Uncovering Patient and Caregiver Goals for Goal-Concordant Care in Kidney Therapy Decisions.

CONTEXT: In kidney therapy (KT) decisions, goal-concordant decision-making is recognized to be important, yet alignment with patients' goals during dialysis initiation is not always achieved. OBJECTIVES: To explore older patients' and caregivers' hopes, goals, and fears related to KT and communication of these elements with members of their health care team. METHODS: The study included patients aged ≥75 years with an estimated glomerular filtration rate ≤25 mL/min/1.73 m2 and their caregivers enrolled in a palliative care intervention for KT decision-making. Patients and caregivers were asked open-ended questions about their hopes, goals, and fears related to KT decisions. A survey assessed if patients shared their goals with members of their health care team. Qualitative data underwent content analysis, supplemented by demographic descriptive statistics. RESULTS: The mean age of patients (n = 26) was 82.7 (±5.7) years, and caregivers (n = 15) had a mean age of 66.4 (±13.7) years. Among the participants, 13 patients and 11 caregivers were women, and 20 patients and 12 caregivers were White. Four themes emerged: (1) Maintaining things as good as they are by avoiding dialysis-related burdens; (2) seeking longevity while avoiding dialysis; (3) avoiding pain, symptoms, and body disfigurement; and (4) deferring decision-making. Patients rarely had shared their goals with the key members of their health care team. CONCLUSION: Patients and caregivers prioritize maintaining quality of life, deferring decision-making regarding dialysis, and avoiding dialysis-related burdens. These goals are often unshared with their family and health care teams. Given our aging population, urgent action is needed to educate clinicians to actively explore and engage with patient goals in KT decision-making.

Long lasting anxiety following early life stress is dependent on glucocorticoid signaling in zebrafish.

Chronic adversity in early childhood is associated with increased anxiety and a propensity for substance abuse later in adulthood, yet the effects of early life stress (ELS) on brain development remain poorly understood. The zebrafish, Danio rerio, is a powerful model for studying neurodevelopment and stress. Here, we describe a zebrafish model of ELS and identify a role for glucocorticoid signaling during a critical window in development that leads to long-term changes in brain function. Larval fish subjected to chronic stress in early development exhibited increased anxiety-like behavior and elevated glucocorticoid levels later in life. Increased stress-like behavior was only observed when fish were subjected to ELS within a precise time window in early development, revealing a temporal critical window of sensitivity. Moreover, enhanced anxiety-like behavior only emerges after two months post-ELS, revealing a developmentally specified delay in the effects of ELS. ELS leads to increased levels of baseline cortisol, and resulted in a dysregulation of cortisol receptors' mRNA expression, suggesting long-term effects on cortisol signaling. Together, these findings reveal a 'critical window' for ELS to affect developmental reprogramming of the glucocorticoid receptor pathway, resulting in chronic elevated stress.

Clinical Factors Affecting Bevacizumab Efficacy With and Without Conventional Chemotherapy in Metastatic Colon Cancer.

PURPOSE: Bevacizumab (BZ) combined with first line chemotherapy (CC) has shown good clinical outcomes in metastatic colorectal cancer (mCRC). Overall survival (OS) and/or progression free survival in mCRC patients receiving BZ with or without 5FU-based CC is thought to be affected by clinical and morphological factor(s). PATIENTS AND METHODS: We reviewed retrospective medical records of all consecutive mCRC patients treated with BZ with or without CC at tertiary care center between 2003 and 2009 out of which149 patients (m = 77, f = 72) were eligible. RESULTS: Our study population had a mean age at diagnosis of 63.5 years (SD = 11) with median follow-up period of 19.4 months. On initial radiological evaluation following BZ therapy, 56 patients (m = 31, f = 25) had complete or partial response categorized as "early responders." Remaining patients (m = 46, f = 47) who were either stable or showed progressive disease were categorized as "non-responders." Fifty percent among early responders and 60% among non-responders [relative risk (RR) 0.67 (95% confidence interval (CI), 0.43-1.06)] demonstrated disease progression on follow up. There was a slightly better OS among early responders compared to non-responders (median 21.5 months days versus 16.8 months, P = 0.07). Cox regression analysis suggested male sex (RR 0.65, 95% CI, 0.43-0.98), hematochezia (RR 0.63, 95% CI, 0.4-0.98), resectable primary tumor (RR 0.42, 95% CI, 0.24-0.72) and resectable metastatic mass (RR 0.32, 95% CI, 0.14-0.74) were found to be associated with longer OS. Abdominal pain (RR 1.76, 95% CI, 1.1-2.8), accompanying diabetes (RR 1.76, 95% CI, 1.09-2.85), and unexplained weight loss (RR 2.73, 95% CI, 1.73-4.29) were associated with poor OS. CONCLUSIONS: Better OS among mCRC patients with resectable primary and metastatic tumors was seen. This is the first study to demonstrate slightly better outcome in males and negative influence of diabetes on outcome in mCRC treated with BZ.

Chrysin activates Notch1 signaling and suppresses tumor growth of anaplastic thyroid carcinoma in vitro and in vivo.

BACKGROUND: Anaplastic thyroid cancer (ATC) is a very aggressive thyroid gland malignancy with very poor prognosis. It is suspected that the Notch signaling pathway, which is not active in ATC, may have a tumor suppressor function in this neoplasm. However, it remains unknown whether activation of Notch can yield therapeutic efficacies in ATC. METHODS: The purpose of this study was to evaluate the effect of chrysin, a potential Notch inducer identified via high-throughput screening, on ATC both in vitro and in vivo. RESULTS: Chrysin treatment of ATC cells led to a dose-dependent inhibition of cellular growth. Protein and messenger RNA levels of Notch1 and Hes1 (hairy/enhancer of split 1), a downstream Notch1 effector, were both up-regulated with treatment. Luciferase reporter assays incorporating the C promoter-binding factor 1 (CBF1) binding site also confirmed the functional activity of chrysin-induced Notch1. Oral administration of chrysin suppressed the growth of ATC xenografts by an average of 59% compared with the vehicle control group (P = .002). In addition, calculated median time to tumor progression was 11 days for control mice and 21 days for the chrysin treatment group (P = .008). Analysis of chrysin-treated ATC tumors revealed an increase in the active intracellular domain of Notch1 protein. Activation of Notch1 in vivo was associated with the induction of cleaved Poly ADP ribose polymerase (PARP) protein, indicating that the growth inhibition was due to apoptosis. CONCLUSIONS: The novel Notch1 activator chrysin inhibits tumor growth in ATC both in vitro and in vivo. Chrysin could be a promising therapeutic candidate for ATC, and this justifies further clinical studies.

Antiproliferative effect of chrysin on anaplastic thyroid cancer.

BACKGROUND: Anaplastic thyroid cancer (ATC) is an undifferentiated, aggressive malignancy, for which there are no effective therapies. Though ATCs only make up less than 2% of all thyroid cancer cases, they represent over half of the thyroid cancer-related deaths. Chrysin, a natural flavonoid, has recently been reported as a potential anti-cancer agent. However, the effect of this compound on ATC cells is not known. Thus, in this study, we evaluated the antiproliferative nature of chrysin in ATC cells. METHODS: HTH7 and KAT18 cells, derived from patients with ATC, were treated with chrysin (25-50 µM) for up to 6 d. Cell proliferation was measured every 2 d using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Western blot analysis for molecular makers of apoptosis was carried out to investigate the effect and mechanism of Chrysin on ATC. RESULTS: Chrysin inhibited proliferation of HTH7 and KAT18 in a dose- and time-dependent manner. HTH7 and KAT18 cells with Chrysin treatment showed a significant increase in cleaved caspase-3, cleaved PolyADP Ribose Polymerase (PARP), along with a decrease in cyclin D1, Mcl-1, and XIAP. Furthermore, the ratio of Bax to Bcl-2 expression in ATC cells revealed an increase after the treatment. CONCLUSIONS: Chrysin inhibits growth in ATC cells via apoptosis in vitro. Therefore, the natural flavonoid chrysin warrants further clinical investigation as a new potential drug for the treatment for ATC.