Resveratrol Suppresses Constitutive Activation of AKT via Generation of ROS and Induces Apoptosis in Diffuse Large B Cell Lymphoma Cell Lines

BACKGROUND: We have recently shown that deregulation PI3-kinase/AKT survival pathway plays an important role in pathogenesis of diffuse large B cell lymphoma (DLBCL). In an attempt to identify newer therapeutic agents, we investigated the role of Resveratrol (trans-3,4', 5-trihydroxystilbene), a naturally occurring polyphenolic compound on a panel of diffuse large B-cell lymphoma (DLBCL) cells in causing inhibition of cell viability and inducing apoptosis. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the action of Resveratrol on DLBCL cells and found that Resveratrol inhibited cell viability and induced apoptosis by inhibition of constitutively activated AKT and its downstream targets via generation of reactive oxygen species (ROS). Simultaneously, Resveratrol treatment of DLBCL cell lines also caused ROS dependent upregulation of DR5; and interestingly, co-treatment of DLBCL with sub-toxic doses of TRAIL and Resveratrol synergistically induced apoptosis via utilizing DR5, on the other hand, gene silencing of DR5 abolished this effect. CONCLUSION/SIGNIFICANCE: Altogether, these data suggest that Resveratrol acts as a suppressor of AKT/PKB pathway leading to apoptosis via generation of ROS and at the same time primes DLBCL cells via up-regulation of DR5 to TRAIL-mediated apoptosis. These data raise the possibility that Resveratrol may have a future therapeutic role in DLBCL and possibly other malignancies with constitutive activation of the AKT/PKB pathway

Analysis of Common and Specific Mechanisms of Liver Function Affected by Nitrotoluene Compounds

BACKGROUND: Nitrotoluenes are widely used chemical manufacturing and munitions applications. This group of chemicals has been shown to cause a range of effects from anemia and hypercholesterolemia to testicular atrophy. We have examined the molecular and functional effects of five different, but structurally related, nitrotoluenes on using an integrative systems biology approach to gain insight into common and disparate mechanisms underlying effects caused by these chemicals. METHODOLOGY/PRINCIPAL FINDINGS: Sprague-Dawley female rats were exposed via gavage to one of five concentrations of one of five nitrotoluenes [2,4,6-trinitrotoluene (TNT), 2-amino-4,6-dinitrotoluene (2ADNT) 4-amino-2,6-dinitrotoulene (4ADNT), 2,4-dinitrotoluene (2,4DNT) and 2,6-dinitrotoluene (2,6DNT)] with necropsy and tissue collection at 24 or 48 h. Gene expression profile results correlated well with clinical data and liver histopathology that lead to the concept that hematotoxicity was followed by hepatotoxicity. Overall, 2,4DNT, 2,6DNT and TNT had stronger effects than 2ADNT and 4ADNT. Common functional terms, gene expression patterns, pathways and networks were regulated across all nitrotoluenes. These pathways included NRF2-mediated oxidative stress response, aryl hydrocarbon receptor signaling, LPS/IL-1 mediated inhibition of RXR function, xenobiotic metabolism signaling and metabolism of xenobiotics by cytochrome P450. One biological process common to all compounds, lipid metabolism, was found to be impacted both at the transcriptional and lipid production level. CONCLUSIONS/SIGNIFICANCE: A systems biology strategy was used to identify biochemical pathways affected by five nitroaromatic compounds and to integrate data that tie biochemical alterations to pathological changes. An integrative graphical network model was constructed by combining genomic, gene pathway, lipidomic, and physiological endpoint results to better understand mechanisms of liver toxicity and physiological endpoints affected by these compounds

Global overview of the management of acute cholecystitis during the COVID-19 pandemic (CHOLECOVID study)

Background: This study provides a global overview of the management of patients with acute cholecystitis during the initial phase of the COVID-19 pandemic. Methods: CHOLECOVID is an international, multicentre, observational comparative study of patients admitted to hospital with acute cholecystitis during the COVID-19 pandemic. Data on management were collected for a 2-month study interval coincident with the WHO declaration of the SARS-CoV-2 pandemic and compared with an equivalent pre-pandemic time interval. Mediation analysis examined the influence of SARS-COV-2 infection on 30-day mortality. Results: This study collected data on 9783 patients with acute cholecystitis admitted to 247 hospitals across the world. The pandemic was associated with reduced availability of surgical workforce and operating facilities globally, a significant shift to worse severity of disease, and increased use of conservative management. There was a reduction (both absolute and proportionate) in the number of patients undergoing cholecystectomy from 3095 patients (56.2 per cent) pre-pandemic to 1998 patients (46.2 per cent) during the pandemic but there was no difference in 30-day all-cause mortality after cholecystectomy comparing the pre-pandemic interval with the pandemic (13 patients (0.4 per cent) pre-pandemic to 13 patients (0.6 per cent) pandemic; P = 0.355). In mediation analysis, an admission with acute cholecystitis during the pandemic was associated with a non-significant increased risk of death (OR 1.29, 95 per cent c.i. 0.93 to 1.79, P = 0.121). Conclusion: CHOLECOVID provides a unique overview of the treatment of patients with cholecystitis across the globe during the first months of the SARS-CoV-2 pandemic. The study highlights the need for system resilience in retention of elective surgical activity. Cholecystectomy was associated with a low risk of mortality and deferral of treatment results in an increase in avoidable morbidity that represents the non-COVID cost of this pandemic

Intravenous busulfan and cyclophosphamide as an autologous transplant conditioning regimen for relapsed non-Hodgkin’s lymphoma

16508 Purpose: High-dose chemotherapy and hematopoietic stem cell transplantation has become the standard of care for chemosensitive relapsed Non-Hodgkin’s Lymphoma. Multiple conditioning regimens including CBV, BEAM, and BEAC have been used in the past with success. Limitations on the supply of carmustine have made it important to find other effective conditioning regimens. Methods: We retrospectively evaluated the use of intravenous Busulfan and Cyclophosphamide (IV Bu/Cy) as a conditioning regimen for autologous stem cell transplantation in Non-Hodgkin’s Lymphoma patients. Patients were given Busulfan 3.2 mg/kg total intravenously on days -7 to -4 (either once daily or in 2 or 4 divided doses) followed by Cyclophosphamide 120 mg/kg intravenously on days -2 and -1. Results: Forty-four patients, ages 20 to 68 years (median 50) were treated from January 2000 to April 2005. Most patients had diffuse large B-cell lymphoma (n = 29). Of the remaining patients, 8 had follicular lymphoma, 4 had mantle cell lymphoma and 3 had peripheral T-cell lymphoma. At the time of transplant, 27 patients had attained a complete response (CR or CRu) to salvage chemotherapy, 13 patients had achieved a partial response, and 4 had stable disease. The patients received a median of 3.0 × 106 CD34+ cells/kg (range 1.3–16.6 × 106). There were 4 treatment-related deaths by day 100: 1 from sepsis, 1 from pneumonia, and 2 from veno-occlusive disease (VOD). With a median follow-up of 42 months, 3-year Kaplan-Meier estimates of event free and overall survival for the entire cohort were 44% and 45%. For the patients that attained a CR or CRu prior to transplant, the EFS and OS were 42% and 53%, respectively. Conclusions: IV Bu/Cy is a safe and effective conditioning regimen. Due to the incidence of VOD, this regimen should be used with caution in patients with pre-existing hepatic dysfunction. Overall, our outcomes are comparable to that of other published regimens. Further investigation of Busulfan with Cyclophosphamide or with other chemotherapy combinations is warranted. No significant financial relationships to disclose

Beyond race: The impact of ethnicity on the treatment outcome of locally advanced head and neck cancer

16500 Background: Self identified racial groups share an unequal burden of head and neck cancer . Recent evidence suggests that outcome among races is different and the causes are multifactorial. Nonetheless, differences among ethnic groups have not been reported. Herein, we decided to analyze differences in treatment response and outcome among our white and Hispanic patient population treated for locally advanced head and neck cancer. Methods: Patients were identified using the tumor registry. We reviewed retrospectively the data from medical records. 100 white Hispanics (WH) and 50 white non-Hispanics (WNH) diagnosed with locally advanced head and neck cancer and treated at our institution from 2004 to 2005, were eligible for the study. Standard statistical analysis, including Kaplan-Meier survival curve and Cox proportional hazard models were used. P value of <0.05 was considered for statistical significance. Results: Preliminary results reveal that, in our study population, median age at diagnosis, gender, performance status (ECOG 0–2) and squamous cell histology did not differ significantly between the two groups. Stage 4 at diagnosis was more commonly observed in Hispanics as opposed to WNH (85.7% vs 68.6%) (P = 0.1). Surgery was more commonly used as an initial treatment option in Hispanics than WNH (42.8% vs 28.6%) (P = 0.18) while chemotherapy was less likely to be used (78.6% vs. 91.4%) (P = 0.15). Hispanics were more likely to smoke than WNH (P = 0.0003) and were equally exposed to chronic alcohol use. Patients from the Hispanic group were more likely to respond to therapy than whites by Chi-squared analysis but this difference was not statistically significant (P = 0.09). No differences were seen in disease free survival. Kaplan-Meier estimate of median overall survival was 16 months for Hispanics vs. 25 months for whites but this difference did not reach statistical significance (P = 0.26). Final analysis will be available at the time of the annual meeting. Conclusion: In our experience, a trend for decrease overall survival was noted in the Hispanic ethnic group. This may be in part due to more advanced stage at presentation. Nonetheless, in order to definitively answer this question, further research is warranted. No significant financial relationships to disclose

Autologous transplantation for relapsed non-Hodgkin lymphoma using intravenous busulfan and cyclophosphamide as conditioning regimen: A single center experience

18508 Background: High-dose chemotherapy followed by autologous stem cell transplanatation has become standard of care for patients with relapsed, chemosensitive non-Hodgkin’s lymphoma (NHL). In an effort to improve safety and efficacy of this therapeutic approach, new conditioning regimens are being developed. Methods: We retrospectively reviewed the clinical data of 44 consecutive patients with relapsed NHL who had been treated with intravenous Busulfan and Cyclophosphamide (BU/CY) as conditioning regimen for autologous stem cell transplantation between January 2000 and April 2005. Busulfan was administered at a total dose of 3.2 mg/kg on days -7 to -4 (given in two or four divided doses), followed by Cyclophosphamide at a dose of 120 mg/kg intravenously on days -3 and -2. We determined treatment-related morbidity and mortality, event-free survival (EFS, defined as time period between transplantation and occurrence of serious morbidity, disease relapse, disease progression, or death), disease-free survival (DFS), and overall survival (OS). Results: The distribution by histologic type of the 44 patients was as follows: 29 diffuse large B-cell lymphoma, 8 follicular lymphoma, 4 mantle cell lymphoma, and 3 peripheral T-cell lymphoma. Median age was 50 (range 20 to 68 years). At the time of transplantation, 27 patients had attained a complete response (CR or CRu) to salvage chemotherapy, 13 had achieved a partial response, and 4 had stable disease. Median time to neutrophil recovery post transplantation was 11 days. Treatment-related toxicities included nausea/vomiting (77%), diarrhea (43%), and mucositis (66%), which were mild in the majority of cases. Neutropenic fever occurred in 82% of patients. The 100-day mortality rate was 4 (9%) of patients: sepsis (n=1), pneumonia (n=1), and hepatic veno-occlusive disease (n=2). After a median follow-up of 52 months, 3-year Kaplan-Meier estimates of EFS, DFS, and OS were 35%, 41% and 44% respectively. Conclusions: Intravenous BU/CY is a safe and effective conditioning regimen as part of autologous transplantation for relapsed NHL. Our outcomes are comparable to those of other published regimens. Further investigation of this treatment approach is warranted. No significant financial relationships to disclose