Cooperative regulation of coupled oncoprotein synthesis and stability in triple-negative breast cancer by EGFR and CDK12/13.

Evidence has long suggested that epidermal growth factor receptor (EGFR) may play a prominent role in triple-negative breast cancer (TNBC) pathogenesis, but clinical trials of EGFR inhibitors have yielded disappointing results. Using a candidate drug screen, we identified that inhibition of cyclin-dependent kinases 12 and 13 (CDK12/13) dramatically sensitizes diverse models of TNBC to EGFR blockade. This combination therapy drives cell death through the 4E-BP1-dependent suppression of the translation and translation-linked turnover of driver oncoproteins, including MYC. A genome-wide CRISPR/Cas9 screen identified the CCR4-NOT complex as a major determinant of sensitivity to the combination therapy whose loss renders 4E-BP1 unresponsive to drug-induced dephosphorylation, thereby rescuing MYC translational suppression and promoting MYC stability. The central roles of CCR4-NOT and 4E-BP1 in response to the combination therapy were further underscored by the observation of CNOT1 loss and rescue of 4E-BP1 phosphorylation in TNBC cells that naturally evolved therapy resistance. Thus, pharmacological inhibition of CDK12/13 reveals a long-proposed EGFR dependence in TNBC that functions through the cooperative regulation of translation-coupled oncoprotein stability.

Ambulatory facial feminization surgery: a comparative analysis of outcomes and complications.

BACKGROUND: To date, there are no studies investigating the safety and outcomes of facial feminization surgery (FFS) as an outpatient procedure. This is the first study of its kind analyzing the outcomes of ambulatory FFS based on a comparison of complications, post-operative emergency department or urgent care (ED/UC) visits, and readmissions between patients who underwent FFS with admission versus same-day surgery. METHODS: A retrospective analysis was conducted on all patients who underwent FFS in a single integrated healthcare system. Patient charts were reviewed for operative details, complications, post-operative ED/UC visits, readmission, and demographic factors. Major outcomes including complications, readmissions, and ED/UC visits were compared between groups with same-day discharge and post-operative hospital admission. RESULTS: Of 242 patients included in the study, ED/UC visits were comparable between patients discharged same-day (18.2%) and patients admitted post-operatively (21.6%, p = 0.52). Logistic regression showed no significant difference in the composite outcomes of minor complications, major complications, and readmissions (15.6% for ambulatory versus 19.3% for admission, p = 0.46). Temporary nerve palsy, infection, and hematoma were the most common post-operative complications. However, covariates of a lower face procedure and operative time were shown to have significant differences in the composite complication outcome (p = 0.04 and p = 0.045, respectively). CONCLUSION: Ambulatory FFS is a safe practice with no associated increase in adverse outcomes including complications, ED/UC visits, and readmission when compared to post-operative admission. Adoption of same-day FFS should be considered by high-volume gender health centers to potentially benefit from increased scheduling flexibility and efficiency, increased access to care, and lower healthcare costs.

Integrative PTEN Enhancer Discovery Reveals a New Model of Enhancer Organization.

Enhancers possess both structural elements mediating promoter looping and functional elements mediating gene expression. Traditional models of enhancer-mediated gene regulation imply genomic overlap or immediate adjacency of these elements. We test this model by combining densely-tiled CRISPRa screening with nucleosome-resolution Region Capture Micro-C topology analysis. Using this integrated approach, we comprehensively define the cis-regulatory landscape for the tumor suppressor PTEN, identifying and validating 10 distinct enhancers and defining their 3D spatial organization. Unexpectedly, we identify several long-range functional enhancers whose promoter proximity is facilitated by chromatin loop anchors several kilobases away, and demonstrate that accounting for this spatial separation improves the computational prediction of validated enhancers. Thus, we propose a new model of enhancer organization incorporating spatial separation of essential functional and structural components.

Newer antiretroviral agents and how to use them.

Several relatively new antiretroviral drugs have been approved or are under investigation. These include nucleoside and nonnucleoside reverse transcriptase inhibitors, protease and integrase strand transfer inhibitors, CCR5 antagonists, and an entirely new class of maturation inhibitors. Although most of these drugs were developed for patients with drug-resistant HIV-1, some have demonstrated a potential role for those starting treatment for the first time. This review incorporates data from the most recent treatment guidelines, peer-reviewed publications, and recent presentations at research meetings about some of these relatively new and emerging antiretroviral agents and offers strategies for incorporating them into clinical practice.

Newer antiretroviral agents and how to use them.

Several relatively new antiretroviral drugs have been approved or are under investigation. These include nucleoside and nonnucleoside reverse transcriptase inhibitors, protease and integrase strand transfer inhibitors, CCR5 antagonists, and an entirely new class of maturation inhibitors. Although most of these drugs were developed for patients with drug-resistant HIV-1, some have demonstrated a potential role for those starting treatment for the first time. This review incorporates data from the most recent treatment guidelines, peer-reviewed publications, and recent presentations at research meetings about some of these relatively new and emerging antiretroviral agents and offers strategies for incorporating them into clinical practice.