integrate oncology and palliative care around individual needs and preferences.

How the APHA Maternal and Child Health Section Advanced the Public Health Approach to Gun Violence Prevention.

This manuscript provides a history of efforts by the American Public Health Association (APHA) Maternal and Child Health Section (MCH Section) Gun Violence Prevention Workgroup (GVP Workgroup) to promote gun violence prevention (GVP) as a key public health priority both within the MCH Section and APHA, and nationally. The MCH Section established a gun violence prevention workgroup in response to the murders of twenty first-grade children and six adults at Sandy Hook Elementary School. This article presents an overview of the accomplishments and challenges of the MCH Section GVP Workgroup in a context of ever-increasing gun violence. As of 2020, firearms became the leading cause of death for U.S. children and teens. Over the past decade, a small group of volunteers helped maintain GVP as one of the top priorities of both the MCH Section and APHA. Endorsement by the MCH Section and APHA leadership facilitated MCH Section GVP Workgroup efforts including organizing a national conference, developing scientific sessions for APHA annual meetings, establishing coalitions, and providing ongoing education and outreach to APHA members. The MCH Section GVP Workgroup helped to both elevate and maintain focus on GVP as a top priority of the MCH Section and APHA, indirectly impacting national efforts to promote a public health approach to GVP. The ongoing epidemic of firearm violence highlights the importance of continuing and strengthening this work. Individuals at other national, state or local organizations might look to the efforts and accomplishment of the MCH Section GVP Workgroup in pursuing critical issues within their own organizations.

Occupation exposure to coal dust and vulnerability to Influenza: Scottish miners and the 1918 Influenza Pandemic.

ObjectiveThere has been little work on the high level of mortality, noted that the time, in coal mining areas during the 1918 Influenza pandemic. Increased risk during viral infection from exposure to particulates (eg cigarette smoke, air pollution) has been studied. ApproachWe use the historic administrative data for Scotland, 1900 to 1930, with standardised codes for occupation and cause of death, and a pseudo household design and Quasi Poisson models, where the spouses of miners are their controls, to test whether miners (aged 20 to 50) were more at risk of death during the main waves of the 1918 pandemic than a matched population. Secondly, we repeat the analysis for Labourers to test if [1] Sex or [2] hard labour and for clerks, if [3] Pulmonary Tuberculosis might explain the effect. ResultsWe find that miners compared to their spouses were significantly more likely to die during all waves of the pandemic but considerably more so during the Autumn wave (RR 4.7). This difference was even greater for younger miners (20 to 35) (RR 7.6). In contrast labourers and clerks had a much lower and often non-significant comparative risk of death during all waves than their spouses. This was true even for those aged 20-35. ConclusionsMale coal miners appear to have been at much higher risk of death compared to matched populations. ImplicationsWorkers with exposure to airborne particulates should be a priority for public health planning during periods of high virus infections.

Endogenous tPA levels: A biomarker for discriminating hemorrhagic stroke from ischemic stroke and stroke mimics.

Stroke is the leading cause of death and disability. Timely differentiation between ischemic stroke, hemorrhagic stroke, and stroke mimics is critical for tailored treatment and triage. To accelerate the identification of stroke's subtype, we propose to use the levels of circulating tPA as a biomarker. Biostroke is an observational study performed at the Caen Hospital. We quantified tPA levels in 110 patients with ischemic strokes, 30 patients with hemorrhagic strokes, and 67 stroke mimic patients upon their arrival at the emergency. Two logistic regression models were formulated: one with parameters measurable in an ambulance (Model A) and one with parameters measurable at the hospital (Model H). These models were both tested with or without plasma tPA measurements. Our initial assessment involved evaluating the effectiveness of both models in distinguishing between hemorrhagic strokes, ischemic strokes, and stroke mimics within our study cohort. Plasmatic tPA levels exhibit significant distinctions between hemorrhagic, ischemic, and mimic stroke patients (1.8; 2.5; 2.4 ng/mL, respectively). The inclusion of tPA in model A significantly enhances the classification accuracy of hemorrhagic patients only, increasing identification from 0.67 (95% CI, 0.59 to 0.75) to 0.78 (95% CI, 0.7 to 0.85) (p = 0.0098). Similarly, in model H, classification accuracy of hemorrhagic patients significantly increased with the addition of tPA, rising from 0.75 (95% CI, 0.67 to 0.83) without tPA to 0.86 (95% CI, 0.81 to 0.91) with tPA (p = 0.024). Our findings underscore the valuable role of tPA levels in distinguishing between stroke subtypes.

KPV and RAPA Self-Assembled into Carrier-Free Nanodrugs for Vascular Calcification Therapy.

Cardiovascular disease (CVD) is a leading cause of death globally, and vascular calcification (VC) is an important independent risk factor for predicting CVD. Currently, there are no established therapeutic strategies for the treatment of VC. Although recognized combination therapies of nanomedicines can provide effective strategies for disease treatment, the clinical application of nanomedicines is limited because of their complex preparation processes, low drug loading rates, and unpredictable safety risks. Thus, developing a simple, efficient, and safe nanodrug to simultaneously regulate inflammation and autophagy may be a promising strategy for treating VC. Herein, an anti-inflammatory peptide (lysine-proline-valine peptides, KPV) and the autophagy activator rapamycin (RAPA) are self-assembled to form new carrier-free spherical nanoparticles (NPs), which shows good stability and biosafety. In vivo and in vitro, KPV-RAPA NPs significantly inhibit VC in mice compared to the other treatment groups. Mechanistically, KPV-RAPA NPs inhibit inflammatory responses and activated autophagy. Therefore, this study indicates that the new carrier-free KPV-RAPA NPs have great potential as therapeutic agents for VC combination therapy, which can promote the development of nanodrugs for VC.

Unraveling the Mechanisms of Magnesium Supplementation in Alleviating Chronic Kidney Disease Complications and Progression: Balancing Risks and Benefits.

Chronic kidney disease (CKD) is a major cause of death and disability worldwide. It is usually diagnosed at early levels because of its slow progression. Treatment should consider CKD complications (such as electrolyte level imbalance, vascular calcification, and bone mineral disorders), as well as the development of CKD itself. Large-scale studies have shown that current treatment guidelines are nearly ineffective and fail to achieve treatment goals. Guidelines have not paid as much attention to magnesium (Mg) as the other electrolytes, while Mg has a significant role in the treatment goals of CKD. Hypomagnesemia is the only electrolyte imbalance that is equally prevalent in all stages of CKD. A lower plasma Mg level in each stage of CKD is associated with a higher risk of CKD progression and cardiac events. Magnesium exerts its effects both directly and via other ions. Mg supplementation increases insulin sensitivity while reducing proteinuria and inflammation. It lowers blood pressure and inhibits vascular calcification primarily because of its effects on calcium and phosphate, respectively. Vitamin D supplementation for low-active vitamin D in CKD patients increases vascular calcification and cardiac events, but magnesium supplementation enhances vitamin D levels and activity without increasing the risk of cardiac events. However, careful attention is required due to the potential threats of hypermagnesemia, particularly in advanced CKD stages. Starting magnesium supplementation early in patients' treatment plans will result in fewer side effects and more advantages. More original research is needed to determine its optimal dose and serum levels.

Inhibition of STAT3 by 2-Methoxyestradiol suppresses M2 polarization and protumoral functions of macrophages in breast cancer

BackgroundBreast cancer metastasis remains the leading cause of cancer-related deaths in women worldwide. Infiltration of tumor-associated macrophages (TAMs) in the tumor stroma is known to be correlated with reduced overall survival. The inhibitors of TAMs are sought after for reprogramming the tumor microenvironment. Signal transducer and activator of transcription 3 (STAT3) is well known to contribute in pro-tumoral properties of TAMs. 2-Methoxyestradiol (2ME2), a potent anticancer and antiangiogenic agent, has been in clinical trials for treatment of breast cancer. Here, we investigated the potential of 2ME2 in modulating the pro-tumoral effects of TAMs in breast cancer.MethodsTHP-1-derived macrophages were polarized to macrophages with or without 2ME2. The effect of 2ME2 on macrophage surface markers and anti-inflammatory genes was determined by Western blotting, flow cytometry, immunofluorescence, qRT‒PCR. The concentration of cytokines secreted by cells was monitored by ELISA. The effect of M2 macrophages on malignant properties of breast cancer cells was determined using colony formation, wound healing, transwell, and gelatin zymography assays. An orthotopic model of breast cancer was used to determine the effect of 2ME2 on macrophage polarization and metastasis in vivo.ResultsFirst, our study found that polarization of monocytes to alternatively activated M2 macrophages is associated with the reorganization of the microtubule cytoskeleton. At lower concentrations, 2ME2 treatment depolymerized microtubules and reduced the expression of CD206 and CD163, suggesting that it inhibits the polarization of macrophages to M2 phenotype. However, the M1 polarization was not significantly affected at these concentrations. Importantly, 2ME2 inhibited the expression of several anti-inflammatory cytokines and growth factors, including CCL18, TGF-β, IL-10, FNT, arginase, CXCL12, MMP9, and VEGF-A, and hindered the metastasis-promoting effects of M2 macrophages. Concurrently, 2ME2 treatment reduced the expression of CD163 in tumors and inhibited lung metastasis in the orthotopic breast cancer model. Mechanistically, 2ME2 treatment reduced the phosphorylation and nuclear translocation of STAT3, an effect which was abrogated by colivelin.ConclusionsOur study presents novel findings on mechanism of 2ME2 from the perspective of its effects on the polarization of the TAMs via the STAT3 signaling in breast cancer. Altogether, the data supports further clinical investigation of 2ME2 and its derivatives as therapeutic agents to modulate the tumor microenvironment and immune response in breast carcinoma.