Splicing reprogramming of TRAIL/DISC-components sensitizes lung cancer cells to TRAIL-mediated apoptosis.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selective killing of cancer cells underlines its anticancer potential. However, poor tolerability and resistance underscores the need to identify cancer-selective TRAIL-sensitizing agents. Apigenin, a dietary flavonoid, sensitizes lung cancer cell lines to TRAIL. It remains unknown, however, whether apigenin sensitizes primary lung cancer cells to TRAIL and its underlying mechanisms. Here we show that apigenin reprograms alternative splicing of key TRAIL/death-inducing-signaling-complex (DISC) components: TRAIL Death Receptor 5 (DR5) and cellular-FLICE-inhibitory-protein (c-FLIP) by interacting with the RNA-binding proteins hnRNPA2 and MSI2, resulting in increased DR5 and decreased c-FLIPS protein levels, enhancing TRAIL-induced apoptosis of primary lung cancer cells. In addition, apigenin directly bound heat shock protein 70 (Hsp70), promoting TRAIL/DISC assembly and triggering apoptosis. Our findings reveal that apigenin directs alternative splicing and inhibits Hsp70 enhancing TRAIL anticancer activity. These findings underscore impactful synergies between diet and cancer treatments opening new avenues for improved cancer treatments.

Oral fluoroquinolones for definitive treatment of gram-negative bacteremia in cancer patients.

PURPOSE: Bloodstream infections (BSI) are significant causes of morbidity and mortality in cancer patients. These patients often receive 10 to 14 days of intravenous (IV) antibiotics. The objective of this study was to compare the outcomes of cancer patients transitioned from IV to oral (PO) therapy compared to continuation of IV treatment. METHODS: This was a single-center, retrospective cohort study of hospitalized adult cancer patients with gram-negative bacteremia. Patients transitioned to a PO fluoroquinolone (FQ) within 5 days were allocated to the IV-to-PO group, while the remaining patients comprised the IV group. The primary outcome was the composite of treatment failure, defined as infection-related readmission, infection recurrence, or inpatient mortality. A multivariable logistic regression model was constructed to account for confounding variables. Secondary outcomes assessed included infection-related length of stay (LOS), hospital LOS, and adverse events, such as Clostridioides difficile infection and catheter-related complications. RESULTS: The IV-to-PO group included 78 patients, while the remaining 133 patients were allocated to the IV group. Differences at baseline included more hematologic malignancy, neutropenia, ICU admissions, and higher Pitt bacteremia scores in the IV group. The rate of treatment failure was significantly higher in the IV group (24% vs 9%; p < 0.01), which persisted in the logistic regression (aOR 3.5, 95% CI 1.3-9.1). The IV-to-PO group had decreased infection-related and hospital length of stay, as well as fewer catheter-related complications. CONCLUSIONS: The use of PO FQ may be considered for the definitive treatment of uncomplicated Enterobacterales BSI in cancer patients.

Comparison of conventional versus liposomal irinotecan in combination with fluorouracil for advanced pancreatic cancer: a single-institution experience.

The majority of pancreatic cancers are diagnosed at an advanced stage, when surgical options are limited and treatment relies on systemic chemotherapy. In the NAPOLI-1 trial, liposomal irinotecan in combination with fluorouracil (nal-iri/5FU) was shown to improve overall survival when compared to fluorouracil alone for metastatic pancreatic cancer. Other retrospective studies have shown the combination of fluorouracil and conventional irinotecan (FOLFIRI) to be a viable option, though no randomized trials have compared nal-iri/5FU to FOLFIRI. The purpose of this single-center, retrospective, cohort study was to determine if nal-iri/5FU and FOLFIRI are similarly effective for the treatment of advanced pancreatic cancer. Due to the potential for treatment bias, inverse probability of treatment weighting was utilized to correct for baseline differences between the groups. The primary outcome of progression-free survival was similar at 4.1 months for nal-iri/5FU and 3.1 months for FOLFIRI. Overall survival and adverse effect frequency were also similar. Pegfilgrastim was used in 16% and 15% of patients, respectively, and nal-iri/5FU patients required significantly less atropine during treatment (36 vs. 70%). A cost analysis was conducted and concluded that the treatment with nal-iri/5FU was nearly 30 times more expensive than FOLFIRI treatment. Together, these data suggest a potential role for FOLFIRI for the treatment of advanced pancreatic cancer in the absence of clear benefits in effectiveness, toxicity, or cost for nal-iri/5FU.