scholarly journals β-Hydroxy-β-Methylbutyrate Supplementation Promotes Antitumor Immunity in an Obesity Responsive Mouse Model of Pancreatic Ductal Adenocarcinoma

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6359
Author(s):  
Michael F. Coleman ◽  
Kristyn A. Liu ◽  
Alexander J. Pfeil ◽  
Suhas K. Etigunta ◽  
Xiaohu Tang ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Antitumor Immunity ◽  
Muscle Growth ◽  
The United States ◽  
Ductal Adenocarcinoma ◽  
Antitumor Activities ◽  
Mouse Muscle ◽  
Fiber Size ◽  
Muscle Sparing ◽  
Gemcitabine Treatment

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the United States, and effective therapies for PDAC are currently lacking. Moreover, PDAC is promoted and exacerbated by obesity, while cachexia and sarcopenia are exceptionally common comorbidities that predict both poor survival and treatment response. Managing PDAC with immunotherapies has thus far proven ineffective, partly due to the metabolically hostile tumor microenvironment. β-hydroxy-β-methylbutyrate (HMB), a metabolite of leucine commonly used as a dietary supplement to boost muscle growth and immune function, may be an attractive candidate to augment PDAC therapy. We therefore sought to test the hypothesis that HMB would enhance antitumor immunity while protecting mouse muscle mass. Control and diet-induced obese C57BL/6 male mice bearing subcutaneously injected Panc02 tumors were supplemented with 1% HMB and treated with or without 50 mg/kg gemcitabine (n = 15/group). HMB was associated with reduced muscle inflammation and increased muscle fiber size. HMB also reduced tumor growth and promoted antitumor immunity in obese, but not lean, mice, independent of the gemcitabine treatment. Separately, in lean tumor-bearing mice, HMB supplementation promoted an anti-PD1 immunotherapy response (n = 15/group). Digital cytometry implicated the decreased abundance of M2-like macrophages in PDAC tumors, an effect that was enhanced by anti-PD1 immunotherapy. We confirmed that HMB augments M1-like macrophage (antitumor) polarization. These preclinical findings suggest that HMB has muscle-sparing and antitumor activities against PDAC in the context of obesity, and that it may sensitize otherwise nonresponsive PDAC to immunotherapy.

Temporal trends of pancreatic ductal adenocarcinoma in young adults in the United States: A Population-Based Study

2020 ◽  
Vol 44 (2) ◽  
pp. 204-210
Author(s):  
Mohamed M. Gad ◽  
Anas M. Saad ◽  
Muneer J. Al-Husseini ◽  
Youssef M. Abdel-Gawad ◽  
Obai M. Alsalhani ◽  
...  
Keyword(s):  
United States ◽  
Young Adults ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Temporal Trends ◽  
The United States ◽  
Population Based ◽  
Ductal Adenocarcinoma ◽  
Population Based Study

KOC (K homology domain containing protein overexpressed in cancer) overexpression and progression-free survival after curative intent resection of pancreatic ductal adenocarcinoma.

2012 ◽  
Vol 30 (30_suppl) ◽  
pp. 48-48
Author(s):  
Benny Johnson ◽  
Maged F. Khalil ◽  
Fan Lin ◽  
Shaobo Zhu ◽  
Lester Kirchner
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Distant Metastasis ◽  
Rna Binding ◽  
Progression Free Survival ◽  
The United States ◽  
Ductal Adenocarcinoma ◽  
Patient Specific ◽  
Rank Test ◽  
Curative Intent ◽  
Free Survival

48 Background: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality in the United States. Unfortunately, effective screening and early detection mechanisms are currently unavailable, thereby 80% of patients present with distant metastasis. Of the subset of patients eligible for curative intent surgery, the 5-year survival rate is only 20%. Negative surgical margins, tumor size, stage, and node negative disease are traditional prognostic indicators. However, these can be limited in their ability to predict patient specific prognosis. KOC is an oncofetal RNA-binding protein involved in RNA stabilization and cell growth during embryogenesis. Previous studies have revealed that KOC mRNA is inappropriately overexpressed in pancreatic cancer and that increased expression correlates with tumor stage. In this study, we attempt to identify whether KOC expression in patients who undergo curative intent surgery correlates with progression free survival. Methods: Tissue microarrays prepared from formalin-fixed, paraffin-embedded specimens of patients with PDAC who underwent curative intent surgery were assessed by immunohistochemistry. Results: A total of 35 patients were included. Comparisons between groups on progression free survival are estimated using the Kaplan-Meier method and the log-rank test. KOC was overexpressed in 23.6% of tumors. It was found that there were zero patients with a high KOC expression and no distant metastasis. Patients with a high KOC expression were more than 3 times more likely to progress compared to those with a low KOC expression (HR=3.54, 95% CI: 1.34, 9.36, p=0.011). Conclusions: KOC is a useful prognostic biomarker for predicting those patients with PDAC who have a high risk for early progression and distant metastasis. Identifying patients with high KOC expression upon initial diagnosis can serve as a way to risk stratify patients to aggressive treatment regimens upfront and early exposure to clinical trials.

scholarly journals A First-In-Class, Humanized Antibody Targeting Alternatively Spliced Tissue Factor: Preclinical Evaluation in an Orthotopic Model of Pancreatic Ductal Adenocarcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Clayton S. Lewis ◽  
Aniruddha Karve ◽  
Kateryna Matiash ◽  
Timothy Stone ◽  
Jingxing Li ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Tissue Factor ◽  
Tumor Tissue ◽  
Single Agent ◽  
The United States ◽  
Ductal Adenocarcinoma ◽  
Boyden Chamber ◽  
Orthotopic Model ◽  
Alternatively Spliced

In 2021, pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer deaths in the United States. This is largely due to a lack of symptoms and limited treatment options, which extend survival by only a few weeks. There is thus an urgent need to develop new therapies effective against PDAC. Previously, we have shown that the growth of PDAC cells is suppressed when they are co-implanted with RabMab1, a rabbit monoclonal antibody specific for human alternatively spliced tissue factor (asTF). Here, we report on humanization of RabMab1, evaluation of its binding characteristics, and assessment of its in vivo properties. hRabMab1 binds asTF with a KD in the picomolar range; suppresses the migration of high-grade Pt45.P1 cells in Boyden chamber assays; has a long half-life in circulation (~ 5 weeks); and significantly slows the growth of pre-formed orthotopic Pt45.P1 tumors in athymic nude mice when administered intravenously. Immunohistochemical analysis of tumor tissue demonstrates the suppression of i) PDAC cell proliferation, ii) macrophage infiltration, and iii) neovascularization, whereas RNAseq analysis of tumor tissue reveals the suppression of pathways that promote cell division and focal adhesion. This is the first proof-of-concept study whereby a novel biologic targeting asTF has been investigated as a systemically administered single agent, with encouraging results. Given that hRabMab1 has a favorable PK profile and is able to suppress the growth of human PDAC cells in vivo, it comprises a promising candidate for further clinical development.

scholarly journals DNA-Methylation-Caused Downregulation of miR-30 Contributes to the High Expression of XPO1 and the Aggressive Growth of Tumors in Pancreatic Ductal Adenocarcinoma

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1101 ◽  
Author(s):  
Asfar S. Azmi ◽  
Yiwei Li ◽  
Amro Aboukameel ◽  
Irfana Muqbil ◽  
Philip A. Philip ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Cells ◽  
Nuclear Export ◽  
The United States ◽  
High Expression ◽  
Ductal Adenocarcinoma ◽  
Multiple Tumor ◽  
Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma is one of the most aggressive cancers, with high mortality in the United States. One of the important signal transduction proteins involved in the regulation of pancreatic cancer’s aggressive progression is the nuclear export protein (XPO1). High expression of XPO1 has been found in pancreatic, lung, breast and other cancers and lymphomas with a poor prognosis of patients with tumors and high proliferative activity of cancer cells. Because XPO1 exports multiple tumor suppressor proteins simultaneously from the nucleus, the inhibition of XPO1 may retain multiple tumor suppressors in the nucleus, resulting in the suppression of cell proliferation and the induction of apoptosis in tumors. In this study, we found that the high expression of XPO1 in pancreatic cancer cells could be, in part, due to the methylation of the miR-30 gene, leading to the low expression level of the miR-30 family. By co-transfection of the XPO1 3′-UTR-Luc target vector with miR-30 mimic, we found that XPO1 is a direct target of the miR-30 family. We also observed that the enforced expression of the miR-30 family inhibited the expression of XPO1, resulting in the suppression of pancreatic cancer growth both in vitro and in vivo. These findings could help to design a novel therapeutic strategy for the treatment of pancreatic cancer by introducing miR-30 into cancer cells.

scholarly journals Trends in the Incidence of Pancreatic Adenocarcinoma in All 50 United States Examined Through an Age-Period-Cohort Analysis

2020 ◽  
Vol 4 (4) ◽  
Author(s):  
Wilson L da Costa ◽  
Abiodun O Oluyomi ◽  
Aaron P Thrift
Keyword(s):  
United States ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cohort Analysis ◽  
The United States ◽  
Incidence Rates ◽  
Ductal Adenocarcinoma ◽  
Birth Cohorts ◽  
Men And Women ◽  
Cancer Statistics ◽  
Incidence Trends

Abstract Background Pancreatic ductal adenocarcinoma is a major contributor to cancer-related mortality in the United States. We aimed to investigate trends in incidence rates from all 50 states from 2001 to 2016, overall and by race, sex, and state and using age-period-cohort analyses. Methods Age-adjusted incidence rates and trends in adults aged 35 years and older were calculated using data from the US Cancer Statistics registry. We used joinpoint regression to compute annual percent changes (APC) and average annual percent changes. We also analyzed incidence trends by age groups and birth cohorts through age-period-cohort modeling. Results Age-standardized incidence rates increased by 1.23% (95% confidence interval [CI] = 0.92% to 1.54%) annually between 2001 and 2008 but were stable between 2008 and 2016 (APC = 0.11%, 95% CI = -0.13% to 0.35%). APCs and inflection points were no different for men and women. Rates increased statistically significantly among non-Hispanic whites (NHW) and non-Hispanic blacks between 2001 and 2007 and between 2001 and 2008, respectively, but, in later years, rates increased slowly among NHWs (APC = 0.36%, 95% CI = 0.12% to 0.60%), and were stable among non-Hispanic blacks (APC = -0.40%, 95% CI = -0.89% to 0.10%). The number of states with age-standardized incidence rates no less than 20.4 per 100 000 increased from 16 in 2001–2003 to 40 by 2015–2016. We found a strong birth cohort effect in both men and women and increasing rates among successive birth cohorts of NHWs. Conclusions The incidence of pancreatic ductal adenocarcinoma has consistently increased in the United States, albeit at slower rates recently. We observed notable increases among NHWs and in some states in the central and southern part of the country.

scholarly journals Obesity-Induced Adipose Tissue Inflammation as a Strong Promotional Factor for Pancreatic Ductal Adenocarcinoma

Cells ◽  
2019 ◽  
Vol 8 (7) ◽  
pp. 673 ◽  
Author(s):  
Hui-Hua Chang ◽  
Guido Eibl
Keyword(s):  
Adipose Tissue ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Visceral Adipose Tissue ◽  
Metabolic Diseases ◽  
The United States ◽  
Ductal Adenocarcinoma ◽  
Adipose Tissue Inflammation ◽  
Tissue Inflammation ◽  
Genetically Engineered Mouse Model ◽  
Visceral Adipose

Pancreatic ductal adenocarcinoma (PDAC) is expected to soon become the second leading cause of cancer related deaths in the United States. This may be due to the rising obesity prevalence, which is a recognized risk factor for PDAC. There is great interest in deciphering the underlying driving mechanisms of the obesity–PDAC link. Visceral adiposity has a strong correlation to certain metabolic diseases and gastrointestinal cancers, including PDAC. In fact, our own data strongly suggest that visceral adipose tissue inflammation is a strong promoter for PDAC growth and progression in a genetically engineered mouse model of PDAC and diet-induced obesity. In this review, we will discuss the relationship between obesity-associated adipose tissue inflammation and PDAC development, with a focus on the key molecular and cellular components in the dysfunctional visceral adipose tissue, which provides a tumor permissive environment.

scholarly journals Development and validation of a Nomogram for predicting the Overall Survival of Patients With Pancreatic Ductal Adenocarcinoma of the Head of the Pancreas

2021 ◽  
Author(s):  
Zhilong Liu ◽  
Haohui Yu ◽  
Mingrong Cao ◽  
Jiexing Li ◽  
Yulin Huang ◽  
...  
Keyword(s):  
Overall Survival ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Staging System ◽  
The United States ◽  
Ductal Adenocarcinoma ◽  
Seer Database ◽  
Training Set ◽  
Head Of The Pancreas ◽  
Ajcc Staging System ◽  
Ajcc Staging

Abstract Background: The purpose of this study is to develop and validate a nomogram to predict the overall survival (OS) of patients with Pancreatic Ductal Adenocarcinoma of the Head of the Pancreas (PDAC-HP).Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database, we collected patients with PDAC-HP in the United States between 2004 and 2015. Patients were randomly divided into training set and validating set at a ratio of 7:3. The training set is used to develop a nomogram for predicting OS. These indicators such as the C index, the area under curve (AUC) of the receiver operating characteristic (ROC), calibration plots and the net reclassification improvement (NRI) and the integrated discrimination improvement (IDI) were used to evaluate the prediction accuracy of the nomogram.Results: A total of 33,893 patients with PDAC-HP over 20 years old were diagnosed between 2004 and 2015 were collected from the SEER database. Using multivariable Cox regression analysis, we identified eight risk factors that were associated with OS, such as age at diagnosis, sex, marital status at diagnosis, race, AJCC staging, surgery, radiotherapy and chemotherapy. A nomogram was constructed based on these variables. Compared with the AJCC staging system, the nomogram has a better C index and AUC in the training set and validatiing set. The calibration plots indicated that the nomogram was able to accurately predict the OS of patients with PDAC-HP at 1, 3, and 5 years.Conclusions: We developed and validated a nomogram, and predicted the OS of patients with PDAC-HP at 1, 3, and 5 years. Compared with the AJCC staging system, the nomogram we constructed has better performance. It shows that our nomogram could be served as an effective tool for prognostic evaluation of patients with PDAC-HP.

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