Therapeutic upregulation of macroautophagy in cancer cells provides an alternative mechanism for cell death. Prolactin (PRL) and its receptor (PRLR) are considered attractive therapeutic targets ...because of their roles as growth factors in tumor growth and progression. We utilized G129R, an antagonist peptide of PRL, to block activity of the tumoral PRL/PRLR axis, which resulted in inhibition of tumor growth in orthotopic models of human ovarian cancer. Prolonged treatment with G129R induced the accumulation of redundant autolysosomes in 3D cancer spheroids, leading to a type II programmed cell death. This inducible autophagy was a noncanonical beclin-1-independent pathway and was sustained by an astrocytic phosphoprotein (PEA-15) and protein kinase C zeta interactome. Lower levels of tumoral PRL/PRLR in clinical samples were associated with longer patient survival. Our findings provide an understanding of the mechanisms of tumor growth inhibition through targeting PRL/PRLR and may have clinical implications.
Display omitted
•PRLR antagonism by G129R inhibits growth of ovarian cancer or cancer spheroids•Autophagy-related cell death is induced by G129R in cancer spheroids•Pea-15 functions as a tumor suppressor to mediate G129R-induced autophagy•Tumoral PRL/PRLR correlates inversely with autophagic factors in clinical samples
Pharmacological manipulation of autophagy represents a new therapeutic opportunity for cancer. Wen et al. show that blockade of the tumoral PRL/PRLR axis with an antagonist, G129R, induces prolonged autophagy. This inducible autophagy is sustained by the PEA-15 and PKC zeta interactome and leads to type II programmed cell death. There was an inverse correlation between tumoral PRL/PRLR expression and survival of ovarian cancer patients. This study reveals a previously unrecognized mechanism related to targeting the tumoral PRL/PRLR pathway.
Although VEGF-targeted therapies are showing promise, new angiogenesis targets are needed to make additional gains. Here, we show that increased Zeste homolog 2 (EZH2) expression in either tumor ...cells or in tumor vasculature is predictive of poor clinical outcome. The increase in endothelial EZH2 is a direct result of VEGF stimulation by a paracrine circuit that promotes angiogenesis by methylating and silencing vasohibin1 (vash1). Ezh2 silencing in the tumor-associated endothelial cells inhibited angiogenesis mediated by reactivation of VASH1, and reduced ovarian cancer growth, which is further enhanced in combination with ezh2 silencing in tumor cells. Collectively, these data support the potential for targeting ezh2 as an important therapeutic approach.
Display omitted
► EZH2 is a key regulator of tumor angiogenesis ► VEGF stimulation increases EZH2 levels in endothelial cells ► Ezh2 silencing inhibits angiogenesis by activating vash1 ► Ezh2 targeting is an attractive therapeutic approach
Background 2009 pandemic influenza A(H1N1) has led to a global increase in severe respiratory illness. Little is known about kidney outcomes and dialytic requirements in critically ill patients ...infected with pandemic H1N1. Study Design Prospective observational study. Setting & Participants 50 patients with pandemic H1N1 admitted to any of 7 intensive care units in Manitoba, Canada, were prospectively followed. Outcome & Measurements Outcomes were kidney injury and kidney failure defined using RIFLE (risk, injury, failure, loss, end-stage disease) criteria or need for dialysis therapy. Results The pandemic H1N1 group was composed of 50 critically ill patients with pandemic H1N1 with severe respiratory syndrome (47 confirmed cases, 3 probable). Kidney injury, kidney failure, and need for dialysis occurred in 66.7%, 66%, and 11% of patients, respectively. Mortality was 16%. Kidney failure was associated with increased death (OR, 11.29; 95% CI, 1.29-98.9), whereas the need for dialysis was associated with an increase in length of stay (RR, 2.38; 95% CI, 2.13-25.75). Limitations Small population studied from single Canadian province; thus, limited generalizability. Conclusions In critically ill patients with pandemic H1N1, kidney injury, kidney failure, and the need for dialysis are common and associated with an increase in mortality and length of intensive care unit stay.
The risks and benefits of anticoagulation for stroke prevention with atrial fibrillation is clearly delineated in the general population. Little evidence exists for patients with end-stage renal ...disease (ESRD) about whether the extrapolation of these guidelines is appropriate. In patients with ESRD who are undergoing hemodialysis, the rates for both stroke and bleeding are 3 to 10 times higher than that for the general population. Furthermore, the proportion of hemorrhagic to ischemic strokes has increased, making the decision of whether to initiate anticoagulation problematic. In this commentary, we discuss the existing literature for stroke in atrial fibrillation, stroke type, risk reduction with anticoagulation, and bleeding risks in the hemodialysis population. We comment on validated risk stratification models of stroke prevention and bleeding and their applicability to patients undergoing hemodialysis. Finally, we recommend treatment strategies that are based on the existing state of knowledge.
Chronic stress is associated with hormonal changes that are known to affect multiple systems, including the immune and endocrine systems, but the effects of stress on cancer growth and progression ...are not fully understood. Here, we demonstrate that human ovarian cancer cells exposed to either norepinephrine or epinephrine exhibit lower levels of anoikis, the process by which cells enter apoptosis when separated from ECM and neighboring cells. In an orthotopic mouse model of human ovarian cancer, restraint stress and the associated increases in norepinephrine and epinephrine protected the tumor cells from anoikis and promoted their growth by activating focal adhesion kinase (FAK). These effects involved phosphorylation of FAKY397, which was itself associated with actin-dependent Src interaction with membrane-associated FAK. Importantly, in human ovarian cancer patients, behavioral states related to greater adrenergic activity were associated with higher levels of pFAKY397, which was in turn linked to substantially accelerated mortality. These data suggest that FAK modulation by stress hormones, especially norepinephrine and epinephrine, can contribute to tumor progression in patients with ovarian cancer and may point to potential new therapeutic targets for cancer management.
First Nations (FN) patients on peritoneal dialysis experience poor outcomes. Whether discrepancies exist regarding the microbiology, rate of infections, and outcomes between FN and non-FN peoples ...remains unknown. Design, setting, participants, & measures: All adult peritoneal dialysis patients (n = 727) from 1997 to 2007 residing in Manitoba, Canada, were included. Parametric and nonparametric tests were used as necessary. Negative binomial regression was used to determine the relationship of rates of exit site infections (ESIs) and peritonitis between FN and non-FN peoples.
A total of 161 FN and 566 non-FN subjects were included in the analyses. The unadjusted relative rates of peritonitis and ESIs in FN subjects were 132.7 and 86.0/100 patient-years compared with 87.8 and 78.2/100 patient-years in non-FN populations, respectively. FN subjects were more likely to have culture-negative peritonitis (36.5 versus 20.8%, P < 0.0001) and Staphylococcus ESIs (54.1 versus 32.9%, P < 0.0001). The crude and adjusted rates of peritonitis were higher in FN subjects for total episodes and culture-negative and gram-negative peritonitis. Catheter removal because of peritonitis was similar in both groups (42.9 versus 38.1% for FN and non-FN subjects, respectively; P = 0.261).
FN patients experience higher rates of peritonitis and similar rates of ESIs compared with non-FN patients. Interventions to improve outcomes and prevent infections should specifically be targeted to the FN population.
The Aboriginal population in Canada experiences high rates of end-stage renal disease and need for dialytic therapies. Our objective was to examine rates of mortality, technique failure and ...peritonitis among adult aboriginal patients receiving peritoneal dialysis in the province of Manitoba. We also aimed to explore whether differences in these rates may be accounted for by location of residence (i.e., urban versus rural).
We included all adult patients residing in the province of Manitoba who received peritoneal dialysis during the period from 1997-2007 (n = 727). We extracted data from a local administrative database and from the Canadian Organ Replacement Registry and the Peritonitis Organism Exit-sites/Tunnel infections (POET) database. We used Cox and logistic regression models to determine the relationship between outcomes and Aboriginal ethnicity. We performed Kaplan-Meier analyses to examine the relationship between outcomes and urban (i.e., 50 km or less from the primary dialysis centre in Winnipeg) versus rural (i.e., more than 50 km from the centre) residency among patients who were aboriginal.
One hundred sixty-one Aboriginal and 566 non-Aboriginal patients were included in the analyses. Adjusted hazard ratios for mortality (HR 1.476, CI 1.073-2.030) and adjusted time to peritonitis (HR 1.785, CI 1.352-2.357) were significantly higher among Aboriginal patients than among non-Aboriginal patients. We found no significant differences in mortality, technique failure or peritonitis between urban- or rural-residing Aboriginal patients.
Compared with non-Aboriginal patients receiving peritoneal dialysis, Aboriginal patients receiving peritoneal dialysis had higher mortality and faster time to peritonitis independent of comorbidities and demographic characteristics. This effect was not influenced by place of residence, whether rural or urban.
Little is known regarding barriers to guideline adherence in the nephrology community. We set out to identify perceived barriers to evidence-based medicine (EBM) and measurement of continuous quality ...indicators (CQI) in an international cohort of peritoneal dialysis (PD) practitioners.
Subscribers to an online nephrology education site (Nephrology Now) were invited to participate in an online survey. Nephrology Now is a non-profit, monthly mailing list that highlights clinically relevant articles in nephrology. Four hundred and seventy-five physicians supplying PD care participated in an online survey assessing their use of EBM and CQI in their PD practice. Ordinal logistic regression was utilized to determine relationships between baseline characteristics and EBM and CQI practices.
The majority of physicians were nephrologists (89.7%), and 50.4% worked in an academic centre. Respondents were from the following geographic regions: 13.5% Canadian, 24% American, 23.8% European, 4.4% Australian, 5.3% South American, 10.7% African and 12.2% Asian. Adherence to PD clinical practice guidelines were generally strong; however, lower adherence was associated with countries with lower healthcare expenditure, not using personal digital assistant (PDA), the longer the physician had been practising and smaller (< 20 patients per centre) PD practice.
International variation in guideline adherence may be influenced by a country's healthcare expenditure, physician's PDA use and experience, and size of PD practice which may impact future guideline development and implementation.
PDF
