ER stress and distinct outputs of the IRE1α RNase control proliferation and senescence in response to oncogenic Ras.

Oncogenic Ras causes proliferation followed by premature senescence in primary cells, an initial barrier to tumor development. The role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in regulating these two cellular outcomes is poorly understood. During ER stress, the inositol requiring enzyme 1α (IRE1α) endoribonuclease (RNase), a key mediator of the UPR, cleave

The impact of procedural activities on musculoskeletal pain experienced by pregnant surgeons.

BACKGROUND: Two-thirds of surgeons report work-related musculoskeletal disorders (WRMD). There is limited data on WRMD symptoms experienced by pregnant surgeons. METHODS: We distributed an electronic survey via personal contacts to attending and trainee surgeons across six academic institutions to assess the impact of procedural activities and surgical ergonomics (SE) on WRMD symptoms during pregnancy. RESULTS: Fifty-three respondents were currently or had been pregnant while clinically active, representing 93 total pregnancies. 94.7% reported that symptoms were exacerbated by workplace activities during pregnancy and 13.2% took unplanned time off work as a result. Beyond 24 weeks of pregnancy, 89.2% of respondents continued to operate/perform procedures, 81.7% worked \u3e24-h shifts and 69.9% performed repetitive lifting \u3e50 pounds. No respondents were aware of any institutional pregnancy-specific SE policies. CONCLUSIONS: Procedural activities can exacerbate pain symptoms for the pregnant surgeon. SE best practices during pregnancy warrant further attention

Host CLIC4 expression in the tumor microenvironment is essential for breast cancer metastatic competence.

The TGF-β-regulated Chloride Intracellular Channel 4 (CLIC4) is an essential participant in the formation of breast cancer stroma. Here, we used data available from the TCGA and METABRIC datasets to show that CLIC4 expression was higher in breast cancers from younger women and those with early-stage metastatic disease. Elevated CLIC4 predicted poor outcome in breast cancer patients and was linked to the TGF-β pathway. However, these associations did not reveal the underlying biological contribution of CLIC4 to breast cancer progression. Constitutive ablation of host Clic4 in two murine metastatic breast cancer models nearly eliminated lung metastases without reducing primary tumor weight, while tumor cells ablated of Clic4 retained metastatic capability in wildtype hosts. Thus, CLIC4 was required for host metastatic competence. Pre- and post-metastatic proteomic analysis identified circulating pro-metastatic soluble factors that differed in tumor-bearing CLIC4-deficient and wildtype hosts. Vascular abnormalities and necrosis increased in primary tumors from CLIC4-deficient hosts. Transcriptional profiles of both primary tumors and pre-metastatic lungs of tumor-bearing CLIC4-deficient hosts were consistent with a microenvironment where inflammatory pathways were elevated. Altogether, CLIC4 expression in human breast cancers may serve as a prognostic biomarker; therapeutic targeting of CLIC4 could reduce primary tumor viability and host metastatic competence