Metallothionein (MT) plays a role in fundamental cellular processes such as proliferation, apoptosis and differentiation. We examined MT expression in women with invasive breast ductal carcinoma who ...underwent mastectomy/lumpectomy without neo-adjuvant treatment. We showed that MT was over-expressed in 87.9% of breast cancer tissues examined, with the mean percentage of positive cells at 30%. There were two patterns of MT expression: predominantly cytoplasmic in 75.9% and nuclear in 24.1% of MT-positive cases. Higher MT scores were associated with poorer histological grade (p = 0.009) but were independent of age, tumour size and oestrogen receptor status. For patients who were treated with adjuvant chemotherapy (cyclophosphamide/methotrexate/5 fluorouracil- or doxorubicin-based regimes), those with high MT expression had a significantly lower recurrence-free survival (p = 0.048), suggesting a role of MT in predicting disease recurrence. Down-regulation of MT in MCF-7 cells by silencing the MT-2A gene (the most abundantly expressed of the 10 known functional MT isoforms) increased chemosensitivity of the cells to doxorubicin. To examine the mechanisms underlying these clinical data, we used siRNAs to decrease MT-2A mRNA expression and protein expression. In MT down-regulated cells challenged with the IC(50) concentration of doxorubicin, we observed a significant reduction in cell viability. Cell cycle analysis also revealed a corresponding increase in apoptosis in the MT down-regulated cells following doxorubicin exposure, showing that down-regulation of MT increased susceptibility to doxorubicin cytotoxicity. The data suggest that MT could be a potential marker of chemoresistance and a molecular therapeutic target.
► Associations between PCBs and thymic involution in UK harbour porpoises was tested. ► Associations between PCBs and thymic cysts in UK harbour porpoises was tested. ► Thymic involution was ...associated with nutritional status and sexual maturity. ► PCBs and thymic involution was associated when total PCB>17mg/kg lipid weight. ► Development of thymic cysts appears predominantly age-related.
The associations between polychlorinated biphenyls (PCBs) exposure and involution of lymphoid tissue and development of epithelial-lined cysts in the thymus of UK-stranded harbour porpoises (Phocoena phocoena) (n=170) were tested. Percentage of thymic lymphoid tissue (%TLT) was histologically quantified. Multiple regression analyses (n=169) demonstrated significant positive correlation between %TLT and nutritional status (p<0.001) and significant negative association between %TLT and onset of sexual maturity (p<0.001). However, in a subgroup of porpoises with total PCB levels above a proposed threshold of toxicity (>17mg/kg lipid weight) (n=109), the negative association between %TLT (as dependent variable) and summed blubber concentrations of 25 chlorobiphenyl congeners (∑25CBs) remained significant (p<0.01) along with nutritional status (p<0.001) and onset of sexual maturity (p<0.001). These results suggest PCB-induced immuno suppression may be occurring in harbour porpoises in UK waters but only at concentrations that exceed proposed toxicity thresholds for marine mammals. In contrast, development of thymic cysts appears predominantly age-related.
Prediabetes, which is a precedent of overt diabetes, is a known risk factor for adverse cardiovascular outcomes. Its impact on adverse cardiovascular outcomes in patients with cancer who are ...prescribed anthracycline-containing chemotherapy (ACT) is uncertain. The objective of this study was to evaluate the association of prediabetes with cardiovascular events in patients with cancer who are prescribed ACT.
The authors identified patients with cancer who received ACT from 2000 to 2019 from Clinical Data Analysis Reporting System of Hong Kong. Patients were divided into diabetes, prediabetes, and normoglycemia groups based on their baseline glycemic profile. The Primary outcome, a major adverse cardiovascular event (MACE), was the composite event of hospitalization for heart failure and cardiovascular death.
Among 12,649 patients at baseline, 3997 had prediabetes, and 5622 had diabetes. Over median follow-up of 8.7 years, the incidence of MACE was 211 (7.0%) in the normoglycemia group, 358 (9.0%) in the prediabetes group, and 728 (12.9%) in the diabetes group. Compared with normoglycemia, prediabetes (adjusted hazard ratio HR, 1.20; 95% confidence interval CI, 1.01-1.43) and diabetes (adjusted HR, 1.46; 95% CI, 1.24-1.70) were associated with an increased risk of MACE. In the prediabetes group, 475 patients (18%) progressed to overt diabetes and exhibited a greater risk of MACE (adjusted HR, 1.76; 95% CI, 1.31-2.36) compared with patients who remained prediabetic.
In patients with cancer who received ACT, those who had prediabetes at baseline and those who progressed to diabetes at follow-up had an increased risk of MACE. The optimization of cardiovascular risk factor management, including prediabetes, should be considered in patients with cancer who are treated before and during ACT to reduce cardiovascular risk.
Patients with cancer who have preexisting diabetes have a higher risk of cardiovascular events, and prediabetes is often overlooked. In this study of 12,649 patients with cancer identified in the Clinical Data Analysis Reporting System of Hong Kong who were receiving treatment with anthracycline drugs, prediabetes was correlated with increased deaths from cardiovascular disease and/or hospitalizations for heart failure. Patients who progressed from prediabetes to diabetes within 2 years had an increased risk of combined hospitalization for heart failure and death from cardiovascular disease. These findings indicate the importance of paying greater attention to cardiovascular risk factors, including how prediabetes is managed, in patients who have cancer and are receiving chemotherapy with anthracyclines, emphasizing the need for surveillance, follow-up strategies, and consideration of prediabetes management in cancer care.
Background Data comparing outcomes in heart failure (HF) across Asia are limited. We examined regional variation in mortality among patients with HF enrolled in the ASIAN-HF (Asian Sudden Cardiac ...Death in Heart Failure) registry with separate analyses for those with reduced ejection fraction (EF; <40%) versus preserved EF (≥50%). Methods and Results The ASIAN-HF registry is a prospective longitudinal study. Participants with symptomatic HF were recruited from 46 secondary care centers in 3 Asian regions: South Asia (India), Southeast Asia (Thailand, Malaysia, Philippines, Indonesia, Singapore), and Northeast Asia (South Korea, Japan, Taiwan, Hong Kong, China). Overall, 6480 patients aged >18 years with symptomatic HF were recruited (mean age: 61.6±13.3 years; 27% women; 81% with HF and reduced rEF). The primary outcome was 1-year all-cause mortality. Striking regional variations in baseline characteristics and outcomes were observed. Regardless of HF type, Southeast Asians had the highest burden of comorbidities, particularly diabetes mellitus and chronic kidney disease, despite being younger than Northeast Asian participants. One-year, crude, all-cause mortality for the whole population was 9.6%, higher in patients with HF and reduced EF (10.6%) than in those with HF and preserved EF (5.4%). One-year, all-cause mortality was significantly higher in Southeast Asian patients (13.0%), compared with South Asian (7.5%) and Northeast Asian patients (7.4%;
<0.001). Well-known predictors of death accounted for only 44.2% of the variation in risk of mortality. Conclusions This first multinational prospective study shows that the outcomes in Asian patients with both HF and reduced or preserved EF are poor overall and worst in Southeast Asian patients. Region-specific risk factors and gaps in guideline-directed therapy should be addressed to potentially improve outcomes. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT01633398.
Little is known regarding the impact of socioeconomic factors on the use of evidence-based therapies and outcomes in patients with heart failure with reduced ejection fraction across Asia.
We ...investigated the association of both patient-level (household income, education levels) and country-level (regional income level by World Bank classification, income disparity by Gini index) socioeconomic indicators on use of guideline-directed therapy and clinical outcomes (composite of 1-year mortality or HF hospitalization, quality of life) in the prospective multinational ASIAN-HF study (Asian Sudden Cardiac Death in Heart Failure).
Among 4540 patients (mean age: 60±13 years, 23% women) with heart failure with reduced ejection fraction, 39% lived in low-income regions; 34% in regions with high-income disparity (Gini ≥42.8%); 64.4% had low monthly household income (<US$1000); and 29.5% had no/only primary education. The largest disparity in treatment across regional income levels pertained to β-blocker and device therapies, with patients from low-income regions being less likely to receive these treatments compared with those from high-income regions and even greater disparity among patients with lower education status and lower household income within each regional income strata. Higher country- and patient-level socioeconomic indicators related to higher quality of life scores and lower risk of the primary composite outcome. Notably, we found a significant interaction between regional income level and both household income and education status (
<0.001 for both), where the association of low household income and low education status with poor outcomes was more pronounced in high-income compared with lower income regions.
These findings highlight the importance of socioeconomic determinants among patients with heart failure in Asia and suggest that attention should be paid to address disparities in access to care among the poor and less educated, including those from wealthy regions. Registration: URL: https://clinicaltrials.gov; Unique Identifier: NCT01633398.
PDF
