Munrohaley6805

Mitochondrial proteostasis, regulated by the mitochondrial unfolded protein response (UPRmt), is crucial for maintenance of cellular functions and survival. Elevated oxidative and proteotoxic stress in mitochondria must be attenuated by the activation of a ubiquitous UPRmt to promote prostate cancer (PCa) growth. Here we show that the 2 key components of the UPRmt, heat shock protein 60 (HSP60, a mitochondrial chaperonin) and caseinolytic protease P (ClpP, a mitochondrial protease), were required for the development of advanced PCa. HSP60 regulated ClpP expression via c-Myc and physically interacted with ClpP to restore mitochondrial functions that promote cancer cell survival. HSP60 maintained the ATP-producing functions of mitochondria, which activated the β-catenin pathway and led to the upregulation of c-Myc. We identified a UPRmt inhibitor that blocked HSP60's interaction with ClpP and abrogated survival signaling without altering HSP60's chaperonin function. Disruption of HSP60-ClpP interaction with the UPRmt inhibitor triggered metabolic stress and impeded PCa-promoting signaling. Treatment with the UPRmt inhibitor or genetic ablation of Hsp60 inhibited PCa growth and progression. Together, our findings demonstrate that the HSP60-ClpP-mediated UPRmt is essential for prostate tumorigenesis and the HSP60-ClpP interaction represents a therapeutic vulnerability in PCa.Most patients with neovascular age-related macular degeneration (nvAMD), the leading cause of severe vision loss in elderly US citizens, respond inadequately to current therapies targeting a single angiogenic mediator, vascular endothelial growth factor (VEGF). Here, we report that aqueous fluid levels of a second vasoactive mediator, angiopoietin-like 4 (ANGPTL4), can help predict the response of patients with nvAMD to anti-VEGF therapies. ANGPTL4 expression was higher in patients who required monthly treatment with anti-VEGF therapies compared with patients who could be effectively treated with less-frequent injections. We further demonstrate that ANGPTL4 acts synergistically with VEGF to promote the growth and leakage of choroidal neovascular (CNV) lesions in mice. Targeting ANGPTL4 expression was as effective as targeting VEGF expression for treating CNV in mice, while simultaneously targeting both was more effective than targeting either factor alone. To help translate these findings to patients, we used a soluble receptor that binds to both VEGF and ANGPTL4 and effectively inhibited the development of CNV lesions in mice. Our findings provide an assay that can help predict the response of patients with nvAMD to anti-VEGF monotherapy and suggest that therapies targeting both ANGPTL4 and VEGF will be a more effective approach for the treatment of this blinding disease.

To explore cancer patients' experience of pain and coping strategies as well as beliefs and representations associated with pain, pain management and treatments.

A qualitative study based on semi-structured interviews was conducted among 16 patients with cancer. The inductive research strategy adopted derived from the Grounded Theory approach and the data transcribed verbatim were gradually analyzed involving researcher triangulation.

The experience of pain and the coping strategies developed by patients to deal with it are shaped by the experience and representations of cancer associated with death and suffering. Pain acts both as an indication to the patients that they are still alive and as an indicator of the progression of the disease. Cancer also models patients' relationships to analgesic treatments and health care providers, since pain is an area in which patients can take back control of what is happening to them. Patients' expression of reluctance to accept analgesic treatments is also influenced by the significance of opioid treatments in this context, which are perceived as an indication that the end of life is close.

The contextualization of pain through the particularities of cancer is critical in order to understand cancer patients' experience of pain.

Not only patients' knowledge but also the meaning-making of pain should be incorporated in interventions targeting pain management.

Not only patients' knowledge but also the meaning-making of pain should be incorporated in interventions targeting pain management.All forms of family violence may negatively affect a child's development. However, research on child maltreatment is primarily focused on the child who is directly maltreated and does not often account for how other children in the family experience the abuse. The central aim of our study was to better understand how children's direct experience of physical abuse and exposure to physical abuse influence their academic outcomes. Data were taken from the Minnesota Departments of Education and Human Services. The sample was developed from a population-level cohort of 8-10 years old children (N = 1740) from two groups Child Protective Service (CPS)-involved (a child who allegedly experienced physical abuse or a child who was exposed to the alleged physical abuse of another child in their household) and the matched comparison. Exposure to intimate partner violence (IPV) was also measured for CPS-involved children. School attendance and academic achievement were examined over 4 years. Descriptive statistics and Generalized Estimating Equations (GEE) were used to answer the three research questions. Over time, declines in attendance for children exposed to physical abuse were significantly greater than those of their matched peers. Exposure to IPV for CPS-involved children resulted in further declines in attendance. Math proficiency of children who experienced physical abuse declined at a significantly faster rate than their matched peers. The decline in reading proficiency of both children who experienced physical abuse and children exposed to physical abuse was more significantly pronounced than that of their matched peers. Differences in math and reading proficiency were eliminated when IPV exposure was taken into account. Child protection workers and school professionals should be aware of negative effects of experiences of and exposures to child maltreatment and work collaboratively to provide academic support, counseling, and other interventions to support children's academic stability.

Prescribing errors occur frequently, especially among junior doctors. Our aim was to investigate prescribing errors made by final-year medical students. Information on these errors can help to improve education on and assessment of clinical pharmacotherapy (CPT).

This was a retrospective cohort study amongst final-year medical students at Erasmus Medical Centre, The Netherlands. Errors made in the final prescribing assessment were analysed. Errors were categorized by type, possible consequence and possibility of reaching the patient in real life.

A total of 381 students wrote 1502 analysable prescriptions. Forty per cent of these contained at least one error, and 54% of errors were of the inadequate information type. The rating of prescriptions for children was lower than for other question categories (P = <.001). Fifty per cent of errors were classified as "would have reached the patient but would not have had the potential to cause harm". In total, 253 (29%) errors would not have been intercepted b case-based CPT education, focusing on the practical issues of prescribing, especially for paediatric cases, and offering more practice time for prescribing during clerkships.Anions play significant roles in the separation of lanthanides and actinides. The molecular-scale details of how these anions behave at aqueous interfaces are not well understood, especially at high ionic strengths. Here, we describe the interfacial structure of thiocyanate anions at a soft charged interface up to 5 M bulk concentration with combined classical and phase-sensitive vibrational sum frequency generation (PS-VSFG) spectroscopy and molecular dynamics (MD) simulations. Selleck Proteasome inhibitor At low concentrations thiocyanate ions are mostly oriented with their sulfur end pointing toward the charged surfactants. The VSFG signal reaches a plateau at around 100 mM bulk concentration, followed by significant changes above 1 M. At high concentrations a new thiocyanate population emerges with their sulfur end pointing toward the bulk liquid. The -CN stretch frequency is different for up and down oriented SCN- ions, indicating different coordination environments. These results provide key molecular-level insights for the interfacial behavior of complex anions in highly concentrated solutions.

Health interventions delivered via smart devices are increasingly being used to address mental health challenges associated with cancer treatment. Engagement with mobile interventions has been associated with treatment success; however, the relationship between mood and engagement among patients with cancer remains poorly understood. A reason for this is the lack of a data-driven process for analyzing mood and app engagement data for patients with cancer.

This study aimed to provide a step-by-step process for using app engagement metrics to predict continuously assessed mood outcomes in patients with breast cancer.

We described the steps involved in data preprocessing, feature extraction, and data modeling and prediction. We applied this process as a case study to data collected from patients with breast cancer who engaged with a mobile mental health app intervention (IntelliCare) over 7 weeks. We compared engagement patterns over time (eg, frequency and days of use) between participants with high and letween app engagement and mood outcomes in patients with breast cancer. The ability to leverage both self-report and engagement features to analyze and predict mood during an intervention could be used to enhance decision-making for researchers and clinicians and assist in developing more personalized interventions for patients with breast cancer.

The results from the case study support the feasibility and potential of our analytic process for understanding the relationship between app engagement and mood outcomes in patients with breast cancer. The ability to leverage both self-report and engagement features to analyze and predict mood during an intervention could be used to enhance decision-making for researchers and clinicians and assist in developing more personalized interventions for patients with breast cancer.Limited data are available on adverse drug reactions (ADRs) of gender-affirming hormone therapy (HT), mainly due to the lack of population-based studies with adequate controls, thus making spontaneous reporting systems a valuable tool to detect potential side reactions. In this nationwide retrospective study, we aimed to analyze ADRs related to gender-affirming HT reported in the French pharmacovigilance database (FPVD). We requested all the individual case safety reports related to gender-affirming HT recorded in the FPVD before May 27, 2020. We excluded previously published cases and those where gender-affirming HT was not the suspected drug. A total of 28 reports of ADRs were identified. Six concerned transgender men (21-40 years) and 22 transgender women (22-68 years). In transgender men taking testosterone enanthate, all reported ADRs were cardiovascular events, with pulmonary embolism in 50% of cases. Median time to onset (TTO) was 34 months. In transgender women, antiandrogens, mainly cyproterone acetate, were involved in 68% of cases, and estrogens in 77% of cases, mostly in association with progestin or cyproterone acetate.