Castration-resistant prostate cancer (CRPC) is associated with an increased reliance on heat shock protein 70 (HSP70), but it is not clear what other protein homeostasis (proteostasis) factors might ...be involved. To address this question, we performed functional and synthetic lethal screens in four prostate cancer cell lines. These screens confirmed key roles for HSP70, HSP90, and their co-chaperones, but also suggested that the mitochondrial chaperone, HSP60/HSPD1, is selectively required in CRPC cell lines. Knockdown of HSP60 does not impact the stability of androgen receptor (AR) or its variants; rather, it is associated with loss of mitochondrial spare respiratory capacity, partly owing to increased proton leakage. Finally, transcriptional data revealed a correlation between HSP60 levels and poor survival of prostate cancer patients. These findings suggest that re-wiring of the proteostasis network is associated with CRPC, creating selective vulnerabilities that might be targeted to treat the disease.
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•Prostate cancer cells depend on proteostasis pathways for survival•Functional genomics screens revealed that CRPC cells depend on HSP60•HSP60 is required for a CRPC-related metabolic switch, not AR stability•HSP60 is a promising drug target for CRPC
Drug targets for castration-resistant prostate cancer (CRPC) are needed. The protein homeostasis (proteostasis) pathways are known to include targets; however, a systematic search had not been performed. Here, Shkedi and Taylor et al. use an shRNA screen targeting ∼130 proteostasis factors to identify HSP60 as a selective vulnerability in CRPC.
Prescription drug misuse (PDM) is a significant public health problem associated with mental health symptoms.
This project investigates the connections between PDM motivations and mental health to ...inform intervention efforts.
Using nationally representative adult data from the 2016-2018 National Survey on Drug Use and Health (N = 128,205; 53% female) this project investigated which motivations for misuse are related to past-year mental health problems including any mental illness, serious mental illness, major depressive episode, and suicidal thoughts. Complex samples logistic regression models of the main motivation of PDM for each mental health problem were conducted separately for each prescription drug class (i.e., opioids, tranquilizers, sedatives, and stimulants) while controlling for demographic characteristics.
Adults that reported PDM were more likely than those with no PDM to endorse past year mental health problems. Compared to those that reported PDM of other medications, those misusing prescription opioids and tranquilizers to help with emotions and misusing sedatives to "relax or relieve tension" were more likely to have all categories of mental health problems. Those that misused prescription stimulants to "help study" had lower odds of all mental health problems.
While there were differences based on prescription drug class, a range of motivations increased adults' likelihood to have mental health problems and common themes were found across drug classes. While causality is still undetermined, prevention and intervention efforts that are multifaceted and individualized, while broadly providing adults with other ways to cope with negative emotions are likely to help reduce PDM.
Emergency physicians are frequently faced with making decisions regarding how aggressive to be in caring for critically ill patients. We aimed to identify factors that influence decisions to limit ...treatment in the Emergency Department (ED) through a systematic search of the available literature.
Prospectively registered systematic review of studies employing any methodology to investigate factors influencing decisions to limit treatment in the ED. Medline and EMBASE were searched from their inception until January 2019. Methodological quality was assessed using the Mixed Methods Appraisal Tool, but no studies were excluded based on quality. Findings were summarised by narrative analysis.
10 studies published between 1998 and 2016 were identified for inclusion in this review, including seven cross-sectional studies investigating factors associated with treatment-limiting decisions, two surveys of physicians making treatment-limiting decisions and one qualitative study of physicians making treatment-limiting decisions. There was significant heterogeneity in patient groups, outcome measures, methodology and quality. Only three studies received a methodology-specific rating of 'high quality'. Important limitations of the literature include the use of small single-centre retrospective cohorts often lacking a comparison group, and survey studies with low response rates employing closed-response questionnaires. Factors influencing treatment-limiting decisions were categorised into 'patient and disease factors' (age, chronic disease, functional limitation, patient and family wishes, comorbidity, quality of life, acute presenting disorder type, severity and reversibility), 'hospital factors' (colleague opinion, resource availability) and 'non-patient healthcare factors' (moral, ethical, social and cost factors).
Several factors influence decisions to limit treatment in the ED. Many factors are objective and quantifiable, but some are subjective and open to individual interpretation. This review highlights the complexity of the subject and the need for more robust research in this field.
We conduct a random survey of Michigan (United States) households to gauge consumer behavior toward, and awareness of, fair trade. Around 58% of respondents have heard of fair trade and just over a ...quarter have knowingly purchased a fair-trade product. Of the 38% of respondents who indicated a willingness to pay a premium for a fair trade product, the median premium they were willing to pay was around 20%. We find that those who are politically liberal, female, younger, and have attained higher levels of education are willing to pay higher premiums for fair trade, other factors held constant. Respondents who are unwilling to pay a fair trade premium are divided between not doing so because of a belief that all voluntary trade is already fair and a fear of potential unintended negative consequences on workers.
The politics of beer Poelmans, Eline; Dove, John A.; Taylor, Jason E.
Public choice,
01/2018, Letnik:
174, Številka:
1/2
Journal Article
Recenzirano
Odprti dostop
Nine days after he took office in March 1933, Franklin Roosevelt asked Congress to amend existing federal Prohibition policy so as to allow for the sale and consumption of 3.2% alcohol beer. Over the ...following 8 days, the so-called “beer bill” was proposed, debated, passed and signed into law. This study analyzes the political decision making behind one of FDR’s earliest New Deal policies. Specifically, we consider how voter preferences, representatives’ ideologies, national party affiliations, and the influence of special interests affected legislative decision making. We find that special interests and party affiliations were particularly important drivers of congressional voting behavior.
Podocytes are major components of the filtration barrier and a renal source of vascular endothelial growth factor (VEGF). Chronic renovascular disease (RVD) progressively degrades the renal function, ...accompanied by podocyte damage and a progressive reduction in VEGF. We showed that the endothelin (ET) pathway contributes to this pathological process and ET-A (but not ET-B) receptor antagonism protects the kidney in RVD. We hypothesize that ET-A-induced renoprotection is largely driven by the protection of podocyte integrity and function.
To mimic the renal environment of chronic RVD, human podocytes were incubated under chronic hypoxia for 96 h and divided in untreated or treated with an ET-A or ET-B receptor antagonist. Cells were quantified after 96 h. Cell homogenates and media were obtained after 1, 24 and 96 h to quantify production of VEGF, anti-VEGF soluble receptor s-Flt1, and the expression of apoptotic mediators. A separate set of similar experiments was performed after addition of a VEGF-neutralizing antibody (VEGF-NA).
Hypoxia decreased podocyte number, which was exacerbated by ET-B but improved after ET-A antagonism. Production of VEGF was preserved by ET-A antagonism, whereas s-Flt1 increased in hypoxic cells after ET-B antagonism only, accompanied by a greater expression of pro-apoptotic mediators. On the other hand, treatment with VEGF-NA diminished ET-A-induced protection of podocytes.
ET-A antagonism preserves podocyte viability and integrity under chronic hypoxia, whereas ET-B antagonism exacerbates podocyte dysfunction and death. Enhanced bioavailability of VEGF after ET-A antagonism could be a pivotal mechanism of podocyte protection that significantly contributes to ET-A receptor blockade-induced renal recovery in chronic RVD.
While most Ascomycetes tend to associate principally with plants, the dimorphic fungi Coccidioides immitis and Coccidioides posadasii are primary pathogens of immunocompetent mammals, including ...humans. Infection results from environmental exposure to Coccidiodies, which is believed to grow as a soil saprophyte in arid deserts. To investigate hypotheses about the life history and evolution of Coccidioides, the genomes of several Onygenales, including C. immitis and C. posadasii; a close, nonpathogenic relative, Uncinocarpus reesii; and a more diverged pathogenic fungus, Histoplasma capsulatum, were sequenced and compared with those of 13 more distantly related Ascomycetes. This analysis identified increases and decreases in gene family size associated with a host/substrate shift from plants to animals in the Onygenales. In addition, comparison among Onygenales genomes revealed evolutionary changes in Coccidioides that may underlie its infectious phenotype, the identification of which may facilitate improved treatment and prevention of coccidioidomycosis. Overall, the results suggest that Coccidioides species are not soil saprophytes, but that they have evolved to remain associated with their dead animal hosts in soil, and that Coccidioides metabolism genes, membrane-related proteins, and putatively antigenic compounds have evolved in response to interaction with an animal host.
Patients with metastatic renal cell cancer (mRCC) who respond to upfront immune checkpoint inhibitor (ICI) combination therapies may be treated with cytoreductive nephrectomy (CN) to remove ...radiographically viable primary tumors. Early data for post-ICI CN suggested that ICI therapies induce desmoplastic reactions in some patients, increasing the risk of surgical complications and perioperative mortality. We evaluated perioperative outcomes for 75 consecutive patients treated with post-ICI CN at four institutions from 2017 to 2022. Our cohort of 75 patients had minimal or no residual metastatic disease but radiographically enhancing primary tumors after ICI and were treated with CN. Intraoperative complications were identified in 3/75 patients (4%) and 90-d postoperative complications in 19/75 (25%), including two patients (3%) with high-grade (Clavien ≥III) complications. One patient was readmitted within 30 d. No patients died within 90 d after surgery. Viable tumor was present in all but one specimen. Approximately half of the patients (36/75, 48%) remained off systemic therapy at last follow-up. These data suggest that CN following ICI therapy is safe and associated with low rates of major postoperative complications in appropriately selected patients at experienced centers. Post-ICI CN may facilitate observation without additional systemic therapy in patients without significant residual metastatic disease.
Current first-line treatment for patients with kidney cancer that has spread to other sites (metastatic cancer) is immunotherapy. For cases in which metastatic sites respond to this therapy but primary tumor is still detected in the kidney, surgical treatment of the tumor is feasible and has a low rate of complications, and may delay the need for further chemotherapy.
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