Stearoyl-CoA-Desaturase 1 inhibition induces apoptosis in Pancreatic Cancer cells

Pancreatic cancer (PC) is an aggressive cancer with advanced disease at diagnosis and lack of effective therapy. PC tumours carry a mutated KRAS gene essential to their growth and spread, which plays a key role in deregulating cell metabolism. Stearoyl-CoA-Desaturase 1 (SCD1) is a highly regulated enzyme responsible for desaturating fatty acids, converting Stearic acid to Oleic acid. The expression of SCD1 is known to be upregulated in PC, indicating that it represents a metabolic bottleneck for cancer cell metabolism and might contribute to the growth and spread of PC. The aim of this study is to determine the effects of inhibiting SCD1 activity on a PC cell line (PANC1) in vitro. PANC1 cells were incubated for 48 hours with various concentrations of CAY10566, a selective SCD1 inhibitor. The cells were trypsinized, stained with Annexin V (AnV) and Propidium Iodide (PI) and analysed using flow cytometry. SCD1 inhibition (INHIB) significantly decreases viable PANC1 cells (AnV-, PI-) compared to a medium-only control (CON) (INHIB 48.76% (± 0.03), CON 60.71% (±0.01), P<0.05) and significantly increased apoptosis (AnV +, PI-) (INHIB 31.56% (±0.07), CON 25.32% (±0.02), P<0.05. Microscopically, the membrane of these cells appears less defined after treatment with the SCD inhibitor, indicating changes in composition may occur. Our results show that SCD1 inhibition significantly affects PC cell death and apoptosis. Further work is required to combine SCD1 inhibition with the standard PC chemotherapy Gemcitabine, and assess if there is a synergistic effect of the two drugs. This supplemented treatment could improve TMN (tumour metastasis node) and progression free survival, both clinical markers of patient outcome, in PC patients

Proteomic Characterization of Circulating Molecular Perturbations Associated With Pancreatic Adenocarcinoma Following Intravenous omega-3 Fatty Acid and Gemcitabine Administration: A Pilot Study

Background: Administration of intravenous ω-3 fatty acid (ω-3FA) in advanced pancreatic adenocarcinoma patients receiving gemcitabine chemotherapy shows disease stabilization and improved progression-free survival. Using high-definition plasma proteomics, the underlying biological mechanisms responsible for these clinical effects are investigated. Methods and Results: A pilot study involving plasma that was collected at baseline from 13 patients with histologically confirmed, unresectable pancreatic adenocarcinoma (baseline group) after 1-month treatment with intravenous gemcitabine and ω-3FA (treatment group) and intravenous gemcitabine only (control group) and was prepared for proteomic analysis. A 2-arm study comparing baseline vs treatment and treatment vs control was performed. Proteins were isolated from plasma with extensive immunodepletion, then digested and labeled with isobaric tandem mass tag peptide tags. Samples were then combined, fractionated, and injected into a QExactive-Orbitrap Mass-Spectrometer and analyzed on Proteome Discoverer and Scaffold with ensuing bioinformatics analysis. Selective reaction monitoring analysis was performed for verification. In total, 3476 proteins were identified. Anti-inflammatory markers (C-reactive protein, haptoglobin, and serum amyloid-A1) were reduced in the treatment group. Enrichment analysis showed angiogenesis downregulation, complement immune systems upregulation, and epigenetic modifications on histones. Pathway analysis identified direct action via the Pi3K-AKT pathway. Serum amyloid-A1 significantly reduced (P <.001) as a potential biomarker of efficacy for ω-3FA. Conclusions: This pilot study demonstrates administration of ω-3FA has potential anti-inflammatory, antiangiogenic, and proapoptotic effects via direct interaction with cancer-signaling pathways in patients with advanced pancreatic adenocarcinoma. Further studies in a larger sample size is required to validate the clinical correlation found in this preliminary study

Peri-operative variables associated with prolonged intensive care stay following cytoreductive surgery for ovarian cancer

Background: Peri-operative variables associated with prolonged Intensive Care Unit (ICU) admission following cytoreductive surgery for ovarian cancer were investigated. Patients and Methods: A retrospective review was carried out of patients admitted to the ICU following cytoreductive surgery for ovarian cancer in a single tertiary referral centre from 2015-2019. Patients were categorized according to length of ICU stay (<48 h and ≥48 h), and peri-operative variables were compared across the two groups. Results: A total of 56 patients were admitted to the ICU post-operatively, 37 for <48 h and 19 for ≥48 h (range=3-11 days). Greater duration of procedure and estimated blood loss, bowel resection, higher post-operative lactate level, lower post-operative albumin level and requirement for post-operative blood products were associated with prolonged ICU stay. Increased intraoperative fluid requirement was an independent predictor of extended ICU stay. Conclusion: Utilizing identified intra-operative risk factors to perform individualized risk assessments might improve planning of ICU resources. Optimizing intraoperative fluid management may improve short-term patient outcomes