Giant Left Ventricular Aneurysm With Dynamic Right Ventricular Compression and Subsequent End-Stage Heart Failure.

We report a case of a patient with a missed anterior myocardial infarction and associated ischemic cardiomyopathy. The patient had a massive true left ventricular aneurysm causing dynamic right ventricular compression, with associated cardiogenic shock, for which a heart transplantation was ultimately performed.

Who Benefits? An Assessment of Resident Benefits at Top 50 Academic Institutions.

OBJECTIVE: Residency serves as a crucial time in the professional and personal development of young physicians. Extensive effort is devoted to the clinical training of residents across the country. However, many residents report concerns with compensation, quality of life, and benefits during their clinical training. We sought to evaluate the benefits packages of resident physicians in comparison with other full-time employees at their institutions. SETTING: "Top 50" Residency programs in Medicine, Surgery, and Pediatrics in the United States. DESIGN: To accomplish this task we selected the, "Top-50," institutions for medicine, pediatrics, and surgery using Doximity's Residency Navigator and compared the benefits of residents at these institutions with full-time employees by accessing benefits offerings listed on institutional websites. RESULTS: We found that residents were more likely to receive parking benefits and gym memberships, while full-time employees were more likely to be offered flexible spending accounts, retirement benefits, and tuition support. CONCLUSIONS: Residents receive different benefits packages than their colleagues employed in full time positions at the same institutions. Further discussion regarding the benefits offered to physicians, and the role that benefits play in resident wellbeing is warranted in light of these findings.

Mediator Kinase Inhibition Impedes Transcriptional Plasticity and Prevents Resistance to ERK/MAPK-Targeted Therapy in KRAS-Mutant Cancers.

Acquired resistance remains a major challenge for therapies targeting oncogene activated pathways. KRAS is the most frequently mutated oncogene in human cancers, yet strategies targeting its downstream signaling kinases have failed to produce durable treatment responses. Here, we developed multiple models of acquired resistance to dual-mechanism ERK/MAPK inhibitors across KRAS-mutant pancreatic, colorectal, and lung cancers, and then probed the long-term events enabling survival against this class of drugs. These studies revealed that resistance emerges secondary to large-scale transcriptional adaptations that are diverse and cell line-specific. Transcriptional reprogramming extends beyond the well-established early response, and instead represents a dynamic, evolved process that is refined to attain a stably resistant phenotype. Mechanistic and translational studies reveal that resistance to dual-mechanism ERK/MAPK inhibition is broadly susceptible to manipulation of the epigenetic machinery, and that Mediator kinase, in particular, can be co-targeted at a bottleneck point to prevent diverse, cell line-specific resistance programs.

Inflammatory Bowel Disease Presenting With Concurrent COVID-19 Multisystem Inflammatory Syndrome.

Coronavirus disease 2019 is associated with a postinfectious multisystem inflammatory syndrome in children (MIS-C). This syndrome is marked by cytokine storm and multiorgan dysfunction, often affecting the gastrointestinal tract, the heart, and the hematopoietic system. We describe the case of a 16-year-old boy with an initial presentation of severe inflammatory bowel disease and concurrent MIS-C. He presented with abdominal pain, diarrhea, and hematochezia and met criteria for the systemic inflammatory response syndrome. Laboratory inflammatory profiling revealed markedly elevated ferritin, D-dimer, C-reactive protein, soluble interleukin 2, and interleukin 6 levels. Endoscopy and colonoscopy revealed severe active gastroduodenitis, patchy colitis, and a normal-appearing terminal ileum. The patient was treated with a combination of steroids, intravenous immunoglobulin, and infliximab, and his symptoms slowly resolved over a 3-week period. In this case, we describe coincident MIS-C with a remarkably severe and difficult-to-treat initial presentation of inflammatory bowel disease and highlight the need to investigate the effect of coronavirus disease 2019 and MIS-C on inflammatory disorders.

Targeting MCL-1/BCL-XL Forestalls the Acquisition of Resistance to ABT-199 in Acute Myeloid Leukemia.

ABT-199, a potent and selective small-molecule antagonist of BCL-2, is being clinically vetted as pharmacotherapy for the treatment of acute myeloid leukemia (AML). However, given that prolonged monotherapy tends to beget resistance, we sought to investigate the means by which resistance to ABT-199 might arise in AML and the extent to which those mechanisms might be preempted. Here we used a pathway-activating genetic screen to nominate MCL-1 and BCL-XL as potential nodes of resistance. We then characterized a panel of ABT-199-resistant myeloid leukemia cell lines derived through chronic exposure to ABT-199 and found that acquired drug resistance is indeed driven by the upregulation of MCL-1 and BCL-XL. By targeting MCL-1 and BCL-XL, resistant AML cell lines could be resensitized to ABT-199. Further, preemptively targeting MCL-1 and/or BCL-XL alongside administration of ABT-199 was capable of delaying or forestalling the acquisition of drug resistance. Collectively, these data suggest that in AML, (1) the selection of initial therapy dynamically templates the landscape of acquired resistance via modulation of MCL-1/BCL-XL and (2) appropriate selection of initial therapy may delay or altogether forestall the acquisition of resistance to ABT-199.

Systematic identification of signaling pathways with potential to confer anticancer drug resistance.

Cancer cells can activate diverse signaling pathways to evade the cytotoxic action of drugs. We created and screened a library of barcoded pathway-activating mutant complementary DNAs to identify those that enhanced the survival of cancer cells in the presence of 13 clinically relevant, targeted therapies. We found that activation of the RAS-MAPK (mitogen-activated protein kinase), Notch1, PI3K (phosphoinositide 3-kinase)-mTOR (mechanistic target of rapamycin), and ER (estrogen receptor) signaling pathways often conferred resistance to this selection of drugs. Activation of the Notch1 pathway promoted acquired resistance to tamoxifen (an ER-targeted therapy) in serially passaged breast cancer xenografts in mice, and treating mice with a γ-secretase inhibitor to inhibit Notch signaling restored tamoxifen sensitivity. Markers of Notch1 activity in tumor tissue correlated with resistance to tamoxifen in breast cancer patients. Similarly, activation of Notch1 signaling promoted acquired resistance to MAPK inhibitors in BRAF(V600E) melanoma cells in culture, and the abundance of Notch1 pathway markers was increased in tumors from a subset of melanoma patients. Thus, Notch1 signaling may be a therapeutic target in some drug-resistant breast cancers and melanomas. Additionally, multiple resistance pathways were activated in melanoma cell lines with intrinsic resistance to MAPK inhibitors, and simultaneous inhibition of these pathways synergistically induced drug sensitivity. These data illustrate the potential for systematic identification of the signaling pathways controlling drug resistance that could inform clinical strategies and drug development for multiple types of cancer. This approach may also be used to advance clinical options in other disease contexts.