American Journal of Physiology-Gastrointestinal and Liver Physiology, 2021
Pancreatic ductal adenocarcinoma is one of the deadliest forms of human cancers. In this study, w... more Pancreatic ductal adenocarcinoma is one of the deadliest forms of human cancers. In this study, we identified a novel signaling mechanism involved in PDAC progression and metastasis. Yes-associated protein 1 mediates the expression of epithelial cell transforming 2, which is elevated in PDAC and correlates with poor survival. Epithelial cell transforming 2 is required for PDAC growth and metastasis. This study provides insights into the development of novel methods for early detection and treatment of PDAC.
Advanced pancreatic ductal adenocarcinoma (PDAC) is characterized by progressive weight loss and ... more Advanced pancreatic ductal adenocarcinoma (PDAC) is characterized by progressive weight loss and nutritional deterioration. This wasting has been linked to poor survival outcomes, alterations in host defenses, decreased functional ability, and diminished health‐related quality of life (HRQOL) in pancreatic cancer patients. There are currently no standardized approaches to the management of pancreatic cancer cachexia. This study explores the feasibility and efficacy of enteral tube feeding of a peptide‐based formula to improve weight stability and patient‐reported outcomes (PROs) in advanced PDAC patients with cachexia.
The treatment of head and neck cancers is complex and associated with significant morbidity, requ... more The treatment of head and neck cancers is complex and associated with significant morbidity, requiring multidisciplinary care and physician expertise. Thus, facility characteristics, such as clinical volume and academic status, may influence outcomes. The current study included 46,567 patients taken from the National Cancer Data Base who were diagnosed with locally advanced invasive squamous cell carcinomas of the oropharynx, larynx, and hypopharynx and were undergoing definitive radiotherapy. High-volume facilities (HVFs) were defined as the top 1% of centers by the number of patients treated from 2004 through 2012. Multivariable Cox regression and propensity score matching were performed to account for imbalances in covariates. The median follow-up was 55.1 months. Treatment at a HVF (hazard ratio, 0.798; 95% confidence interval, 0.753-0.845 [P<.001]) and treatment at an academic facility (hazard ratio, 0.897; 95% confidence interval, 0.871-0.923 [P<.001]) were found to be i...
Introduction: The COVID-19 pandemic demands an urgent response from the transplant community in o... more Introduction: The COVID-19 pandemic demands an urgent response from the transplant community in order to protect our vulnerable patient population We present the rare case of COVID-19 in a combined liver-kidney transplant recipient from the United States Case Report: The patient is a 77 year-old diabetic woman who presented to our transplant center with decompensated cryptogenic cirrhosis She underwent combined liver-kidney transplant Postoperatively, her liver enzymes normalized, and she no longer required dialysis She was discharged to a rehabilitation facility 12 days after transplant (POD #12) On POD #13, the patient had rehabilitation sessions with an occupational therapist who later tested positive for COVID-19 This day is presumed to be her first exposure, and subsequent days will be referred to as 'post-exposure days' (PEXD) On PEXD #9 (POD #22), the patient developed a fever of 103 degrees, accompanied by chills and nausea However, no dyspnea, cough, or respiratory complaints were present at presentation Other than an elevation in alkaline phosphatase of 168 U/L, her liver enzymes and creatinine were normal (Table 1) Chest CT only showed trace right pleural effusion with no pulmonary infiltrates, no ground-glass opacification, and no consolidation (Figure 1) Abdominal CT revealed a 20 x 15 cm fluid collection surrounding the left kidney graft Mycophenolate mofetil was discontinued, but prednisone and tacrolimus were continued Tacrolimus dosing was adjusted to achieve a target daily through level range of 6 - 10 ng/mL The following morning (PEXD #10), the patient underwent percutaneous drainage of her perinephric abscess Her fever and pain subsided following intervention On PEXD #11, the patient's COVID-19 test resulted as positive Isolation precautions were maintained Chest X ray was clear She had no dyspnea or cough, and she maintained oxygen saturation of 96-100% on room air A five-day course of treatment with oral hydroxychloroquine at 400 mg was planned, and started on PEXD #11 However, the patient had a significant elevation in liver enzymes immediately following treatment initiation The drug was discontinued on PEXD #13 The patient's liver enzymes improved following drug cessation We decided to initiate treatment with azithromycin on PEXD #15, completing a five-day treatment course The patient remained asymptomatic and did not require oxygen therapy at any point On PEXD #23 (hospital day 14, POD# 36), the patient was discharged home MMF was not restarted Tacrolimus and steroid taper were continued as scheduled Allograft function and chest imaging prior to discharge were normal Conclusions: Calcineurin inhibitors interfere with the cyclophilins and FKBP required by various coronaviridae for replication Along with steroids, they also dampen the cytokine storm The antiviral potential of calcineurin inhibitors and steroids warrants further investigation into their role as viable therapy for COVID-19
BACKGROUND & AIMS Methionine adenosyltransferase 1A (MAT1A) is responsible for S-adenosylmeth... more BACKGROUND & AIMS Methionine adenosyltransferase 1A (MAT1A) is responsible for S-adenosylmethionine (SAMe) biosynthesis in the liver. Mice lacking Mat1a have hepatic SAMe depletion, develop non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) spontaneously. Several kinases are activated in Mat1a knockout (KO) mice livers. However, the phosphos-proteome has not been characterized and whether they contribute to liver pathology is largely unknown. Our study aimed to fill this gap. APPROACH & RESULTS We performed phospho-proteomics in Mat1a KO mice livers with and without SAMe treatment to identify SAMe-dependent changes that may contribute to liver pathology. Our studies used Mat1a KO mice at different ages treated with and without SAMe, cell lines, in vitro translation and kinase assays, and human liver specimens. We found the most striking change was hyperphosphorylation and increased content of La-Related Protein 1 (LARP1), which in the unphosphorylated form negatively regulates translation of 5'-terminal oligopyrimidine (TOP)-containing mRNAs. Consistently, multiple TOP proteins are induced in the KO livers. The translation of TOP mRNAs RPS3 and RPL18 was enhanced by LARP1 overexpression in liver cancer cells. We identified LARP1-T449 as a novel, SAMe-sensitive phospho-site of cyclin-dependent kinase 2 (CDK2). Knocking down CDK2 lowered LARP1 phosphorylation and prevented LARP1 overexpression mediated increase in translation. LARP1-T449 phosphorylation induced global translation, cell growth, migration, invasion, and expression of oncogenic TOP-ribosomal proteins in HCC cells. LARP1 expression is increased in human NASH and HCC. CONCLUSION Our results reveal a novel SAMe-sensitive mechanism of LARP1 phosphorylation that may be involved in the progression of NASH to HCC.
TPS487 Background: Targeted inhibition of PARP1/2 is one way to further exploit the well-known sy... more TPS487 Background: Targeted inhibition of PARP1/2 is one way to further exploit the well-known synergy between gemcitabine (G) and radiotherapy (RT) in locally advanced pancreatic cancer (LAPC). PARP1/2 inhibitors, such as veliparib (V), have shown excellent anti-tumor activity when used with other cytotoxic therapies. This synergy may be further exploited in pancreatic cancer by targeting tumors with pre-existing defects in double- strand DNA repair. Extrapolating from our own laboratory findings (Tuli et al, Transl Oncol, 2014) and based on our hypothesis that PARP1/2 inhibition with G and RT will result in enhanced tumor control, we are conducting an IRB- approved phase I study in patients with borderline resectable and LAPC. Methods: The primary objective of this study is to determine the maximum tolerated dose (MTD) of V, which is defined as the dose level resulting in a probability (θ = 0.4) that a dose limiting toxicity (DLT) will occur within six weeks. Treatment cycle is 3 ...
329 Background: The majority of patients undergoing potentially curative surgery for pancreatic d... more 329 Background: The majority of patients undergoing potentially curative surgery for pancreatic ductal adenocarcinoma (PDA) will face recurrence. While other types of metastatic tumors are often treated with loco-regional therapy, this approach is rarely applied to metastatic PDA. We examined recurrence patterns of PDA and the potential application of loco-regional treatment. Methods: Evaluation of a prospective database of patients undergoing pancreaticoduodenctomy at an academic institution by a single surgeon. Patients: Pancreaticoduodenectomy for PDA was performed in 95 patients between 2002 and 2012. Margin status was R0 in 88 (93%) and R1 in the remainder. Results: Overall median survival was 27 months and 1 and 3 year survival was 68% and 41%. Known recurrence occurred in 44 of 64 patients (69%) at a median of 20.9 months, while the status of 31 patients was unknown. The most common site of initial recurrence was liver (n=19, median 9.2 months post-surgery), followed by local...
378 Background: Surgical resection is the preferred approach for localized pancreatic adenocarcin... more 378 Background: Surgical resection is the preferred approach for localized pancreatic adenocarcinoma, yet likelihood of margin positive resection precludes its use in patients with locally advanced (LAPA) disease. Whereas CT imaging is the standard for defining resectability, studies suggest reduced accuracy following radiotherapy (RT). Given the potential clinical implications, improved methods to define resectability are needed. We investigate whether PET and other clinical factors can be used to predict likelihood of margin negative resection in LAPA patients. Methods: We reviewed LAPA patients treated with RT from 2011-2013 who also underwent pre- and 6-week post-RT PET/CT. Mann-Whitney test and Cox modeling were used to identify predictors of margin negative resection and progression-free survival (PFS), respectively. Variables assessed included: pre- and post-RT SUV max, mean, coefficient of variation (CV), total lesion glycolysis, CA19-9 and tumor size. Results: Eighteen LAPA...
American Journal of Physiology-Gastrointestinal and Liver Physiology, 2021
Pancreatic ductal adenocarcinoma is one of the deadliest forms of human cancers. In this study, w... more Pancreatic ductal adenocarcinoma is one of the deadliest forms of human cancers. In this study, we identified a novel signaling mechanism involved in PDAC progression and metastasis. Yes-associated protein 1 mediates the expression of epithelial cell transforming 2, which is elevated in PDAC and correlates with poor survival. Epithelial cell transforming 2 is required for PDAC growth and metastasis. This study provides insights into the development of novel methods for early detection and treatment of PDAC.
Advanced pancreatic ductal adenocarcinoma (PDAC) is characterized by progressive weight loss and ... more Advanced pancreatic ductal adenocarcinoma (PDAC) is characterized by progressive weight loss and nutritional deterioration. This wasting has been linked to poor survival outcomes, alterations in host defenses, decreased functional ability, and diminished health‐related quality of life (HRQOL) in pancreatic cancer patients. There are currently no standardized approaches to the management of pancreatic cancer cachexia. This study explores the feasibility and efficacy of enteral tube feeding of a peptide‐based formula to improve weight stability and patient‐reported outcomes (PROs) in advanced PDAC patients with cachexia.
The treatment of head and neck cancers is complex and associated with significant morbidity, requ... more The treatment of head and neck cancers is complex and associated with significant morbidity, requiring multidisciplinary care and physician expertise. Thus, facility characteristics, such as clinical volume and academic status, may influence outcomes. The current study included 46,567 patients taken from the National Cancer Data Base who were diagnosed with locally advanced invasive squamous cell carcinomas of the oropharynx, larynx, and hypopharynx and were undergoing definitive radiotherapy. High-volume facilities (HVFs) were defined as the top 1% of centers by the number of patients treated from 2004 through 2012. Multivariable Cox regression and propensity score matching were performed to account for imbalances in covariates. The median follow-up was 55.1 months. Treatment at a HVF (hazard ratio, 0.798; 95% confidence interval, 0.753-0.845 [P<.001]) and treatment at an academic facility (hazard ratio, 0.897; 95% confidence interval, 0.871-0.923 [P<.001]) were found to be i...
Introduction: The COVID-19 pandemic demands an urgent response from the transplant community in o... more Introduction: The COVID-19 pandemic demands an urgent response from the transplant community in order to protect our vulnerable patient population We present the rare case of COVID-19 in a combined liver-kidney transplant recipient from the United States Case Report: The patient is a 77 year-old diabetic woman who presented to our transplant center with decompensated cryptogenic cirrhosis She underwent combined liver-kidney transplant Postoperatively, her liver enzymes normalized, and she no longer required dialysis She was discharged to a rehabilitation facility 12 days after transplant (POD #12) On POD #13, the patient had rehabilitation sessions with an occupational therapist who later tested positive for COVID-19 This day is presumed to be her first exposure, and subsequent days will be referred to as 'post-exposure days' (PEXD) On PEXD #9 (POD #22), the patient developed a fever of 103 degrees, accompanied by chills and nausea However, no dyspnea, cough, or respiratory complaints were present at presentation Other than an elevation in alkaline phosphatase of 168 U/L, her liver enzymes and creatinine were normal (Table 1) Chest CT only showed trace right pleural effusion with no pulmonary infiltrates, no ground-glass opacification, and no consolidation (Figure 1) Abdominal CT revealed a 20 x 15 cm fluid collection surrounding the left kidney graft Mycophenolate mofetil was discontinued, but prednisone and tacrolimus were continued Tacrolimus dosing was adjusted to achieve a target daily through level range of 6 - 10 ng/mL The following morning (PEXD #10), the patient underwent percutaneous drainage of her perinephric abscess Her fever and pain subsided following intervention On PEXD #11, the patient's COVID-19 test resulted as positive Isolation precautions were maintained Chest X ray was clear She had no dyspnea or cough, and she maintained oxygen saturation of 96-100% on room air A five-day course of treatment with oral hydroxychloroquine at 400 mg was planned, and started on PEXD #11 However, the patient had a significant elevation in liver enzymes immediately following treatment initiation The drug was discontinued on PEXD #13 The patient's liver enzymes improved following drug cessation We decided to initiate treatment with azithromycin on PEXD #15, completing a five-day treatment course The patient remained asymptomatic and did not require oxygen therapy at any point On PEXD #23 (hospital day 14, POD# 36), the patient was discharged home MMF was not restarted Tacrolimus and steroid taper were continued as scheduled Allograft function and chest imaging prior to discharge were normal Conclusions: Calcineurin inhibitors interfere with the cyclophilins and FKBP required by various coronaviridae for replication Along with steroids, they also dampen the cytokine storm The antiviral potential of calcineurin inhibitors and steroids warrants further investigation into their role as viable therapy for COVID-19
BACKGROUND & AIMS Methionine adenosyltransferase 1A (MAT1A) is responsible for S-adenosylmeth... more BACKGROUND & AIMS Methionine adenosyltransferase 1A (MAT1A) is responsible for S-adenosylmethionine (SAMe) biosynthesis in the liver. Mice lacking Mat1a have hepatic SAMe depletion, develop non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) spontaneously. Several kinases are activated in Mat1a knockout (KO) mice livers. However, the phosphos-proteome has not been characterized and whether they contribute to liver pathology is largely unknown. Our study aimed to fill this gap. APPROACH & RESULTS We performed phospho-proteomics in Mat1a KO mice livers with and without SAMe treatment to identify SAMe-dependent changes that may contribute to liver pathology. Our studies used Mat1a KO mice at different ages treated with and without SAMe, cell lines, in vitro translation and kinase assays, and human liver specimens. We found the most striking change was hyperphosphorylation and increased content of La-Related Protein 1 (LARP1), which in the unphosphorylated form negatively regulates translation of 5'-terminal oligopyrimidine (TOP)-containing mRNAs. Consistently, multiple TOP proteins are induced in the KO livers. The translation of TOP mRNAs RPS3 and RPL18 was enhanced by LARP1 overexpression in liver cancer cells. We identified LARP1-T449 as a novel, SAMe-sensitive phospho-site of cyclin-dependent kinase 2 (CDK2). Knocking down CDK2 lowered LARP1 phosphorylation and prevented LARP1 overexpression mediated increase in translation. LARP1-T449 phosphorylation induced global translation, cell growth, migration, invasion, and expression of oncogenic TOP-ribosomal proteins in HCC cells. LARP1 expression is increased in human NASH and HCC. CONCLUSION Our results reveal a novel SAMe-sensitive mechanism of LARP1 phosphorylation that may be involved in the progression of NASH to HCC.
TPS487 Background: Targeted inhibition of PARP1/2 is one way to further exploit the well-known sy... more TPS487 Background: Targeted inhibition of PARP1/2 is one way to further exploit the well-known synergy between gemcitabine (G) and radiotherapy (RT) in locally advanced pancreatic cancer (LAPC). PARP1/2 inhibitors, such as veliparib (V), have shown excellent anti-tumor activity when used with other cytotoxic therapies. This synergy may be further exploited in pancreatic cancer by targeting tumors with pre-existing defects in double- strand DNA repair. Extrapolating from our own laboratory findings (Tuli et al, Transl Oncol, 2014) and based on our hypothesis that PARP1/2 inhibition with G and RT will result in enhanced tumor control, we are conducting an IRB- approved phase I study in patients with borderline resectable and LAPC. Methods: The primary objective of this study is to determine the maximum tolerated dose (MTD) of V, which is defined as the dose level resulting in a probability (θ = 0.4) that a dose limiting toxicity (DLT) will occur within six weeks. Treatment cycle is 3 ...
329 Background: The majority of patients undergoing potentially curative surgery for pancreatic d... more 329 Background: The majority of patients undergoing potentially curative surgery for pancreatic ductal adenocarcinoma (PDA) will face recurrence. While other types of metastatic tumors are often treated with loco-regional therapy, this approach is rarely applied to metastatic PDA. We examined recurrence patterns of PDA and the potential application of loco-regional treatment. Methods: Evaluation of a prospective database of patients undergoing pancreaticoduodenctomy at an academic institution by a single surgeon. Patients: Pancreaticoduodenectomy for PDA was performed in 95 patients between 2002 and 2012. Margin status was R0 in 88 (93%) and R1 in the remainder. Results: Overall median survival was 27 months and 1 and 3 year survival was 68% and 41%. Known recurrence occurred in 44 of 64 patients (69%) at a median of 20.9 months, while the status of 31 patients was unknown. The most common site of initial recurrence was liver (n=19, median 9.2 months post-surgery), followed by local...
378 Background: Surgical resection is the preferred approach for localized pancreatic adenocarcin... more 378 Background: Surgical resection is the preferred approach for localized pancreatic adenocarcinoma, yet likelihood of margin positive resection precludes its use in patients with locally advanced (LAPA) disease. Whereas CT imaging is the standard for defining resectability, studies suggest reduced accuracy following radiotherapy (RT). Given the potential clinical implications, improved methods to define resectability are needed. We investigate whether PET and other clinical factors can be used to predict likelihood of margin negative resection in LAPA patients. Methods: We reviewed LAPA patients treated with RT from 2011-2013 who also underwent pre- and 6-week post-RT PET/CT. Mann-Whitney test and Cox modeling were used to identify predictors of margin negative resection and progression-free survival (PFS), respectively. Variables assessed included: pre- and post-RT SUV max, mean, coefficient of variation (CV), total lesion glycolysis, CA19-9 and tumor size. Results: Eighteen LAPA...
Uploads