Abstract Non-small cell lung cancer (NSCLC) is a primary type of lung cancer and a leading cause of cancer-related mortality worldwide. The Warburg effect, characterized by increased glycolysis and reduced oxidative phosphorylation, is a hallmark of NSCLC and presents a therapeutic target. Annonacin, a natural compound found in fruits from the Annonaceae family, interferes with oxidative phosphorylation by inhibiting mitochondrial complex I. 2-deoxy-d-glucose (2DG), a glucose analog, disrupts glycolysis. This study examines the effects of Annonacin and 2DG on NSCLC A549 cells, both individually and in combination, with the hypothesis that inhibiting both metabolic pathways simultaneously will lead to more effective cancer treatment. In addition, we explored how these treatments might alter the tumor microenvironment, oxidative stress, and effects on normal epithelial bronchial cells. A549 NSCLC cells were exposed to different concentrations of Annonacin (0, 1, 2, 4, 6 µM) and 2DG (0,1.25, 2.5, 5, 10 mM), separately and together. Cell viability was measured using the MTT assay. Genotoxicity was assessed through the Comet Assay, and oxidative stress was evaluated by measuring superoxide dismutase and glutathione peroxidase activities. The long-term ability of the cells to proliferate was tested using colony-forming assays. The NL20 bronchial epithelial cell line was tested as a parallel control. Both Annonacin and 2DG showed a dose-dependent ability to kill A549 cells. However, when used together, these substances had a stronger effect, significantly lowering the number of surviving cells compared to when each was used alone. The response of this combination treatment on genotoxicity using Comet Assay is being pursued. Changes in oxidative stress responses were found, as shown by the altered superoxide dismutase and glutathione peroxidase enzyme activities. The ability of A549 cells to form colonies was greatly reduced following combination treatment, indicating a reduction in their long-term proliferative capacity. The combination of Annonacin and 2DG effectively inhibits the growth of NSCLC A549 cells by targeting their metabolic weaknesses, which may lead to increased DNA damage and oxidative stress. These results suggest simultaneous targeting glycolysis and oxidative phosphorylation could be a promising new approach for treating NSCLC. Future in vivo studies will evaluate this combination in live models and can offer insights into efficacy and possible translation to clinical application. Citation Format: Bhoj Raj Bhattarai, Cora Teets, Avinash Tope. Targeting metabolic vulnerability of non-small cell lung cancer with annonacin and 2-deoxy-d-glucose in individual and combination modality [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A016.
Introduction: The aim of our study is to determine the clinical, biochemical, and imaging factors that affect the duration of hospital stay in patients admitted with normotensive acute pulmonary embolism. Methods: This was a single-center retrospective study conducted in a community hospital in New York metropolitan area for patients admitted from October 2015 to October 2017. Results: A total of 79 patients were included, the mean age was 55.76 (SD = 17.33), 29 cases were males (37%) and 50 cases were females (63%). Among all patients, 17 cases had short length of stay (LOS) (≤2 days) and 62 cases had long LOS (>2 days). There were statistically significant differences in age (p = .041), presence of lung disease (p = .036), number of comorbidities (p = .043), and pulmonary embolism severity index (PESI) scores (original and simplified; p = .002 and .001, respectively). Logistic regression analysis showed that PESI score significantly predicted long LOS (OR 1.067, 95% CI [1.001, 1.137], p = .048). Similarly, sPESI significantly predicted long LOS (OR 0.223, 95% CI [0.050, 0.999], p = .050). Both regression models were adjusted for age, lung disease, and number of comorbidities. Conclusion: Both original and simplified PESI scores were statistically significant predictors of duration of hospital stay. Patients with multiple comorbidities or with chronic lung disease were also likely to have prolonged hospital stay. None of the cardiac biomarkers affected the duration of hospital stay, neither did the presence of right ventricular dysfunction nor treatment modality.
Introduction: Von Willebrand factor (vWF) is essential in platelet adhesion and aggregation. High concentration of vWF is associated with cerebrovascular accidents (CVA); however, it is yet unclear if its deficiency could protect against CVA. This study aims to compare the prevalence and relative risk (RR) of CVA in patients with and without vWD. Methods: Discharge data of the National Inpatient Sample (NIS) from 2009 to 2014 were analyzed and records for vWD and CVA were identified using ICD-9 codes. Log-binomial model was used to estimate the RR of CVA in patients with and without vWD after adjustment for CVA risk factors. Results: A total of 224,475,443 weight adjusted hospital discharge sample of patients, including 82,809 patients with vWD, were identified. The prevalence of CVA was lower in patients with vWD than those without vWD (1.31% vs 2.04%), with a RR of 0.64 (95% CI: 0.60-0.68) (table 1). Adjusted RR for CVA risk factors was 0.71 (95% CI: 0.67-0.76) (table 2). Conclusion: Patients with vWD showed a lower risk of developing CVA when compared to those without vWD, this lower RR persisted after controlling for other CVA risk factors. These findings suggest that vWD could be protective against CVA, and vWF might be a potential therapeutic target that requires further investigation in individuals at high risk of developing CVA.
Clozapine is the preferred antipsychotic used for the treatment of resistant schizophrenia with suicidal ideation. The drug is started at a low dose and gradually increased to a target dose of 300-450 mg/day. It is well known to cause agranulocytosis and neutropenia. Several cases of fatal sepsis have been reported in neutropenic patients and emphasis is placed on monitoring for agranulocytosis; however, clozapine also causes intestinal hypomotility and constipation, which if unrecognized can lead to intestinal obstruction, bowel necrosis, and intra-abdominal sepsis. Reduced behavioral pain reactivity in schizophrenics may alter the ability to express pain, potentially leading to a delay in the presentation for medical attention. We report a case of fatal intra-abdominal sepsis secondary to an unrecognized case of clozapine-related constipation.
Sarcoidosis is a granulomatous disease of unknown etiology which may present with systemic manifestations. The diagnosis of gastric sarcoidosis needs much effort to accomplish as it is exceedingly rare, and the treatment is usually recommended exclusively for symptomatic disease. Here, we present a case of gastric sarcoidosis in a 31-year old black female patient with symptoms of nausea and epigastric pain. A diagnosis of gastric sarcoidosis was mainly based on the presence of non-necrotizing granulomas on biopsy following esophagogastroduodenoscopy (EGD). She was treated with steroid with high dose at first, followed by a slow taper and the symptoms responded to the treatment.
Brugada syndrome is an inherited arrhythmogenic disease, characterised by a coved-type ST segment elevation in right precordial leads and an increased risk of sudden cardiac death due to ventricular arrhythmia. To unmask or exacerbate a Brugada ECG pattern, class IA or IC antiarrhythmic agents are used, and clinicians can predict sudden cardiac death in a high-risk patient. However, phenytoin, one of the class IB agents, may induce a Brugada pattern ECG at a supra-therapeutic level and this association has rarely been reported. We describe a case of a patient with a phenytoin level about twice as high as the therapeutic level, which led to the emergence of a type 1 Brugada pattern ECG. Awareness should be made between this important association of supra-therapeutic phenytoin level and type 1 Brugada pattern ECG because symptomatic Brugada syndrome can lead to sudden cardiac death.
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