Asperuloside as a Novel NRF2 Activator to Ameliorate Endothelial Dysfunction in High Fat Diet-Induced Obese Mice.

AIMS: Current treatments are inadequate in alleviating obesity-associated vascular diseases. The development of effective therapies to ameliorate endothelial dysfunction and attenuate oxidative stress is of utmost importance. Asperuloside (ASP), a bioactive compound extracted from Eucommia species, exhibits anti-obesity properties. However, the effects of ASP on vasculopathy have not been investigated. Therefore, the effects of ASP on vascular dysfunction and related mechanisms were elucidated. RESULTS: ASP significantly reversed the impaired endothelium-dependent relaxations (EDRs) in obese mice and IL-1ß-treated aortas. ASP suppressed endothelial activation in obese mice aortas and IL-1ß-treated endothelial cells. ASP attenuated oxidative stress, scavenged mitochondrial ROS and upregulated HO-1 expression in endothelium, independently of its anti-inflammatory properties. HO-1 knockdown diminished the protective effects of ASP against impaired EDRs, ROS overproduction and endothelial activation. Endothelial cell-specific Nrf2 knockdown eliminated the ASP-mediated vascular protective effects and endothelial HO-1 upregulation, emphasizing that ASP improves endothelial function by activating Nrf2/HO-1 signaling. ASP facilitated Nrf2 nuclear translocation and the direct binding of Nrf2 to ARE, thereby enhancing HO-1 transcription and scavenging ROS. CETSA results provide the first experimental characterization of the direct binding of ASP to Nrf2. INNOVATION: Effective Nrf2 activators targeting obesity-associated endothelial dysfunction are not available. This study demonstrates that Asperuloside could be a novel Nrf2 activator to alleviate obesity-associated endothelial dysfunction, suggesting a promising redox-based therapy for vasculopathy. CONCLUSIONS: These findings demonstrate that ASP ameliorates obesity-associated endothelial dysfunction by activating Nrf2/HO-1 signaling and maintaining redox hemostasis, demonstrating its potential as a novel Nrf2-targeted therapeutic agent and dietary supplement for vasculopathy.

Large language models' responses to liver cancer surveillance, diagnosis, and management questions: accuracy, reliability, readability.

PURPOSE: To assess the accuracy, reliability, and readability of publicly available large language models in answering fundamental questions on hepatocellular carcinoma diagnosis and management. METHODS: Twenty questions on liver cancer diagnosis and management were asked in triplicate to ChatGPT-3.5 (OpenAI), Gemini (Google), and Bing (Microsoft). Responses were assessed by six fellowship-trained physicians from three academic liver transplant centers who actively diagnose and/or treat liver cancer. Responses were categorized as accurate (score 1; all information is true and relevant), inadequate (score 0; all information is true, but does not fully answer the question or provides irrelevant information), or inaccurate (score - 1; any information is false). Means with standard deviations were recorded. Responses were considered as a whole accurate if mean score was > 0 and reliable if mean score was > 0 across all responses for the single question. Responses were also quantified for readability using the Flesch Reading Ease Score and Flesch-Kincaid Grade Level. Readability and accuracy across 60 responses were compared using one-way ANOVAs with Tukey's multiple comparison tests. RESULTS: Of the twenty questions, ChatGPT answered nine (45%), Gemini answered 12 (60%), and Bing answered six (30%) questions accurately; however, only six (30%), eight (40%), and three (15%), respectively, were both accurate and reliable. There were no significant differences in accuracy between any chatbot. ChatGPT responses were the least readable (mean Flesch Reading Ease Score 29; college graduate), followed by Gemini (30; college) and Bing (40; college; p < 0.001). CONCLUSION: Large language models provide complex responses to basic questions on hepatocellular carcinoma diagnosis and management that are seldomly accurate, reliable, or readable.

The burden of cardiovascular disease in Asia from 2025 to 2050: a forecast analysis for East Asia, South Asia, South-East Asia, Central Asia, and high-income Asia Pacific regions.

Background: Given the rapidly growing burden of cardiovascular disease (CVD) in Asia, this study forecasts the CVD burden and associated risk factors in Asia from 2025 to 2050. Methods: Data from the Global Burden of Disease 2019 study was used to construct regression models predicting prevalence, mortality, and disability-adjusted life years (DALYs) attributed to CVD and risk factors in Asia in the coming decades. Findings: Between 2025 and 2050, crude cardiovascular mortality is expected to rise 91.2% despite a 23.0% decrease in the age-standardised cardiovascular mortality rate (ASMR). Ischaemic heart disease (115 deaths per 100,000 population) and stroke (63 deaths per 100,000 population) will remain leading drivers of ASMR in 2050. Central Asia will have the highest ASMR (676 deaths per 100,000 population), more than three-fold that of Asia overall (186 deaths per 100,000 population), while high-income Asia sub-regions will incur an ASMR of 22 deaths per 100,000 in 2050. High systolic blood pressure will contribute the highest ASMR throughout Asia (105 deaths per 100,000 population), except in Central Asia where high fasting plasma glucose will dominate (546 deaths per 100,000 population). Interpretation: This forecast forewarns an almost doubling in crude cardiovascular mortality by 2050 in Asia, with marked heterogeneity across sub-regions. Atherosclerotic diseases will continue to dominate, while high systolic blood pressure will be the leading risk factor. Funding: This was supported by the NUHS Seed Fund (NUHSRO/2022/058/RO5+6/Seed-Mar/03), National Medical Research Council Research Training Fellowship (MH 095:003/008-303), National University of Singapore Yong Loo Lin School of Medicine's Junior Academic Fellowship Scheme, NUHS Clinician Scientist Program (NCSP2.0/2024/NUHS/NCWS) and the CArdiovascular DiseasE National Collaborative Enterprise (CADENCE) National Clinical Translational Program (MOH-001277-01).

Comparison of Claudin-4, BerEP4, Carcinoembryonic Antigen and MOC31 in Serous Fluids Metastases Demonstrate High Sensitivity of Claudin-4 at Low Cellularity.

INTRODUCTION: Claudin-4 has been described as a highly sensitive immunocytochemical marker for detection of metastatic carcinoma cells in effusion cytology specimens. This study aims to challenge the performance of claudin-4 in different types of malignancies and low cellularity specimens, by comparison with other markers in a large cohort of carcinomatous effusion specimens. METHODOLOGY: Cell block preparations from peritoneal and pleural fluid specimens were retrieved, with malignant (carcinoma) diagnoses confirmed by review of hospital diagnosis code and pathology reports. Claudin-4, BerEP4, CEA, and MOC31 immunocytochemistry were performed and scored by expression proportion and intensity. Tumor cellularity was assessed for subgroup analysis of low cellularity specimens. RESULTS: Totally 147 specimens (70 pleural, 77 peritoneal) of 68 lung, 62 breast, 9 gynecological, and 7 gastrointestinal carcinomas were retrieved. The average proportion expression of claudin-4 was highest (89.6%, vs. CEA 40.5%, BerEp4 18.6%, MOC31 16.8%) and the percentage of strong expression was highest for claudin-4 (72.1%). Expression levels of claudin-4 were consistently higher than other markers in subgroups of all primary sites. The difference was more significant for low cellularity specimens. High (≥50%) proportion expression was seen for 96.61% of cases for claudin-4 (vs. BerEp4 8.77%, CEA 46.55%, MOC31 8.77%, p < 0.001). These factors contributed to a low concordance between claudin-4 and BerEp4, CEA and MOC31 (K = 0.010-0.043). CONCLUSION: Claudin-4 is more sensitive than CEA, BerEp4 and MOC31, suitable for low cellularity specimens of most types of metastatic carcinoma and is a robust immunocytochemical marker for carcinoma that can be used solitarily.

Clinical and electrocardiographic characteristics of immune checkpoint inhibitor-related myocarditis.

BACKGROUND: Immune checkpoint inhibitor (ICI) has become a major breakthrough in the field of tumor therapy, leading to improved survival. This study evaluated the clinical and electrocardiographic characteristics of patients with ICI-related myocarditis. METHODS: Patients with ICI-related myocarditis were enrolled from 4 centers in China until September 2023. Demographic data (age, sex, comorbidity), types of ICI, clinical manifestations, electrocardiogram (ECG) and treatment were analyzed retrospectively. Arrhythmia and characteristics of ECG were compared according to prognosis and grading. RESULTS: A total of 29 participants (13 females with a median age of 63.25 years) with ICI-related myocarditis were enrolled. Lung cancer was the most, with a proportion of 31.03 % (9/29). The median time from the first administration of ICI to the diagnosis of myocarditis was 50 days. Camrelizumab was the main type of ICI (9/29). Most patients had non-specific symptoms, dyspnea (n = 16) and palpitation (n = 9) were common. The overall mortality rate was 37.93 % (11/29) with a median follow-up of 9(4,11) days. Compared with the survivors, P-wave abnormality was more common in participants who were dead (24.14 %vs6.90 %, p = 0.010). A total of 19 patients with severe ICI-related myocarditis were included in this study. The proportions of sinus tachycardia (34.48 %vs0.00 %, p = 0.005), premature ventricular complex (27.59 %vs0.00 %, p = 0.027) and atrioventricular block (34.48 %vs3.45 %, p = 0.044) were higher in severe ICI-related myocarditis. CONCLUSIONS: Clinical manifestations of ICI-related myocarditis usually lacked specificity. ECGs can be manifested as new-onset arrhythmias, ST-T segment changes, fragmented QRS complex, abnormal P wave, prolonged QTc interval and multi­lead low voltage.

Association between "weekend warrior" physical activity and the incidence of neurodegenerative diseases.

While guidelines recommend 150 â€‹min of moderate to vigorous physical activity (MVPA) weekly to enhance health, it remains unclear whether concentrating these activities into 1-2 days of the week, "weekend warrior" (WW) pattern, has the same benefit for neurodegenerative diseases (NDDs). This study aimed to evaluate the associations of WW pattern and the risk of NDDs. This prospective study was conducted using accelerometer-based physical activity data for a full week from June 2013 to December 2015 in the UK Biobank. These individuals were categorized into distinct physical activity patterns, including the WW pattern (i.e., over 50% or 75% of recommended MVPA achieved over 1-2 days), regular pattern, and inactive pattern. Cox proportional hazards model was used to evaluate the association between physical activity patterns and outcomes. Compared to inactive group, WW pattern and regular pattern was similarly linked to a reduced risk of all-cause dementia (WW: Hazard Ratio [HR]: 0.68, 95% Confidence Interval [CI]: 0.56-0.84; regular: HR: 0.86, 95% CI: 0.67-1.1) and all-cause Parkinsonism (WW: HR: 0.47, 95% CI: 0.35-0.63; regular: HR: 0.69, 95% CI: 0.5-0.95). When the exercise threshold was increased to 75% of MVPA, both patterns still were associated with decreased risk of incident all-cause dementia (WW: HR: 0.61, 95% CI: 0.41-0.91; regular: HR: 0.76, 95% CI: 0.63-0.92) and all-cause Parkinsonism (WW: HR: 0.22, 95% CI: 0.10-0.47; regular: HR: 0.59, 95% CI: 0.46-0.75). Concentrating recommended physical activities into 1-2 days per week is associated with a lower incidence of NDDs.

Left Atrial Electrophysiological Properties after Pulmonary Vein Isolation Predict the Recurrence of Atrial Fibrillation: A Cohort Study.

Background: The aim of this work was to investigate left atrial electrophysiological properties for their ability to predict the recurrence of atrial fibrillation (AF) following pulmonary vein isolation (PVI). Methods: The study comprised 53 patients with AF [62 (interquartile range (IQR): 52-68) years old; 47.2% females]. High-density, three-dimensional electro-anatomic mapping using PentaRay was conducted during sinus rhythm in the left atrium (LA) immediately after PVI. LA conduction time, conduction velocity in predefined anterior and posterior routes, low voltage area percentage and distribution were assessed. Results: The AF recurrence group had longer LA conduction time compared to the non-recurrence group [11 (IQR: 10-12) ms vs. 9 (IQR: 8-10) ms, p = 0.001). The percent low voltage area was greater in the recurrence group than the non-recurrence group [31.2 (IRQ: 7.1-49.3)% vs. 7.7 (IQR: 4.3-15.2)%, p = 0.008]. Multivariate Cox regression revealed that LA conduction time independently predicted AF recurrence following ablation over a median follow-up of 235 days [IQR: 154-382 days; hazard ratio (HR): 2.37, 95% confidence interval (CI): 1.08-5.23, p = 0.031]. The optimal cut-off for LA conduction time was 98 ms [area under curve (AUC): 0.926, sensitivity: 0.833, specificity: 0.894, p < 0.01]. Kaplan-Meier analysis revealed that patients with a conduction time > 98 ms had a higher rate of AF recurrence following ablation (p < 0.001). Conclusions: Patients with longer LA conduction time after PVI had more frequent AF recurrence.

Cardiovascular disease burden in patients with urological cancers: The new discipline of uro-cardio-oncology.

Cancer remains a major cause of mortality worldwide, and urological cancers are the most common cancers among men. Several therapeutic agents have been used to treat urological cancer, leading to improved survival for patients. However, this has been accompanied by an increase in the frequency of survivors with cardiovascular complications caused by anticancer medications. Here, we propose the novel discipline of uro-cardio-oncology, an evolving subspecialty focused on the complex interactions between cardiovascular disease and urological cancer. In this comprehensive review, we discuss the various cardiovascular toxicities induced by different classes of antineoplastic agents used to treat urological cancers, including androgen deprivation therapy, vascular endothelial growth factor receptor tyrosine kinase inhibitors, immune checkpoint inhibitors, and chemotherapeutics. In addition, we discuss possible mechanisms underlying the cardiovascular toxicity associated with anticancer therapy and outline strategies for the surveillance, diagnosis, and effective management of cardiovascular complications. Finally, we provide an analysis of future perspectives in this emerging specialty, identifying areas in need of further research.

Prognostic value of cardiovascular magnetic resonance in immune checkpoint inhibitor-associated myocarditis: A systematic review and meta-analysis.

Background: Immune checkpoint inhibitors (ICI) are increasingly used in the first-line treatment of malignant tumors. There is increasing recognition of their cardiotoxicity and, in particular, their potential to lead to myocarditis. Cardiovascular magnetic resonance (CMR) can quantify pathological changes, such as myocardial edema and fibrosis. The purpose of this systematic review and meta-analysis was to examine the evidence for the roles of CMR in predicting prognosis in ICI-associated myocarditis. Methods: PubMed, Cochrane Library, and Web of Science databases were searched until October 2023 for published works investigating the relationship between CMR parameters and adverse events in patients with ICI-associated myocarditis. The analysis included studies reporting the incidence of late gadolinium enhancement (LGE), T1 values, T2 values, and CMR-derived left ventricular ejection fraction (LVEF). Odds ratios (OR) and weighted mean differences (WMD) were combined for binary and continuous data, respectively. Newcastle-Ottawa Scale was used to assess the methodological quality of the included studies. Results: Five cohort studies were included (average age 65-68 years; 25.4% female). Of these, four studies were included in the meta-analysis of LGE-related findings. Patients with major adverse cardiovascular events (MACE) had a higher incidence of LGE compared with patients without MACE (OR = 4.18, 95% CI: 1.72-10.19, p = 0.002). A meta-analysis, incorporating data from two studies, showed that patients who developed MACE exhibited significantly higher T1 value (WMD = 36.16 ms, 95% CI: 21.43-50.89, p < 0.001) and lower LVEF (WMD = - 8.00%, 95% CI: -13.60 to -2.40, p = 0.005). Notably, T2 value (WMD = -0.23 ms, 95% CI: -1.86 to -1.39, p = 0.779) was not associated with MACE in patients with ICI-related myocarditis. Conclusions: LGE, T1 value, and LVEF measured by CMR imaging have potential prognostic value for long-term adverse events in patients with ICI-related myocarditis.

FOXP4 is a Direct YAP1 Target that Promotes Gastric Cancer Stemness and Drives Metastasis.

The Hippo-YAP1 pathway is an evolutionally conserved signaling cascade that controls organ size and tissue regeneration. Dysregulation of Hippo-YAP1 signaling promotes initiation and progression of several types of cancer, including gastric cancer (GC). As the Hippo-YAP1 pathway regulates expression of thousands of genes, it is important to establish which target genes contribute to the oncogenic program driven by YAP1 to identify strategies to circumvent it. Here, we identified a vital role of FOXP4 in YAP1-driven gastric carcinogenesis by maintaining stemness and promoting peritoneal metastasis. Loss of FOXP4 impaired GC spheroid formation and reduced stemness marker expression, while FOXP4 upregulation potentiated cancer cell stemness. RNA-seq analysis revealed SOX12 as downstream target of FOXP4, and functional studies established that SOX12 supports stemness in YAP1-induced carcinogenesis. A small molecule screen identified 42-(2-Tetrazolyl)rapamycin as a FOXP4 inhibitor, and targeting FOXP4 suppressed GC tumor growth and enhanced the efficacy of 5-FU chemotherapy in vivo. Collectively, these findings revealed that FOXP4 upregulation by YAP1 in GC regulates stemness and tumorigenesis by upregulating SOX12. Targeting the YAP1-FOXP4-SOX12 axis represents a potential therapeutic strategy for GC.

Postoperative QRS duration to left ventricular end-diastolic diameter ratio as a predictor for the risk of postoperative atrial fibrillation in cardiac surgery: A single-center prospective study.

Background and aims: Postoperative atrial fibrillation (POAF) is a frequent complication following cardiac surgery and is associated with adverse clinical outcomes. Our study aimed at determining the clinical and echocardiographic predictors of POAF in patients with cardiac surgery and management of this group of patients may improve their outcome. Methods: We prospectively enrolled patients from the department of cardiovascular surgery in the Second Hospital of Tianjin Medical University from October 23, 2020 to October 30, 2022, without a history of atrial fibrillation. Cox regression was used to identify significant predictors of POAF. Results: A total of 217 patients (79 [36.41 %] were female, 63.96 ± 12.32 years) were included. 88 (40.55 %) patients met the criteria for POAF. Cox regression showed that preoperative left atrial diameter (LAD) (HR: 1.040, 95 % CI 1.008-1.073, p = 0.013) and postoperative QRS/LVEDD (HR: 0.398, 95 % CI 0.193-0.824, p = 0.013) and E/e' (HR: 1.029, 95 % CI 1.002-1.057，p = 0.033) were predictors of POAF. Conclusion: Preoperative LAD and postoperative QRS/LVEDD and E/e' were predictors of POAF in patients undergoing cardiac surgery. Trial registration site: http://www.chictr.org.cn. Registration number: ChiCTR2200063344.

Transcatheter closure of multiple coronary artery fistulas: a coronary computed tomography angiography-based anatomic classification.

INTRODUCTION AND OBJECTIVES: This study aimed to retrospectively analyze the anatomical characteristics and classification of multiple coronary artery fistulas (MCAFs), and to compare the outcomes of transcatheter closure between MCAFs and single fistulas. METHODS: All patients who underwent attempts at transcatheter closure of coronary artery fistulas (CAFs) at Fuwai Hospital from 2010 to 2023 were retrospectively reviewed. Patients were categorized into single fistula and MCAFs groups, and anatomical characteristics and transcatheter closure outcomes were compared between the 2 groups. RESULTS: This retrospective study included 146 patients who underwent attempted transcatheter closure of CAFs, with a 14.38% failure rate. Among the 146 patients with CAFs, 32.19% were identified as having MCAFs, with types I, II, and III constituting 40.43%, 42.55%, and 17.02%, respectively. Unlike single fistulas, which predominantly originated from the right coronary artery and terminated in the left ventricle, MCAFs mainly had simultaneous origins from the right coronary artery and left anterior descending artery (29.79%), and predominantly drained into the pulmonary artery (70.21%), with a notable prevalence of plexus-like morphology (38.3% vs 2.02%, P<.001). The success rate of transcatheter closure was significantly lower for multiple fistulas compared with single fistula (64.29% vs 84.34%, P=.011). Multivariate regression analysis indicated that the risk of closure failure for MCAFs was 2.64 times that of single fistulas. CONCLUSIONS: MCAFs are common among CAFs and can be classified into 3 types based on the number and location of their origins and terminations. The risk of failure of transcatheter closure is significantly higher in MCAFs than in single fistulas.

Associations Between Social Determinants of Health and Cardiovascular Health of U.S. Adult Cancer Survivors.

Background: Relationships between the social determinants of health (SDOH) and cardiovascular health (CVH) of cancer survivors are underexplored. Objectives: This study sought to investigate associations between the SDOH and CVH of adult cancer survivors. Methods: Data from the U.S. National Health Interview Survey (2013-2017) were used. Participants reporting a history of cancer were included, excluding those with only nonmelanotic skin cancer, or with missing data for any domain of SDOH or CVH. SDOH was quantified with a 6-domain, 38-item score, consistent with the Centers for Disease Control and Prevention recommendations (higher score indicated worse deprivation). CVH was quantified based on the American Heart Association's Life's Essential 8, but due to unavailable detailed dietary data, a 7-item CVH score was used, with a higher score indicating worse CVH. Survey-specific multivariable Poisson regression was used to test associations between SDOH quartiles and CVH. Results: Altogether, 8,254 subjects were analyzed, representing a population of 10,887,989 persons. Worse SDOH was associated with worse CVH (highest vs lowest quartile: risk ratio 1.30; 95% CI: 1.25-1.35; P < 0.001), with a grossly linear relationship between SDOH and CVH scores. Subgroup analysis found significantly stronger associations in younger participants (P interaction = 0.026) or women (P interaction = 0.001) but without significant interactions with race (P interaction = 0.051). Higher scores in all domains of SDOH were independently associated with worse CVH (all P < 0.001). Higher SDOH scores were also independently associated with each component of the CVH score (all P < 0.05 for highest SDOH quartile). Conclusions: An unfavorable SDOH profile was independently associated with worse CVH among adult cancer survivors in the United States.

Comparison of infection risk between enzalutamide and abiraterone in patients with prostate cancer.

BACKGROUND: Enzalutamide and abiraterone may differ in their immunomodulatory effects, and the prednisone coadministered with abiraterone can be immunosuppressive. This study aimed to compare the risk of different types of infection in patients with prostate cancer receiving enzalutamide or abiraterone in combination with androgen deprivation therapy. METHODS: Patients with prostate cancer receiving enzalutamide or abiraterone in addition to androgen deprivation therapy in Hong Kong between December 1999 to March 2021 were identified in this retrospective cohort study and followed up until September 2021, death, or crossover. Outcomes, including any sepsis, pneumonia, urinary tract infection, cellulitis or skin abscess, central nervous system infections, and tuberculosis, were analyzed as both time-to-event outcomes (multivariable Fine-Gray regression, with mortality considered a competing event) and recurrent-event outcomes (multivariable negative binomial regression). RESULTS: Altogether, 1582 patients were analyzed (923 abiraterone users; 659 enzalutamide users) with a median follow-up of 10.6 months (interquartile range: 5.3-19.9 months). Compared to abiraterone users, enzalutamide users had lower cumulative incidences of sepsis (adjusted subhazard ratio [SHR] 0.70 [0.53-0.93], p = .014), pneumonia (adjusted SHR 0.76 [0.59-0.99], p = .040), and cellulitis or skin abscess (adjusted SHR 0.55 [0.39-0.79], p = .001), but not urinary tract infection (adjusted SHR 0.91 [0.62-1.35], p = .643). Associations between exposure and central nervous system infections and tuberculosis were not assessed because of low event rates. Analyzing the outcomes as recurrent events gave similar results. Enzalutamide use may be associated with a lower risk of urinary tract infection in patients with diabetes mellitus. CONCLUSIONS: Compared to abiraterone users, enzalutamide users have significantly lower risks of sepsis, pneumonia, cellulitis, or skin abscess.

Control for multiple risk factors and incident heart failure and mortality in patients with diabetes mellitus: Insights from the Kailuan cohort study.

BACKGROUND: This study evaluated the relationship between controlling multiple risk factors and diabetes-related heart failure and all-cause mortality, and the extent to which the excess risk can be reduced. METHODS: 17,676 patients with diabetes and 69,493 matched non-diabetic control subjects were included in the Kailuan study, with a median follow-up of 11.19 years. The risk factor control was defined by the attainment of target values for systolic blood pressure, body mass index, low-density lipoprotein cholesterol, fasting blood glucose, high-sensitive C-reactive protein and smoking. Fine-Gray and Cox models were used to estimate associations between the degree of risk factor control and risk of heart failure and all-cause mortality respectively. RESULTS: Among diabetes patients, there was a gradual reduction in the risk of outcomes as the degree of risk factor control increased. For each additional risk factor that was controlled, there was an associated 16 % decrease in heart failure risk and a 10 % decrease in all-cause mortality risk. Among diabetes patients with ≥5 well-controlled risk factors, the adjusted hazard ratio compared to controls for heart failure and all-cause mortality was 1.25 (95 %CI: 0.99-1.56) and 1.17(95 %CI: 1.05-1.31) respectively. The protective effect of comprehensive risk factor control on the risk of heart failure was more pronounced in men and those using antihypertensive medications. CONCLUSIONS: Control for multiple risk factors is associated with reduced heart failure and all-cause mortality risks in a cumulative and sex-specific manner. However, despite optimization of risk factor control, diabetes patients still face increased risks compared to the general population.

Cytokeratin 15 is a novel and independent predictor of poor outcome in luminal B HER2-negative breast carcinomas.

Cytokeratin 15 (CK15) has been described as a stem cell marker in human organs and its expression is seen in breast tissue. CK15 expression is associated with aggressive features in endometrial and oesophageal cancers, but data on the breast are lacking. This study aims to investigate the clinicopathological associations and prognostic significance of CK15 in breast carcinomas. A multi-institute cohort of breast carcinomas were retrieved. Clinicopathological and outcome data were obtained and compared with immunohistochemical expression CK15 and a panel of biomarkers. In total, 1,476 cases were included, with an expression rate of 3.5%, preferentially expressed in luminal subtypes (p=0.024), with luminal B carcinomas being the highest (4.7%), as opposed to basal-like (1%) and HER2-overexpressed carcinomas (0%). Except for nodal stage (p=0.013) and nodal metastasis (p=0.048), oestrogen (p=0.035) and progesterone receptor (p=0.001) positivity, there were no associations with other clinicopathological parameters. A trend was observed with shorter breast cancer specific survival (BCSS) in CK15-positive luminal B carcinomas (p=0.062). On further subgroup multivariate analysis of luminal B HER2-negative carcinomas, CK15 expression exhibited robust correlation with shorter BCSS (HR=9.004, p=0.001) and disease-free survival (HR=7.085, p<0.001). Restricted to luminal breast carcinomas, specifically luminal B HER2-negative, CK15 is demonstrated to be a robust independent predictor of higher risk of recurrence and shorter survival, with potential as a clinical prognostic marker and an exclusive stem cell marker for this subgroup of carcinomas.

Prognostic Significance of CD163+ and/or CD206+ Tumor-Associated Macrophages Is Linked to Their Spatial Distribution and Tumor-Infiltrating Lymphocytes in Breast Cancer.

Tumor-associated macrophages (TAMs) is a key element in the breast tumor microenvironment. CD163 and CD206 have been utilized for TAM identification, but the clinical implications of TAMs identified by these markers have not been thoroughly explored. This study conducted a comparative analysis of CD163 and CD206 TAMs using digital image analysis, focusing on their spatial distribution and prognostic significance in relation to tumor-infiltrating lymphocytes (TILs). Distinct clinico-pathological and prognostic characteristics were noted between the two types of TAMs. CD163 TAMs were linked to high-grade tumors (p = 0.006), whereas CD206 TAMs were associated with a higher incidence of nodal metastasis (p = 0.033). CD206 TAMs were predominantly found in the stroma, with more cases being stromal CD206-high (sCD206-high) than tumoral CD206-high (tCD206-high) (p = 0.024). Regarding prognostication, patients stratified according to stromal and tumoral densities of CD163 showed different disease-free survival (DFS) time. Specifically, those that were sCD163-low but tCD163-high exhibited the poorest DFS (chi-square = 10.853, p = 0.013). Furthermore, a high sCD163-to-stromal-TILs ratio was identified as an independent predictor of unfavorable survival outcomes (DFS: HR = 3.477, p = 0.018). The spatial distribution and interactions with TILs enhanced the prognostic value of CD163 TAMs, while CD206 TAMs appeared to have limited prognostic utility in breast cancer cases.

Human epidermal growth factor receptor 2 (HER2) status in breast cancer: practice points and challenges.

Human epidermal growth factor receptor 2 (HER2)-enriched breast cancer benefits significantly from anti-HER2 targeted therapies. This highlights the critical need for precise HER2 immunohistochemistry (IHC) interpretation serving as a triage tool for selecting patients for anti-HER2 regimens. Recently, the emerging eligibility of patients with HER2-low breast cancers for a novel HER2-targeted antibody-drug conjugate (T-DXd) adds challenges to HER2 IHC scoring interpretation, notably in the 0-1+ range, which shows high interobserver and interlaboratory staining platform variability. In this review, we navigate evolving challenges and suggest practical recommendations for HER2 IHC interpretation.