A Ketogenic Diet Sensitizes Pancreatic Cancer to Inhibition of Glutamine Metabolism.

Pancreatic cancer is the third leading cause of cancer death in the United States, and while conventional chemotherapy remains the standard treatment, responses are poor. Safe and alternative therapeutic strategies are urgently needed 1 . A ketogenic diet has been shown to have anti-tumor effects across diverse cancer types but will unlikely have a significant effect alone. However, the diet shifts metabolism in tumors to create new vulnerabilities that can be targeted (1). Modulators of glutamine metabolism have shown promise in pre-clinical models but have failed to have a marked impact against cancer in the clinic. We show that a ketogenic diet increases TCA and glutamine-associated metabolites in murine pancreatic cancer models and under metabolic conditions that simulate a ketogenic diet in vitro. The metabolic shift leads to increased reliance on glutamine-mediated anaplerosis to compensate for low glucose abundance associated with a ketogenic diet. As a result, glutamine metabolism inhibitors, such as DON and CB839 in combination with a ketogenic diet had robust anti-cancer effects. These findings provide rationale to study the use of a ketogenic diet with glutamine targeted therapies in a clinical context.

IDH1 Inhibition Potentiates Chemotherapy Efficacy in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is associated with a 5-year overall survival rate of just 13%, and development of chemotherapy resistance is nearly universal. PDAC cells overexpress wild-type isocitrate dehydrogenase 1 (IDH1) that can enable them to overcome metabolic stress, suggesting it could represent a therapeutic target in PDAC. Here, we found that anti-IDH1 therapy enhanced the efficacy of conventional chemotherapeutics. Chemotherapy treatment induced reactive oxygen species (ROS) and increased tricarboxylic acid cycle activity in PDAC cells, along with the induction of wild-type IDH1 expression as a key resistance factor. IDH1 facilitated PDAC survival following chemotherapy treatment by supporting mitochondrial function and antioxidant defense to neutralize ROS through the generation of α-ketoglutarate and NADPH, respectively. Pharmacologic inhibition of wild-type IDH1 with ivosidenib synergized with conventional chemotherapeutics in vitro and potentiated the efficacy of subtherapeutic doses of these drugs in vivo in murine PDAC models. This promising treatment approach is translatable through available and safe oral inhibitors and provides the basis of an open and accruing clinical trial testing this combination (NCT05209074). Significance: Targeting IDH1 improves sensitivity to chemotherapy by suppressing mitochondrial function and inducing oxidative stress, supporting the potential of the combination as an effective strategy for treating pancreatic cancer.

National and Regional Fraction of Cancer Incidence and Death Attributable to Current Tobacco and Water-Pipe Smoking in the Eastern Mediterranean Countries in 2020.

INTRODUCTION: We aimed to calculate the Population Attributable Fraction (PAF) of cancers due to tobacco use in the Eastern Mediterranean Region (EMRO), where water-pipe smoking is prevalent but its effect was not considered in previous studies. AIMS AND METHODS: We applied Levin's formula to estimate PAFs of cancers due to tobacco use (defined as all type tobacco including both cigarette and water-pipe). We also calculated PAF of water-pipe smoking separately. Exposure prevalence data were retrieved from representative national and subnational surveys. Data on cancer incidence and death were also and cancer cases were obtained GLOBOCAN 2020. We also obtained associated relative risks from published meta-analyses. RESULTS: Of the total 715 658 incident adult cancer cases that were reported in 2020 in EMRO, 14.6% (n = 104 800) was attributable to tobacco smoking (26.9% [n = 92 753]) in men versus 3.3% (n = 12 048) in women. Further, 1.0% of incident adult cancers were attributable to current water-pipe use (n = 6825) (1.7% [n = 5568]) in men versus 0.4% (n = 1257 in women). CONCLUSIONS: PAFs of cancers due to tobacco smoking in EMRO were higher in our study than previous reports. This could be due to the neglected role of water-pipe in previous studies that is a common tobacco smoking method in EMRO. The proportion of cancers attributable to water-pipe smoking in EMRO might be underestimated due to lack of research on the risk of cancers associated with water-pipe smoking and also less developed cancer registries in EMRO. IMPLICATIONS: In this study, we found higher PAFs for cancers due to tobacco smoking in the Eastern Mediterranean (EMR) region than previous reports. This difference could be due to ignoring the role of water-pipe smoking in previous studies. In 2020, 1% of incident cancers and 1.3% of cancer-related deaths in EMRO were attributable to water-pipe smoking. We also found a big difference in PAFs of cancers due to tobacco and water-pipe smoking across EMRO countries, with Tunisia, Lebanon, and Jordan having the highest, and Djibouti, Sudan, and Somalia having the lowest proportions of cancers attributable to tobacco and water-pipe smoking.

Trends of in-hospital and ICU mortality in COVID-19 patients over the fourth and fifth COVID-19 surges in Iran: a retrospective cohort study from Iran.

OBJECTIVE: The current study aimed to investigate the temporal trend of in-hospital and intensive care unit (ICU) mortality of coronavirus disease 2019 (COVID-19) patients over 6 months in the spring and summer of 2021 in Iran. DESIGN: We performed an observational retrospective cohort study. SETTING: Qazvin Province- Iran during 6 month from April to September 2021. PARTICIPANTS: All 14355 patients who were hospitalized with confirmed COVID-19 in hospitals of Qazvin Province. INTERVENTION: No intervention. MAIN OUTCOME MEASURES: The trends of overall in-hospital mortality and ICU mortality were the main outcome of interest. We obtained crude and adjusted in-hospital and ICU mortality rates for each month of admission and over surge and lull periods of the disease. RESULTS: The overall in-hospital mortality, early mortality and ICU mortality were 8.8%, 3.2% and 67.6%, respectively. The trend for overall mortality was almost plateau ranging from 6.5% in July to 10.7% in April. The lowest ICU mortality was 60.0% observed in April, whereas it reached a peak in August (ICU mortality = 75.7%). Admission on surge days of COVID-19 was associated with an increased risk of overall mortality (Odds ratio = 1.3, 95% confidence interval = 1.1, 1.5). The comparison of surge and lull status showed that the odds of ICU mortality in the surge of COVID-19 was 1.7 higher than in the lull period (P-value < 0.001). CONCLUSIONS: We found that the risk of both overall in-hospital and ICU mortality increased over the surge period and fourth and fifth waves of severe acute respiratory syndrome coronavirus 2 infection in Iran. The lack of hospital resources and particularly ICU capacities to respond to the crisis during the surge period is assumed to be the main culprit.