Hemodynamic Response to Oral Vasodilator Therapy in Systemic Sclerosis-Related Pulmonary Hypertension.

PURPOSE: Although classified as group 1 pulmonary arterial hypertension (PAH), patients with systemic sclerosis-related pulmonary hypertension (SSc-PH) experience poorer clinical response to PAH therapy and increased mortality compared to those with idiopathic PAH. Due to heterogeneity in phenotypes, identifying patients likely to respond to therapy is challenging. The goal of this study was to determine clinical factors associated with hemodynamic response, defined by a > 20% reduction in pulmonary vascular resistance on repeat right heart catheterization. METHODS: We applied a time-to-event model using a retrospective cohort of 39 patients with precapillary SSc-PH, defined by a mean pulmonary artery pressure of ≥ 25 mmHg and pulmonary arterial wedge pressure (PAWP) ≤ 15 mmHg on right heart catheterization. RESULTS: Patients with PAWP ≤ 8 mmHg were nearly fourfold more likely to achieve a hemodynamic response compared to those with PAWP > 8 mmHg (HR 3.88; 95% CI: 1.20, 12.57); each 1 mmHg increase in PAWP was associated with a decreased hazard for hemodynamic response (HR 0.84; 95% CI: 0.70, 1.00). CONCLUSION: In patients with precapillary SSc-PH, PAWP was associated with time to hemodynamic response, suggesting the importance of subclinical cardiac disease in determining hemodynamic response to oral vasodilator therapy.

Whole-genome doubling confers unique genetic vulnerabilities on tumour cells.

Whole-genome doubling (WGD) is common in human cancers, occurring early in tumorigenesis and generating genetically unstable tetraploid cells that fuel tumour development1,2. Cells that undergo WGD (WGD+ cells) must adapt to accommodate their abnormal tetraploid state; however, the nature of these adaptations, and whether they confer vulnerabilities that can be exploited therapeutically, is unclear. Here, using sequencing data from roughly 10,000 primary human cancer samples and essentiality data from approximately 600 cancer cell lines, we show that WGD gives rise to common genetic traits that are accompanied by unique vulnerabilities. We reveal that WGD+ cells are more dependent than WGD- cells on signalling from the spindle-assembly checkpoint, DNA-replication factors and proteasome function. We also identify KIF18A, which encodes a mitotic kinesin protein, as being specifically required for the viability of WGD+ cells. Although KIF18A is largely dispensable for accurate chromosome segregation during mitosis in WGD- cells, its loss induces notable mitotic errors in WGD+ cells, ultimately impairing cell viability. Collectively, our results suggest new strategies for specifically targeting WGD+ cancer cells while sparing the normal, non-transformed WGD- cells that comprise human tissue.

Marijuana-induced Coronary Vasospasm with Persistent Inter-coronary Connection: A Case Report and Review of Literature.

Coronary vasospasm is a well-known entity causing acute chest syndrome and can lead to myocardial infarction, ventricular arrhythmias, and even sudden cardiac death. While there are extensive case series showing the association of coronary vasospasm with cocaine, studies reporting marijuana-induced coronary vasospasm are limited in number. We herein present a case of coronary vasospasm in a middle-aged African-American male who presented to the emergency department after an episode of syncope. His urine drug screen was positive only for marijuana. He had a transient elevation of ST segments on his EKG with concomitant wall motion abnormalities on echocardiogram and was later found to have vasospasm of coronary arteries on coronary angiogram without any evidence of focal atherosclerotic disease. Another interesting finding was the persistent inter-coronary communication or coronary arcade connecting the left circumflex artery to the right coronary artery. There was bi-directional flow through the inter-coronary communication and hence, we believe this communication prevented our patient from experiencing acute chest symptoms or myocardial infarction. It is important for the clinicians to recognize the association of marijuana with coronary vasospasm. At the same time, these patients should be treated as acute coronary syndromes until proven otherwise by ischemia evaluation.