Management of Hormone Receptor-Positive Metastatic Breast Cancer

Hormone-receptor positive HER2-negative breast cancer constitutes about 2/3 of breast cancer. Hormonal therapy such as tamoxifen and aromatase inhibitors has been the main stay of treatment which gives favorable quality of life compared with traditional chemotherapy. However, the efficacy of subsequent hormonal therapy declines rapidly after the patients develops resistance to first line hormonal therapy. In recent years, there have been many breakthrough in the treatment of this cancer. A number of targeted agents including CDK4/6 inhibitor and mTOR inhibitor are now part of standard treatment paradigm to help prolong the use of hormonal therapy. New understanding in potential biomarker of resistance such as ESR1 mutation or PIK3CA mutation has also empowered us to develops personalized approach in treatment. This article will explain the treatment logistic for this cancer, current knowledge in hormonal resistance, findings of key clinical trials that define the current treatment paradigm, efficacy and major side effect precaution of the targeted agents, and the unmet needs

Systemic Management of Advanced Hepatocellular Carcinoma Patients: The Role of Multi-Targeted Anti-Angiogenic Inhibitors

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Mesenchymal adenomatous polyposis coli plays critical and diverse roles in regulating lung development.

BackgroundAdenomatous polyposis coli (Apc) is a tumor suppressor that inhibits Wnt/Ctnnb1. Mutations of Apc will not only lead to familial adenomatous polyposis with associated epithelial lesions, but will also cause aggressive fibromatosis in mesenchymal cells. However, the roles of Apc in regulating mesenchymal cell biology and organogenesis during development are unknown.ResultsWe have specifically deleted the Apc gene in lung mesenchymal cells during early lung development in mice. Loss of Apc function resulted in immediate mesenchymal cell hyperproliferation through abnormal activation of Wnt/Ctnnb1, followed by a subsequent inhibition of cell proliferation due to cell cycle arrest at G0/G1, which was caused by a mechanism independent of Wnt/Ctnnb1. Meanwhile, abrogation of Apc also disrupted lung mesenchymal cell differentiation, including decreased airway and vascular smooth muscle cells, the presence of Sox9-positive mesenchymal cells in the peripheral lung, and excessive versican production. Moreover, lung epithelial branching morphogenesis was drastically inhibited due to disrupted Bmp4-Fgf10 morphogen production and regulation in surrounding lung mesenchyme. Lastly, lung mesenchyme-specific Apc conditional knockout also resulted in altered lung vasculogenesis and disrupted pulmonary vascular continuity through a paracrine mechanism, leading to massive pulmonary hemorrhage and lethality at mid-gestation when the pulmonary circulation should have started.ConclusionsOur study suggests that Apc in lung mesenchyme plays central roles in coordinating the proper development of several quite different cellular compartments including lung epithelial branching and pulmonary vascular circulation during lung organogenesis

Comparison of DNA methylation profiles from saliva in Coeliac disease and non-coeliac disease individuals

Coeliac disease (CD) is a autoimmune disease characterised by mucosal inflammation in the small intestine in response to dietary gluten. Genetic factors play a key role with CD individuals carrying either the HLADQ2 or HLA-DQ8 haplotype, however these haplotypes are present in half the general population making them necessary but insufficient to cause CD. Epigenetic modifications, including DNA methylation that can change in response to environmental exposure could help to explain how interactions between genes and environmental factors combine to trigger disease development. Identifying changes in DNA methylation profiles in individuals with CD could help discover novel genomic regions involved in the onset and development of CD

Impact of salt crystal size on in-mouth delivery of sodium and saltiness perception from snack foods

Fried, sliced potato crisps were flavored with sodium chloride of varying size fractions to investigate the impact of salt crystal size on the delivery rate of sodium to the tongue and resultant saltiness, measured over 65 s with a defined chew protocol (three chews, then holding the bolus in the mouth without swallowing). Salt crystal size impacted upon the delivery rate and perceived saltiness. The smallest crystal size fraction dissolved and diffused throughout the mouth to the tongue saliva faster than the medium and the largest ones; the smallest crystal size fraction also had the highest maximum concentration and greatest total sodium. These results correlated well with the sensory perceived saltiness, where the smallest crystal size fraction resulted in the fastest Tmax, highest maximum saltiness intensity and maximum total saltiness. The different delivery rates can be explained by differential dissolution kinetics and enhanced mass transfer of sodium across the saliva

Brca1 Controls Homology-Directed DNA Repair

AbstractGermline mutations in BRCA1 confer a high risk of breast and ovarian tumors. The role of BRCA1 in tumor suppression is not yet understood, but both transcription and repair functions have been ascribed. Evidence that BRCA1 is involved in DNA repair stems from its association with RAD51, a homolog of the yeast protein involved in the repair of DNA double-strand breaks (DSBs) by homologous recombination. We report here that Brca1-deficient mouse embryonic stem cells have impaired repair of chromosomal DSBs by homologous recombination. The relative frequencies of homologous and nonhomologous DNA integration and DSB repair were also altered. The results demonstrate a caretaker role for BRCA1 in preserving genomic integrity by promoting homologous recombination and limiting mutagenic nonhomologous repair processes

Menopausal hormone therapy is associated with having high blood pressure in postmenopausal women : observational cohort study

Background: The relationship between menopausal hormone therapy (MHT) and cardiovascular risk remains controversial, with a number of studies advocating the use of MHT in reducing risk of cardiovascular diseases, while others have shown it to increase risk. The aim of this study was to determine the association between menopausal hormone therapy and high blood pressure. Methods and Findings: A total of 43,405 postmenopausal women were included in the study. Baseline data for these women were sourced from the 45 and Up Study, Australia, a large scale study of healthy ageing. These women reported being postmenopausal, having an intact uterus, and had not been diagnosed with high blood pressure prior to menopause. Odds ratios for the association between MHT use and having high blood pressure were estimated using logistic regression, stratified by age (<56 years, 56-61 years, 62-70 years and over 71 years) and adjusted for demographic and lifestyle factors. MHT use was associated with higher odds of having high blood pressure: past menopausal hormone therapy use: <56 years (adjusted odds ratio 1.59, 99% confidence interval 1.15 to 2.20); 56-61 years (1.58, 1.31 to 1.90); 62-70 years (1.26, 1.10 to 1.44). Increased duration of hormone use was associated with higher odds of having high blood pressure, with the effect of hormone therapy use diminishing with increasing age. Conclusions: Menopausal hormone therapy use is associated with significantly higher odds of having high blood pressure, and the odds increase with increased duration of use. High blood pressure should be conveyed as a health risk for people considering MHT use

Transcriptional Control of Adipose Lipid Handling by IRF4

SummaryAdipocytes store triglyceride during periods of nutritional affluence and release free fatty acids during fasting through coordinated cycles of lipogenesis and lipolysis. While much is known about the acute regulation of these processes during fasting and feeding, less is understood about the transcriptional basis by which adipocytes control lipid handling. Here, we show that interferon regulatory factor 4 (IRF4) is a critical determinant of the transcriptional response to nutrient availability in adipocytes. Fasting induces IRF4 in an insulin- and FoxO1-dependent manner. IRF4 is required for lipolysis, at least in part due to direct effects on the expression of adipocyte triglyceride lipase and hormone-sensitive lipase. Conversely, reduction of IRF4 enhances lipid synthesis. Mice lacking adipocyte IRF4 exhibit increased adiposity and deficient lipolysis. These studies establish a link between IRF4 and the disposition of calories in adipose tissue, with consequences for systemic metabolic homeostasis

The Relationship of Pyroptosis-Related Genes, Patient Outcomes, and Tumor-Infiltrating Cells in Bladder Urothelial Carcinoma (BLCA)

Introduction: The role of pyroptosis and its effects on tumor-infiltrating cells (TICs) in the pathogenesis and treatment outcomes of patients with bladder urothelial carcinoma (BLCA) remains unclear.Methods: We conducted a bioinformatics analysis on the pyroptosis-related genes (PRGs) and TICs using data from public domains, and evaluated their impact on the pathogenesis and clinical outcomes of BLCA patients. A risk score based on PRGs and a prognostic risk model that incorporated patient demographics, tumor characteristics, and differentially expressed genes (DEGs) were developed.Results: Twenty-three DEGs of 52 PRGs were identified in BLCA and normal samples from the TCGA database. Missense mutations and single nucleotide polymorphisms in PRGs are the most common genetic abnormalities. Patients with high PRG risk scores showed an inferior survival compared to those with low risk scores. The prognostic risk model based on patient demographics, tumor characteristics, and DEGs showed good predictive values for patient survival at 1, 3, and 5 years in BLCA patients. Caspase-8 (CASP8) was the only intersection gene of the prognostic genes, DEGs, and different genes expressed in tissue. Patients with a high CASP8 expression had improved survival, and an increased CASP8 expression level was observed in activated CD4 memory T cells, follicular T helper cells, resting NK cells, M0 macrophages, and activated dendritic cells. CASP8 expression also showed a positive correlation with the IL7R expression—a key cell marker of CD4 memory T cells. CASP8 expression also showed correlations with immune checkpoints (PDCD1, CD274, and CTLA4) and response to immune checkpoint inhibitors.Conclusion: Our data suggest that PRGs, especially CASP8, showed strong associations with patient outcomes and TICs in BLCA. If validated, these results could potentially aid in the prognostication and guide treatment in BLCA patients

Endovascular stent grafting and open surgical replacement for chronic thoracic aortic aneurysms: a systematic review and prospective cohort study

Background: The management of chronic thoracic aortic aneurysms includes conservative management, watchful waiting, endovascular stent grafting and open surgical replacement. The Effective Treatments for Thoracic Aortic Aneurysms (ETTAA) study investigates timing and intervention choice. Objective: To describe pre- and post-intervention management of and outcomes for chronic thoracic aortic aneurysms. Design: A systematic review of intervention effects; a Delphi study of 360 case scenarios based on aneurysm size, location, age, operative risk and connective tissue disorders; and a prospective cohort study of growth, clinical outcomes, costs and quality of life. Setting: Thirty NHS vascular/cardiothoracic units. Participants: Patients aged > 17 years who had existing or new aneurysms of ≥ 4 cm in diameter in the arch, descending or thoracoabdominal aorta. Interventions: Endovascular stent grafting and open surgical replacement. Main outcomes: Pre-intervention aneurysm growth, pre-/post-intervention survival, clinical events, readmissions and quality of life; and descriptive statistics for costs and quality-adjusted life-years over 12 months and value of information using a propensity score-matched subsample. Results: The review identified five comparative cohort studies (endovascular stent grafting patients, n = 3955; open surgical replacement patients, n = 21,197). Pooled short-term all-cause mortality favoured endovascular stent grafting (odds ratio 0.71, 95% confidence interval 0.51 to 0.98; no heterogeneity). Data on survival beyond 30 days were mixed. Fewer short-term complications were reported with endovascular stent grafting. The Delphi study included 20 experts (13 centres). For patients with aneurysms of ≤ 6.0 cm in diameter, watchful waiting was preferred. For patients with aneurysms of > 6.0 cm, open surgical replacement was preferred in the arch, except for elderly or high-risk patients, and in the descending aorta if patients had connective tissue disorders. Otherwise endovascular stent grafting was preferred. Between 2014 and 2018, 886 patients were recruited (watchful waiting, n = 489; conservative management, n = 112; endovascular stent grafting, n = 150; open surgical replacement, n = 135). Pre-intervention death rate was 8.6% per patient-year; 49.6% of deaths were aneurysm related. Death rates were higher for women (hazard ratio 1.79, 95% confidence interval 1.25 to 2.57; p = 0.001) and older patients (age 61–70 years: hazard ratio 2.50, 95% confidence interval 0.76 to 5.43; age 71–80 years: hazard ratio 3.49, 95% confidence interval 1.26 to 9.66; age > 80 years: hazard ratio 7.01, 95% confidence interval 2.50 to 19.62; all compared with age < 60 years, p < 0.001) and per 1-cm increase in diameter (hazard ratio 1.90, 95% confidence interval 1.65 to 2.18; p = 0.001). The results were similar for aneurysm-related deaths. Decline per year in quality of life was greater for older patients (additional change –0.013 per decade increase in age, 95% confidence interval –0.019 to –0.007; p < 0.001) and smokers (additional change for ex-smokers compared with non-smokers 0.003, 95% confidence interval –0.026 to 0.032; additional change for current smokers compared with non-smokers –0.034, 95% confidence interval –0.057 to –0.01; p = 0.004). At the time of intervention, endovascular stent grafting patients were older (age difference 7.1 years; 95% confidence interval 4.7 to 9.5 years; p < 0.001) and more likely to be smokers (75.8% vs. 66.4%; p = 0.080), have valve disease (89.9% vs. 71.6%; p < 0.0001), have chronic obstructive pulmonary disease (21.3% vs. 13.3%; p = 0.087), be at New York Heart Association stage III/IV (22.3% vs. 16.0%; p = 0.217), have lower levels of haemoglobin (difference –6.8 g/l, 95% confidence interval –11.2 to –2.4 g/l; p = 0.003) and take statins (69.3% vs. 42.2%; p < 0.0001). Ten (6.7%) endovascular stent grafting and 15 (11.1%) open surgical replacement patients died within 30 days of the procedure (p = 0.2107). One-year overall survival was 82.5% (95% confidence interval 75.2% to 87.8%) after endovascular stent grafting and 79.3% (95% confidence interval 71.1% to 85.4%) after open surgical replacement. Variables affecting survival were aneurysm site, age, New York Heart Association stage and time waiting for procedure. For endovascular stent grafting, utility decreased slightly, by –0.017 (95% confidence interval –0.062 to 0.027), in the first 6 weeks. For open surgical replacement, there was a substantial decrease of –0.160 (95% confidence interval –0.199 to –0.121; p < 0.001) up to 6 weeks after the procedure. Over 12 months endovascular stent grafting was less costly, with higher quality-adjusted life-years. Formal economic analysis was unfeasible. Limitations: The study was limited by small numbers of patients receiving interventions and because only 53% of patients were suitable for both interventions. Conclusions: Small (4–6 cm) aneurysms require close observation. Larger (> 6 cm) aneurysms require intervention without delay. Endovascular stent grafting and open surgical replacement were successful for carefully selected patients, but cost comparisons were unfeasible. The choice of intervention is well established, but the timing of intervention remains challenging. Future work: Further research should include an analysis of the risk factors for growth/rupture and long-term outcomes. Trial registration: Current Controlled Trials ISRCTN04044627 and NCT02010892