Outcomes of Transcatheter Aortic Valve Implant Among Patients With A Previous Coronary Artery Bypass Graft: A Nationwide Analysis.

There is a paucity of data regarding the temporal trends and outcomes of transcatheter aortic valve implant (TAVI) among patients with a previous coronary artery bypass graft (CABG) surgery. We queried the Nationwide Readmissions Database (2016 to 2019) for hospitalized patients who underwent TAVI using the appropriate International Classification of Diseases, Tenth Revision procedural codes. A multivariable regression analysis was used to adjust for the patients' and hospitals' characteristics in comparing the study groups. The primary outcome was in-hospital mortality. The final analysis included 237,829 patients who underwent TAVI, of whom 42,671 (17.9%) had a previous CABG. During the study period, there was a decrease in the proportion of patients with previous CABG who underwent TAVI (21.0% in 2016 vs 15.5% in 2019, ptrend = 0.01), although there was no change in their in-hospital mortality rate (1.08% in 2016 vs 1.25% in 2019, ptrend = 0.43). Patients with a previous CABG were younger and less likely to be women than those without a previous CABG. TAVI among those with a previous CABG was associated with lower in-hospital mortality (adjusted odds ratio [aOR] 0.79, 95% confidence interval [CI] 0.69 to 0.91), similar rate of ischemic stroke (aOR 0.81, 95% CI 0.71 to 0.93) and permanent pacemaker implant (aOR 1.00, 95% CI 0.93 to 1.05). Patients with a previous CABG had a lower all-cause 90-day readmission (odds ratio 0.95, 95% CI 0.94 to 1.06) but higher readmission for transient ischemic attack. Among those with a previous CABG, female gender and chronic kidney disease stage ≥3 were independently associated with a higher in-hospital mortality, whereas obesity was associated with a lower in-hospital mortality. In conclusion, there was a decrease in the proportion of patients with a previous CABG among those who underwent TAVI. TAVI among those with a previous CABG was not associated with increased in-hospital adverse events or 90-day all-cause readmissions.

Compound C Inhibits Ovarian Cancer Progression via PI3K-AKT-mTOR-NFκB Pathway.

Epithelial Ovarian cancer (OvCa) is the leading cause of death from gynecologic malignancies in the United States, with most patients diagnosed at late stages. High-grade serous cancer (HGSC) is the most common and lethal subtype. Despite aggressive surgical debulking and chemotherapy, recurrence of chemo-resistant disease occurs in ~80% of patients. Thus, developing therapeutics that not only targets OvCa cell survival, but also target their interactions within their unique peritoneal tumor microenvironment (TME) is warranted. Herein, we report therapeutic efficacy of compound C (also known as dorsomorphin) with a novel mechanism of action in OvCa. We found that CC not only inhibited OvCa growth and invasiveness, but also blunted their reciprocal crosstalk with macrophages, and mesothelial cells. Mechanistic studies indicated that compound C exerts its effects on OvCa cells through inhibition of PI3K-AKT-NFκB pathways, whereas in macrophages and mesothelial cells, CC inhibited cancer-cell-induced canonical NFκB activation. We further validated the specificity of the PI3K-AKT-NFκB as targets of compound C by overexpression of constitutively active subunits as well as computational modeling. In addition, real-time monitoring of OvCa cellular bioenergetics revealed that compound C inhibits ATP production, mitochondrial respiration, and non-mitochondrial oxygen consumption. Importantly, compound C significantly decreased tumor burden of OvCa xenografts in nude mice and increased their sensitivity to cisplatin-treatment. Moreover, compound C re-sensitized patient-derived resistant cells to cisplatin. Together, our findings highlight compound C as a potent multi-faceted therapeutic in OvCa.

Metabolomic credentialing of murine carcinogen-induced urothelial cancer.

Bladder cancer (BCa) is the most common malignancy of the urinary system with increasing incidence, mortality, and limited treatment options. Therefore, it is imperative to validate preclinical models that faithfully represent BCa cellular, molecular, and metabolic heterogeneity to develop new therapeutics. We performed metabolomic profiling of premalignant and non-muscle invasive bladder cancer (NMIBC) that ensued in the chemical carcinogenesis N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) mouse model. We identified the enriched metabolic signatures that associate with premalignant and NMIBC. We found that enrichment of lipid metabolism is the forerunner of carcinogen-induced premalignant and NMIBC lesions. Cross-species analysis revealed the prognostic value of the enzymes associated with carcinogen-induced enriched metabolic in human disease. To date, this is the first study describing the global metabolomic profiles associated with early premalignant and NMIBC and provide evidence that these metabolomic signatures can be used for prognostication of human disease.

SPARC Inhibits Metabolic Plasticity in Ovarian Cancer.

The tropism of ovarian cancer (OvCa) to the peritoneal cavity is implicated in widespread dissemination, suboptimal surgery, and poor prognosis. This tropism is influenced by stromal factors that are not only critical for the oncogenic and metastatic cascades, but also in the modulation of cancer cell metabolic plasticity to fulfill their high energy demands. In this respect, we investigated the role of Secreted Protein Acidic and Rich in Cysteine (SPARC) in metabolic plasticity of OvCa. We used a syngeneic model of OvCa in Sparc-deficient and proficient mice to gain comprehensive insight into the paracrine effect of stromal-SPARC in metabolic programming of OvCa in the peritoneal milieu. Metabolomic and transcriptomic profiling of micro-dissected syngeneic peritoneal tumors revealed that the absence of stromal-Sparc led to significant upregulation of the enzymes involved in glycolysis, TCA cycle, and mitochondrial electron transport chain (ETC), and their metabolic intermediates. Absence of stromal-Sparc increased reactive oxygen species and perturbed redox homeostasis. Recombinant SPARC exerted a dose-dependent inhibitory effect on glycolysis, mitochondrial respiration, ATP production and ROS generation. Comparative analysis with human tumors revealed that SPARC-regulated ETC-signature inversely correlated with SPARC transcripts. Targeting mitochondrial ETC by phenformin treatment of tumor-bearing Sparc-deficient and proficient mice mitigated the effect of SPARC-deficiency and significantly reduced tumor burden, ROS, and oxidative tissue damage in syngeneic tumors. In summary, our findings provide novel insights into the role of SPARC in regulating metabolic plasticity and bioenergetics in OvCa, and shines light on its potential therapeutic efficacy.

Role of tumor microenvironment in the pathobiology of ovarian cancer: Insights and therapeutic opportunities.

Ovarian cancer is the fifth most common cancer affecting women and at present, stands as the most lethal gynecologic malignancy. The poor disease outcome is due to the nonspecific symptoms and the lack of effective treatment at advanced stages. Thus, it is of utmost importance to understand ovarian carcinoma through several lenses and to dissect the role that the unique peritoneal tumor microenvironment plays in ovarian cancer progression and metastasis. This review seeks to highlight several determinants of this unique tumor microenvironment, their influence on disease outcome and ongoing clinical trials targeting these determinants.

Role of tumor microenvironment in ovarian cancer pathobiology.

Ovarian cancer is the fifth most common cancer affecting the female population and at present, stands as the most lethal gynecologic malignancy. Poor prognosis and low five-year survival rate are attributed to nonspecific symptoms and below par diagnostic criteria at early phases along with a lack of effective treatment at advanced stages. It is thus of utmost importance to understand ovarian carcinoma through several lenses including its molecular pathogenesis, epidemiology, histological subtypes, hereditary factors, diagnostic approaches and methods of treatment. Above all, it is crucial to dissect the role that the unique peritoneal tumor microenvironment plays in ovarian cancer progression and metastasis. This review seeks to highlight several important aspects of ovarian cancer pathobiology as a means to provide the necessary background to approach ovarian malignancies in the future.