Duedideriksen8698

This mechanism of disruption links phosphorylation of the prion-like domain of an oncogenic fusion protein to DNA damage after ionizing radiation and reveals that a dependence on oncogenic chromatin remodeling underlies sensitivity to radiation therapy in myxoid liposarcoma.Collagen remodeling contributes to many physiological and pathological processes. In primary tumors, the linearization of collagen fibers promotes cancer cell invasion and metastasis and is indicative of poor prognosis. However, it remains unknown whether there are endogenous inhibitors of collagen linearization that could be exploited therapeutically. Here, we show that collagen linearization is controlled by two secreted matricellular proteins with antagonistic functions. Specifically, WISP1 was secreted by cancer cells, bound to type I collagen (Col I), and linearized Col I via its cysteine-rich C-terminal (CT) domain. In contrast, WISP2, which lacks a CT domain, inhibited Col I linearization by preventing WISP1-Col I binding. Analysis of patient data revealed that WISP2 expression is lower in most solid tumors, in comparison to normal tissues. Consequently, genetic or pharmacological restoration of higher WISP2 levels impaired collagen linearization and prevented tumor cell invasion and metastasis in vivo in models of human and murine breast cancer. Thus, this study uncovers WISP2 as the first inhibitor of collagen linearization ever identified and reveals that collagen architecture can be normalized and metastasis inhibited by therapeutically restoring a high WISP2WISP1 ratio.Methylthioadenosine phosphorylase (MTAP) is a key enzyme associated with the salvage of methionine and adenine that is deficient in 20%-30% of pancreatic cancer. Our previous study revealed that MTAP-deficiency indicates a poor prognosis for pancreatic ductal adenocarcinoma (PDAC) patients. In this study, bioinformatics analysis of The Cancer Genome Atlas (TCGA) data indicated that PDACs with MTAP deficiency display a signature of elevated glycolysis. Metabolomics studies showed that that MTAP deletion-mediated metabolic reprogramming enhanced glycolysis and de novo purine synthesis in pancreatic cancer cells. Western blot analysis revealed that MTAP knockout stabilized hypoxia-inducible factor 1α (HIF-1α) protein via posttranslational phosphorylation. RIO kinase 1 (RIOK1), a downstream kinase upregulated in MTAP-deficient cells, interacted with and phosphorylated HIF-1α to regulate its stability. In vitro experiments demonstrated that the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) and the de novo purine synthesis inhibitor L-alanosine synergized to kill MTAP-deficient pancreatic cancer cells. Collectively, these results reveal that MTAP deficiency drives pancreatic cancer progression by inducing metabolic reprogramming, providing a novel target and therapeutic strategy for treating MTAP-deficient disease.Ferroptosis is a lipid peroxidation-dependent cell death caused by metabolic dysfunction. Ferroptosis-associated enzymes are promising therapeutic targets for cancer treatment. However, such therapeutic strategies show limited efficacy due to drug resistance and other largely unknown underlying mechanisms. Here we report that cystine transporter SLC7A11 is upregulated in lung cancer stem-like cells (CSLC) and can be activated by stem cell transcriptional factor SOX2. Mutation of SOX2 binding site in SLC7A11 promoter reduced SLC7A11 expression and increased sensitivity to ferroptosis in cancer cells. Oxidation at Cys265 of SOX2 inhibited its activity and decreased the self-renewal capacity of CSLCs. Moreover, tumors with high SOX2 expression were more resistant to ferroptosis, and SLC7A11 expression was positively correlated with SOX2 in both mouse and human lung cancer tissue. Together, our study provides a mechanism by which cancer cells evade ferroptosis and suggests that oxidation of SOX2 can be a potential therapeutic target for cancer treatment.

The goal of this study was to determine the impact refusal of surgery has on overall survival in patients with endometrial cancer.

From January 2004 to December 2015, the National Cancer Database was queried for patients with pathologically proven endometrial cancer who were recommended surgery and refused. Inverse probability of treatment weighting was used to account for differences in baseline characteristics between patients who underwent surgery and those who refused. Kaplan-Meier analyses and doubly robust estimation with multivariate Cox proportional hazards modeling were used to analyze overall survival.

Of the 300 675 patients identified, 534 patients (0.2%) were recommended surgical treatment but refused 18% (95/534) were age ≤40 years. The 5-year overall survival for all patients who refused surgery was significantly decreased compared with patients who underwent surgery (29.2% vs 71.9%, P<0.01). This was demonstrated at ages 41-64 years (65.5% vs 91.0%, P<0.01) and ≥65 years (23.4% vs 75.3%, P<0.01). The 5-year overall survival did not meet statistical significance at age ≤40 years (90.1% vs 87.8% P<0.19). However, there were few patients in this cohort. On multivariate analysis, factors associated with refusal of surgery included Medicaid insurance, Black race, Hispanic Race, Charlson Comorbidity Index scores of 2 or greater, stage II or III, and if patient received external beam radiation therapy alone. Factors associated with undergoing surgery included age greater than 41, stage IB, and if the patient received brachytherapy.

Refusal of surgery for endometrial cancer is uncommon and leads to decreased overall survival.

Refusal of surgery for endometrial cancer is uncommon and leads to decreased overall survival.The prognosis of Ewing sarcoma caused by EWS/FLI1 fusion is poor, especially after metastasis. Although therapy with CTLs targeted against altered EWS/FLI1 sequences at the gene break/fusion site may be effective, CTLs generated from peripheral blood are often exhausted because of continuous exposure to tumor antigens. We addressed this by generating induced pluripotent stem cell (iPSC)-derived functionally rejuvenated CTLs (rejT) directed against the neoantigen encoded by the EWS/FLI1 fusion gene. In this study, we examined the antitumor effects of EWS/FLI1-rejTs against Ewing sarcoma. The altered amino acid sequence at the break/fusion point of EWS/FLI1, when presented as a neoantigen, evokes an immune response that targets EWS/FLI1 + sarcoma. Although the frequency of generated EWS/FLI1-specific CTLs was only 0.003%, we successfully established CTL clones from a healthy donor. We established iPSCs from a EWS/FLI1-specific CTL clone and redifferentiated them into EWS/FLI1-specific rejTs. To evaluate cytotoxicity, we cocultured EWS/FLI1-rejTs with Ewing sarcoma cell lines. EWS/FLI1-rejTs rapidly and continuously suppressed the proliferation of Ewing sarcoma for >40 hours. Using a Ewing sarcoma xenograft mouse model, we verified the antitumor effect of EWS/FLI1-rejTs via imaging, and EWS/FLI1-rejTs conferred a statistically significant survival advantage. "Off-the-shelf" therapy is less destructive and disruptive than chemotherapy, and radiation is always desirable, particularly in adolescents, whom Ewing sarcoma most often affects. Thus, EWS/FLI1-rejTs targeting a Ewing sarcoma neoantigen could be a promising new therapeutic tool.Objective. To review the use of the business model canvas, a one-page visual description of a business initiative, as a tool for teaching pharmacy students about entrepreneurship and business planning in pharmacy practice settings. Findings. Students often struggle to develop the mindset, skillset, and toolset to effectively apply business modeling and planning processes to pharmacy practice settings. Over years of experimentation and various iterations in a pharmacy practice management class, a new business model canvas was developed and refined. The canvas contains thirteen sections which emphasize key terms, concepts, and ideas crucial for achieving entrepreneurial competencies. Using the Zone of Proximal Development as a framework, the course structure offered a range of supportive activities that guided students to independent competence. selleck kinase inhibitor The business model canvas formed a framework around which assigned course readings, exercises, and group assignments helped pharmacy students build confidence and competence in completing a capstone business plan assignment. Summary. This paper provides recommendations and examples of how to structure a course in the Doctor of Pharmacy (PharmD) curricula using an entrepreneurial tool, the business model canvas, to help students master business competencies. Recommendations and lessons-learned are provided.It is well-established that race is a social construct that has little to no biological relevance in the absence of context such as the significant impact of the social, political, and environmental systems that contribute to health and health inequities. However, pharmacy school curricula often misrepresent race as the basis of disease diagnosis and reinforce race-based clinical guidelines without contextualization. Pharmacy schools, through the partnership of students and faculty, should 1) contextualize the mention of race and the differences in disease burden, and 2) provide evidence for race-based guidelines and clinical decision-making in education materials. In this way, we can work to halt the perpetuation of teaching bias to future healthcare professionals.Objectives. Clinical reasoning (CR) is integral to the provision of patient-centered care as outlined in the Pharmacists' Patient Care Process (PPCP). However, the PPCP was not created to foster CR in student pharmacists and cannot be the sole tool used to characterize or cultivate these skills. This article seeks to describe elements of CR, the relationship between CR and PPCP, and concepts from the CR literature that should inform the teaching of CR skills. Findings. Key elements of the PPCP were identified in CR definitions, but differences emerged. The literature supports CR as a bidirectional, fluid process that is highly collaborative. Effective CR requires multiple types of "thinking", interaction with others and the environment, self-assessment, and a tolerance for nuance or ambiguity. Teaching strategies can be used in the didactic and experiential setting to target the cognitive and contextual factors associated with CR. Summary. Educators should consult the CR literature to enhance our understanding of CR in seeking to teach, model, and foster these skills in our students. Future scholarship should include the development of models to support CR within the profession of pharmacy, adoption and experimentation with CR teaching techniques, and valuation of the utility of various assessment tools and processes.This commentary examines the curriculum chair's responsibilities and discusses considerations when assuming this role, using a captain of the ship metaphor. From knowing the crew to managing a diverse set of responsibilities, the path to becoming an effective chair is challenging and each captain's stripe must be earned. Advice is provided to assist with understanding the curriculum and governance processes, as well as the chair's various roles and professional development. The need for both leadership and management is also emphasized.