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Background: Neoadjuvant trastuzumab/pertuzumab (HP) plus chemotherapy for HER2-positive breast cancer (BC) achieved promising efficacy. The additional cardiotoxicity still existed. Brecan study evaluated the efficacy and safety of neoadjuvant pegylated liposomal doxorubicin (PLD)/cyclophosphamide and sequential nab-paclitaxel based on HP (PLD/C/HP-nabP/HP)., Patients and Methods: Brecan was a single-arm phase II study. Eligible patients with stages IIA-IIIC HER2-positive BC received 4 cycles of PLD, cyclophosphamide, and HP, followed by 4 cycles of nab-paclitaxel and HP. Definitive surgery was scheduled after 21 days for patients completing treatment or experiencing intolerable toxicity. The primary endpoint was the pathological complete response (pCR)., Results: Between January 2020 and December 2021, 96 patients were enrolled. Ninety-five (99.0%) patients received 8 cycles of neoadjuvant therapy and all underwent surgery with 45 (46.9%) breast-conserving surgery and 51 (53.1%) mastectomy. The pCR was 80.2% (95%CI, 71.2%-87.0%). Four (4.2%) experienced left ventricular insufficiency with an absolute decline in LVEF (43%-49%). No congestive heart failure and ≥grade 3 cardiac toxicity occurred. The objective response rate was 85.4% (95%CI, 77.0%-91.1%), including 57 (59.4%) complete responses and 25 (26.0%) partial responses. The disease control rate was 99.0% (95%CI, 94.3%-99.8%). For overall safety, ≥grade 3 AEs occurred in 30 (31.3%) and mainly included neutropenia (30.2%) and asthenia (8.3%). No treatment-related deaths occurred. Notably, age of >30 (P = .01; OR = 5.086; 95%CI, 1.44-17.965) and HER2 IHC 3+ (P = .02; OR = 4.398; 95%CI, 1.286-15.002) were independent predictors for superior pCR (ClinicalTrials.gov Identifier NCT05346107)., Conclusion: Brecan study demonstrated the encouraging safety and efficacy of neoadjuvant PLD/C/HP-nabP/HP, suggesting a potential therapeutic option in HER2-positive BC., (© The Author(s) 2023. Published by Oxford University Press.)

Human prostate stem and progenitor cells express estrogen receptor (ER)α and ERβ and exhibit proliferative responses to estrogens. In this study, membrane-initiated estrogen signaling was interrogated in human prostate stem/progenitor cells enriched from primary epithelial cultures and stem-like cell lines from benign and cancerous prostates. Subcellular fractionation and proximity ligation assays localized ERα and ERβ to the cell membrane with caveolin-1 interactions. Exposure to 17β-estradiol (E2) for 15 to 60 minutes led to sequential phosphorylation of signaling molecules in MAPK and AKT pathways, IGF1 receptor, epidermal growth factor receptor, and ERα, thus documenting an intact membrane signalosome that activates diverse downstream cascades. Treatment with an E2-dendrimer conjugate or ICI 182,870 validated E2-mediated actions through membrane ERs. Overexpression and knockdown of ERα or ERβ in stem/progenitor cells identified pathway selectivity; ERα preferentially activated AKT, whereas ERβ selectively activated MAPK cascades. Furthermore, prostate cancer stem-like cells expressed only ERβ, and brief E2 exposure activated MAPK but not AKT cascades. A gene subset selectively regulated by nongenomic E2 signaling was identified in normal prostate progenitor cells that includes BGN, FOSB, FOXQ1, and MAF. Membrane-initiated E2 signaling rapidly modified histone methyltransferases, with MLL1 cleavage observed downstream of phosphorylated AKT and EZH2 phosphorylation downstream of MAPK signaling, which may jointly modify histones to permit rapid gene transcription. Taken together, the present findings document ERα and ERβ membrane-initiated signaling in normal and cancerous human prostate stem/progenitor cells with differential engagement of downstream effectors. These signaling pathways influence normal prostate stem/progenitor cell homeostasis and provide novel therapeutic sites to target the elusive prostate cancer stem cell population., (Copyright © 2019 Endocrine Society.)

Background: The benefits of hospice palliative care (HPC) for end-of-life (EoL) patients have been widely acknowledged in recent years. There is still limited knowledge about cancer patients' willingness toward HPC. This study aimed to investigate the willingness of cancer patients to receive HPC and the influencing factors., Methods: A cross-sectional study was conducted with cancer patients enrolled from teaching hospitals in Taiwan. The questionnaire included demographic characteristics, EoL care preferences, and scales for measuring the willingness to receive HPC, HPC knowledge, and attitude towards HPC. Data were collected by senior nurses and they were analyzed using descriptive and a regression analysis., Results: A total of 148 valid questionnaires were collected. The participants indicated that they 'willing to receive' HPC (mean3.8 on a 5-point scale). The predictors for their willingness to receive HPC were knowledge about HPC (P = 0.001), positive attitude towards HPC (P = 0.008), preference for hospital death (P = 0.022), and preference for quality of life (P = 0.047) as the goal of EoL care. These factors explained 32.7% of the total variance in the willingness to receive HPC., Conclusions: Cancer patients were generally willing to receive HPC. Clinician should discuss EoL care with them earlier. Develop appropriate educational strategies that can provide cancer patients with sufficient and tailored HPC information to develop their knowledge and to create a positive attitude about HPC is necessary, thereby to allow for early HPC intervention and to fulfill the patients' need for HPC., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Bisphenol A (BPA) is a ubiquitous endocrine disruptor exerting lifelong effects on gene expression in rodent prostate cancer (PCa) models. Here, we aimed to determine whether epigenetic events mediating the action of BPA on human prostaspheres enriched in epithelial stem-like/progenitor cells is linked to PCa. We performed genome-wide transcriptome and methylome analyses to identify changes in prostaspheres treated with BPA (10 nM, 200 nM, and 1000 nM) or estradiol-17β (E2) (0.1 nM) for 7 days and validated changes in expression, methylation, and histone marks in parallel-treated prostaspheres. BPA/E2-treatment altered expression of 91 genes but not the methylation status of 485,000 CpG sites in BPA/E2-treated prostaspheres. A panel of 26 genes was found repressed in all treatment groups. Fifteen of them were small nucleolar RNAs with C/D motif (SNORDs), which are noncoding, small nucleolar RNAs known to regulate ribosomal RNA assembly and function. Ten of the most down-regulated SNORDs were further studied. All 10 were confirmed repressed by BPA, but only 3 ratified as E2-repressed. SNORD suppression showed no correlation with methylation status changes in CpG sites in gene regulatory regions. Instead, BPA-induced gene silencing was found to associate with altered recruitments of H3K9me3, H3K4me3, and H3K27me3 to 5'-regulatory/exonic sequences of 5 SNORDs. Expression of 4 out of these 5 SNORDs (SNORD59A, SNORD82, SNORD116, and SNORD117) was shown to be reduced in PCa compared with adjacent normal tissue. This study reveals a novel and unique action of BPA in disrupting expression of PCa-associated SNORDs and a putative mechanism for reprogramming the prostasphere epigenome via histone modification.

Major advances during the past decade have permitted a clearer understanding of processes that regulate stem cell self-renewal and lineage commitment toward differentiated progeny that populate all tissues. Considerable evidence has also accumulated to indicate that aberrations in the stem and progenitor cell populations can lead to increased cancer risk in specific organs systems. It is long recognized that environmental factors play a major role in cancer etiology, and emerging data suggest that endocrine-disrupting chemicals (EDCs) may contribute to an increased cancer risk. Using the prostate gland as a model system, the present review highlights recent data that find that estrogens and EDCs can reprogram prostate stem and progenitor cell populations, leading to increased cancer susceptibility. We propose that stem cell programming during early development in hormone-regulated tissues may lead to heightened sensitivity to early-life EDC exposures and that aberrant stem cell reprogramming by EDCs may contribute to the developmental basis of adult cancer risk.

Previous studies in rodent models have shown that early-life exposure to bisphenol A (BPA) reprograms the prostate and enhances its susceptibility to hormonal carcinogenesis with aging. To determine whether the human prostate is similarly sensitive to BPA, the current study used human prostate epithelial stem-like cells cultured from prostates of young, disease-free donors. Similar to estradiol-17β (E2), BPA increased stem-progenitor cell self-renewal and expression of stem-related genes in a dose-dependent manner. Further, 10 nM BPA and E2 possessed equimolar membrane-initiated signaling with robust induction of p-Akt and p-Erk at 15 minutes. To assess in vivo carcinogenicity, human prostate stem-progenitor cells combined with rat mesenchyme were grown as renal grafts in nude mice, forming normal human prostate epithelium at 1 month. Developmental BPA exposure was achieved through oral administration of 100 or 250 μg BPA/kg body weight to hosts for 2 weeks after grafting, producing free BPA levels of 0.39 and 1.35 ng/mL serum, respectively. Carcinogenesis was driven by testosterone plus E2 treatment for 2 to 4 months to model rising E2 levels in aging men. The incidence of high-grade prostate intraepithelial neoplasia and adenocarcinoma markedly increased from 13% in oil-fed controls to 33% to 36% in grafts exposed in vivo to BPA (P < .05). Continuous developmental BPA exposure through in vitro (200 nM) plus in vivo (250 μg/kg body weight) treatments increased high-grade prostate intraepithelial neoplasia/cancer incidence to 45% (P < .01). Together, the present findings demonstrate that human prostate stem-progenitor cells are direct BPA targets and that developmental exposure to BPA at low doses increases hormone-dependent cancer risk in the human prostate epithelium.

Objective: The aim of the study was to explore the relationships between truth telling, patients' psycho-spiritual state and do not resuscitate consent., Methods: Cancer patients who had consulted with hospice care at the National Taiwan University Hospital in Taipei were approached. Patients excluded from the study included those who were unable to give informed consent, not well enough to complete the questionnaire survey, would be discharged within 24 h or who could not communicate in Chinese or Taiwanese. The 90 patients recruited for the study were grouped according to their awareness of their terminal prognosis ('aware' or 'unaware'). A structured questionnaire was used for data collection, including questions on uncertainty, the Hospital Anxiety and Depression Scale and the Spiritual Well-being Scale., Results: Truth telling reduced cancer patients' uncertainty (P = 0.023) and anxiety (P = 0.005), and did not affect their state of spiritual well-being (P = 0.868). Before hospice referral, patients aware of their prognosis were more likely to sign the do not resuscitate consent (P = 0.040). In the aware group, 28% signed the do not resuscitate themselves, whereas in the unaware group, only 5% signed the do not resuscitate themselves (P = 0.031). The median time between signing the do not resuscitate and death was 29 days in the aware group and 16 days in the unaware group. Data revealed that 82% of the aware group died having given their do not resuscitate consent and did not receive a vasopressor or intubation, whereas only 52% of the unaware group died in this manner., Conclusions: Truth telling can reduce cancer patients' uncertainty and anxiety. Patients aware of their prognosis tended to sign the do not resuscitate consent willingly and had more dignified and peaceful deaths.

Objective: Community physicians have a vital role in delivering palliative care, yet their willingness and factors that influence its provision have rarely been explored. Our aims were to identify the willingness of community physicians to provide palliative care for patients with terminal cancer and to investigate the factors that influence their willingness to provide such care., Methods: Through a structured questionnaire, this nationwide study surveyed 708 community physicians who were potential pilots to provide palliative care. Four hundred and ten valid questionnaires (58.0%) were retrieved and analysed., Results: The majority of respondents expressed a willingness (92.4%) to provide palliative care if they encountered patients with terminal cancer. However, they would limit their services to consultation (83.4%) and referral (86.8%), and were less likely to see patients and prescribe medicine (62.0%), to provide phone follow-ups (45.6%), to provide home visits (42.2%) or to offer bereavement care for the family (35.1%). The results of stepwise logistic regression analysis for the willingness to provide home visits showed that 'less perception of barriers', 'family medicine specialist' and 'older than 50 years' significantly predicted higher willingness, while 'female' predicted lower willingness. There was no significant association between the willingness and the knowledge score., Conclusions: Community physicians' beliefs and experience in palliative care rather than their knowledge influence their willingness to provide palliative care for patients with terminal cancer. Only through active participation in the real-world clinical setting and active health policy administration can community physicians overcome obstacles to providing palliative care.

The present study sought to determine whether estrogens with testosterone support are sufficient to transform the normal human prostate epithelium and promote progression to invasive adenocarcinoma using a novel chimeric prostate model. Adult prostate stem/early progenitor cells were isolated from normal human prostates through prostasphere formation in three-dimensional culture. The stem/early progenitor cell status and clonality of prostasphere cells was confirmed by immunocytochemistry and Hoechst staining. Normal prostate progenitor cells were found to express estrogen receptor α, estrogen receptor β, and G protein-coupled receptor 30 mRNA and protein and were responsive to 1 nm estradiol-17β with increased numbers and prostasphere size, implicating them as direct estrogen targets. Recombinants of human prostate progenitor cells with rat urogenital sinus mesenchyme formed chimeric prostate tissue in vivo under the renal capsule of nude mice. Cytodifferentiation of human prostate progenitor cells in chimeric tissues was confirmed by immunohistochemistry using epithelial cell markers (p63, cytokeratin 8/18, and androgen receptor), whereas human origin and functional differentiation were confirmed by expression of human nuclear antigen and prostate-specific antigen, respectively. Once mature tissues formed, the hosts were exposed to elevated testosterone and estradiol-17β for 1-4 months, and prostate pathology was longitudinally monitored. Induction of prostate cancer in the human stem/progenitor cell-generated prostatic tissue was observed over time, progressing from normal histology to epithelial hyperplasia, prostate intraepithelial neoplasia, and prostate cancer with local renal invasion. These findings provide the first direct evidence that human prostate progenitor cells are estrogen targets and that estradiol in an androgen-supported milieu is a carcinogen for human prostate epithelium.

Background: Family physicians in Taiwan have expressed low willingness to provide palliative home care., Objective: To explore the medical needs of terminal cancer patients in home care and thus clarify the role and tasks of family physicians in providing palliative home care., Methods: Seventy-seven terminal cancer patients discharged from a palliative care unit from July 2003 to July 2004 who had received family physician home visits were enrolled. A structured assessment form was applied to each visit., Results: Under the collaboration by the palliative home care team and family physicians, the average interval from discharge to the first physician visit was 20.3 days and the average interval between physician visits was 37.9 days. The patients had an average of 5.9 active medical problems: the most frequent problem was pain (58.4%), followed by anorexia (42.9%) and constipation (42.9%). Forty-four patients (58.7%) died at home, while 31 patients (41.3%) eventually died in the hospital. Through multiple logistic regression analysis, patients who had never been rehospitalized [odds ratio (OR) = 12.95, 95% confidence interval (CI) = 3.41-49.19], who preferred to die at home (OR = 4.68, 95% CI = 1.21-18.09) and who were most functionally dependent with an Eastern Cooperative Oncology Group scale = 4 (OR = 4.36, 95% CI = 1.02-18.64) were found to be most likely to die at home under this care model., Conclusion: Through palliative home care with the participation of family physicians, patients' preference could be a significant determinant of home death. Our finding can be helpful to the establishment of an ethical care model for terminal cancer patients.

Background: Increased growth and contraction of vascular smooth muscle cells (VSMCs) are major abnormalities in many vascular disorders. To investigate the signaling pathways that mediate these processes, we studied the expression of smooth muscle myosin light chain kinase (smMLCK) in VSMCs., Methods: Primary cultured VSMCs isolated from normotensive Wistar-Kyoto (WKY) rats were treated with angiotensin II (Ang II). smMLCK expression was examined in the cells using western blot analysis. In vivo, a specific inhibitor of smMLCK or MAP kinase kinase (MEK) was delivered to spontaneously hypertensive rats (SHRs) using an osmotic pump, and their blood pressures were measured using tail-cuff sphygmomanometry., Results: Expression of smMLCK protein is rapidly increased by Ang II, an important agonist responsible for increased vasoconstriction and vascular remodeling, in concert with increased myosin light chain phosphorylation. Inhibiting Ang II type 1 (AT1) receptor, Ras, or MEK blocked the Ang II-induced increase in smMLCK expression. In vivo, inhibiting MEK decreased smMLCK expression, blood pressure, and vascular thickening in SHRs. Moreover, inhibiting smMLCK activity decreased blood pressure and smooth muscle mass in arteries in SHRs., Conclusions: The regulation of smMLCK expression by Ang II via Ras signaling is important in the regulation of vascular remodeling and blood pressure. Targeting this pathway could be an effective strategy for developing novel therapeutics to treat hypertension.

Background: Early treatment with captopril prevents the development of hypertension by inhibiting the generation of angiotensin II and smooth muscle contraction. Although smooth muscle contraction is regulated by myosin light chain phosphorylation (MLC-P), the role of MLC-P in captopril effects in hypertension has not been described. Therefore, we treated spontaneously hypertensive rats (SHR) with captopril and investigated the effects of this agent on downstream signaling., Methods: Male SHR (n = 12) were treated with captopril (3.7 mmol/L in drinking water) beginning in utero and continuing up to 12 weeks of age. Age- and sex-matched untreated SHR and Wistar-Kyoto (WKY) rats were used as controls. Rats were split into three subgroups and were sacrificed at 12, 18, or 24 weeks of age. Systolic blood pressure, left ventricular weight, and body weight were measured. Mesenteric arteries were removed for histologic and biochemical studies., Results: At 12 weeks, captopril significantly decreased systolic blood pressure (from 198 +/- 10 to 125+/-16 mm Hg), reduced left ventricular weight-to-body weight ratios (from 2.94 +/- 0.06 to 2.17 +/- 0.08 mg/g), and prevented vascular remodeling in mesenteric arteries in SHR. Ras expression, extracellular receptor kinase phosphorylation (ERK-P), myosin light chain kinase (MLCK) expression, and MLC-P were all significantly increased in mesenteric arteries in untreated SHR compared with WKY rats. Early captopril treatment in SHR significantly inhibited Ras and MLCK expression at all ages and decreased ERK-P and MLC-P at 12 and 18 weeks in mesenteric arteries., Conclusions: These data demonstrate that the antihypertensive effects of captopril are correlated with inhibition of Ras-regulated ERK activation, MLCK expression, and MLC-P.

Angiotensin II (Ang II) and transforming growth factor-beta (TGF-beta) modulate cell growth and metabolism. Our objective was to evaluate the effect of Ang II on the characteristics and expression of TGF-beta receptors on vascular smooth muscle cells (VSMC) from Wistar-Kyoto rats. The addition of TGF-beta1 elicited a biphasic response on DNA synthesis in cultured VSMC in the absence of Ang II, but TGF-beta1 did not stimulate DNA synthesis in the presence of Ang II. TGF-beta binding data showed that Ang II increased the specific binding of 125I-TGF-beta1 by enhancing the expression of lower affinity receptors and increasing the number of binding sites. Ang II alone did not stimulate DNA synthesis in these cultures. However, Ang II significantly stimulated DNA synthesis after the inhibition of endogenous TGF-beta with a neutralizing antibody. The DNA synthesis stimulated by phorbol ester milisterol (PMA) was not affected by the TGF-beta neutralizing antibody. Affinity labeling data revealed receptor-ligand complexes of 280, 85, and 70 kDa, corresponding to TGF-beta type III, II, and I receptors, respectively. Incubation of VSMC with Ang II but not with PMA markedly increased the expression of the TGF-beta type I receptor. Reverse transcription and polymerase chain reaction data also indicated that Ang II, but not PMA, significantly increased the expression of TGF-beta type I receptor mRNA. Results suggest that Ang II increases the binding of TGF-beta with upregulation of TGF-beta type I receptor via a C-kinase-independent pathway. The enhanced expression of the TGF-beta type I receptor may counteract Ang II-promoted growth of VSMC.