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Pancreatic cancer and metabolism

Qingcai Meng, Jin Xu, Chen Liang, Jiang Liu, Jie Hua, Yiyin Zhang, Quanxing Ni, Si Shi, Xianjun Yu
Given the dense stroma and poor vascularization, access to nutrients is limited in the microenvironment of pancreatic ductal adenocarcinoma (PDA). PDA cells can efficiently recycle various metabolic substrates through the activation of different rescuing pathways, including the autophagy pathway. However, the precise roles of autophagy in cancer metabolism are not yet fully understood. In the present study, we first monitored the effect of glucose deprivation on autophagy and on the expression of glutathione peroxidase-1 (GPx1) in PDA cells under the glucose-free environment...
December 11, 2018: Cell Death & Disease
Hao Liu, Liquan Gao, Xinhe Yu, Lijun Zhong, Jiyun Shi, Bing Jia, Nan Li, Zhaofei Liu, Fan Wang
Integrin αvβ6 is expressed at an undetectable level in normal tissues, but is remarkably upregulated during many pathological processes, especially in cancer and fibrosis. Noninvasive imaging of integrin αvβ6 expression using a radiotracer with favorable in vivo pharmacokinetics would facilitate disease diagnosis and therapy monitoring. Through disulfide-cyclized method, we synthesized in this study, a new integrin αvβ6-targeted cyclic peptide (denoted as cHK), and radiolabeled it with 99m Tc. The ability of the resulting radiotracer 99m Tc-HYNIC-cHK to detect integrin αvβ6 expression in pancreatic cancer xenografts and idiopathic pulmonary fibrosis was evaluated using small-animal single-photon emission computed tomography (SPECT)/computed tomography (CT)...
2018: Biophysics Reports
Afreen Idris Shariff, Sohail Syed, Rebecca A Shelby, Jeremy Force, Jeffrey Melson Clarke, David D'Alessio, Leonor Corsino
Over the last decade, there has been a shift in the focus of cancer therapy from conventional cytotoxic drugs to therapies more specifically directed to cancer cells. These novel therapies include immunotherapy, targeted therapy and precision medicine, each developed in great part with a goal of limiting collateral destruction of normal tissues, while enhancing tumor destruction. Although this approach is sound in theory, even new, specific therapies have some undesirable, 'off target effects', in great part due to molecular pathways shared by neoplastic and normal cells...
February 1, 2019: Journal of Molecular Endocrinology
Y Kanjanapan, D Day, M O Butler, L Wang, A M Joshua, D Hogg, N B Leighl, A R Abdul Razak, A R Hansen, S Boujos, M Chappell, K Chow, B Sherwin, L-A Stayner, L Soultani, A Zambrana, L L Siu, P L Bedard, A Spreafico
BACKGROUND: Immunotherapy (IO) agents can cause late-onset immune-related adverse events (irAEs). In phase I trials, observation for dose-limiting toxicities (DLTs) is typically limited to the first cycle. The incidence of delayed-onset DLTs and their potential impact on dose determination have not been fully elucidated. PATIENTS AND METHODS: Consecutive patients enrolled in early phase IO trials at Princess Margaret Cancer Centre between August 2012 and September 2016 were retrospectively reviewed, applying trial-specific definitions for DLTs...
December 6, 2018: European Journal of Cancer
Hiroshi Kurahara, Kosei Maemura, Yuko Mataki, Masahiko Sakoda, Satoshi Iino, Yota Kawasaki, Takaaki Arigami, Shinichiro Mori, Yuko Kijima, Shinichi Ueno, Hiroyuki Shinchi, Shoji Natsugoe
BACKGROUND: A metabolic shift to glycolysis is reportedly involved in radioresistance. We examined whether pretreatment 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET), which can detect enhanced glucose uptake, was able to predict the therapeutic response to chemoradiotherapy (CRT) in patients with pancreatic cancer (PC). METHODS: Of 125 PC patients (75 unresectable and 50 borderline resectable), 37 and 26 underwent induction chemotherapy before CRT and surgical resection after CRT, respectively...
December 6, 2018: Annals of Surgical Oncology
Maciej Serda, Matthew J Ware, Jared M Newton, Sanchit Sachdeva, Martyna Krzykawska-Serda, Lam Nguyen, Justin Law, Andrew O Anderson, Steven A Curley, Lon J Wilson, Stuart J Corr
AIM: Glycoconjugated C60 derivatives are of particular interest as potential cancer targeting agents due to an upregulated metabolic glucose demand, especially in the case of pancreatic adenocarcinoma and its dense stroma, which is known to be driven by a subset of pancreatic stellate cells. MATERIALS & METHODS: Herein, we describe the synthesis and biological characterization of a hexakis-glucosamine C60 derivative (termed 'Sweet-C60 '). RESULTS: Synthesized fullerene derivative predominantly accumulates in the nucleus of pancreatic stellate cells; is inherently nontoxic up to concentrations of 1 mg/ml; and is photoactive when illuminated with blue and green light, allowing its use as a photodynamic therapy agent...
December 3, 2018: Nanomedicine
Lisa M Velez-Velez, Caren L Hughes, Pashtoon Murtaza Kasi
Pharmacogenomic testing may have clinical value in the treatment of patients with gastrointestinal malignancies such as colorectal and pancreatic cancer. These types of cancer are often treated with combination chemotherapy regimens. These regimens can lead to severe adverse effects in patients with diminished drug tolerability potentially due to certain genetic variants in the enzymes involved in the metabolism of the chemotherapies. Genetic variants resulting in decreased enzymatic activity of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and dihydropyrimidine dehydrogenase (DPD) are known to increase irinotecan and 5-fluorouracil-related toxicity, respectively...
2018: Frontiers in Pharmacology
Courtney Griffiths, Edward Jimenez, Eva Chalas
INTRODUCTION: Gynecologic malignancies are estimated to affect 110,070 women and will be the cause of death in approximately 32,120 in 2018. Endometrial cancer is among the most prevalent with 63,320 estimated new cases and approximately 11,350 deaths, followed by ovarian cancer with an estimate of 22,000 new cases and 14,000 deaths annually. Obesity is one of the most modifiable risk factors. Providers should engage in a multifaceted approach to patient education and healthcare to decrease the projected cases of obesity-related cancers...
August 4, 2018: Current Problems in Cancer
Vasilios Karavasilis, Epaminontas Samantas, Georgia-Angeliki Koliou, Anna Kalogera-Fountzila, George Pentheroudakis, Ioannis Varthalitis, Helena Linardou, Grigorios Rallis, Maria Skondra, Georgios Papadopoulos, George Papatsibas, Joseph Sgouros, Athina Goudopoulou, Konstantine T Kalogeras, Christos Dervenis, Dimitrios Pectasides, George Fountzilas
BACKGROUND: The prognosis of patients with advanced pancreatic cancer is dismal, and there is a need for novel and effective treatments. OBJECTIVES: Tο determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of a novel gemcitabine (G) and temsirolimus (T) combination (phase I) and estimate the 6-month progression-free survival (PFS) in patients treated with the T + G combination (phase II). PATIENTS AND METHODS: Eligible patients with histologically confirmed inoperable or metastatic pancreatic carcinoma (MPC) were entered into the trial...
November 28, 2018: Targeted Oncology
Helena Verdaguer, Alvaro Arroyo, Teresa Macarulla
Only a limited number of therapeutic strategies are available for patients diagnosed with pancreatic adenocarcinoma, and disease recurrence and mortality are consequently high. For metastatic disease, two combinations are approved in the first line setting: a triplet with 5-fluoruracil, irinotecan, and oxaliplatin, and the combination of gemcitabine and nab-paclitaxel. In patients who have progressed on gemcitabine, a new nanoliposomal formulation of irinotecan has recently been approved. While these treatments have demonstrated some efficacy, there has been little increase in survival rates for metastatic pancreatic cancer patients...
November 23, 2018: Targeted Oncology
Naiara Santana-Codina, Anjali A Roeth, Yi Zhang, Annan Yang, Oksana Mashadova, John M Asara, Xiaoxu Wang, Roderick T Bronson, Costas A Lyssiotis, Haoqiang Ying, Alec C Kimmelman
Oncogenic KRAS is the key driver of pancreatic ductal adenocarcinoma (PDAC). We previously described a role for KRAS in PDAC tumor maintenance through rewiring of cellular metabolism to support proliferation. Understanding the details of this metabolic reprogramming in human PDAC may provide novel therapeutic opportunities. Here we show that the dependence on oncogenic KRAS correlates with specific metabolic profiles that involve maintenance of nucleotide pools as key mediators of KRAS-dependence. KRAS promotes these effects by activating a MAPK-dependent signaling pathway leading to MYC upregulation and transcription of the non-oxidative pentose phosphate pathway (PPP) gene RPIA, which results in nucleotide biosynthesis...
November 23, 2018: Nature Communications
Patricia Santofimia-Castaño, Wenjun Lan, Jennifer Bintz, Odile Gayet, Alice Carrier, Gwen Lomberk, José Luis Neira, Antonio González, Raul Urrutia, Philippe Soubeyran, Juan Iovanna
It was already described that genetic inhibition of NUPR1 induces tumor growth arrest. In this paper we studied the metabolism changes after NUPR1 downregulation in pancreatic cancer cells, which results in a significant decrease of OXPHOS activity with a concomitant lower ATP production which precedes the necrotic cell death. We demonstrated that NUPR1 downregulation induces a mitochondrial failure with a loss of the mitochondrial membrane potential, a strong increase in ROS production and a concomitant relocalization of mitochondria to the vicinity of the endoplasmic reticulum (ER)...
November 19, 2018: Scientific Reports
Balakrishnan Rekha, Ganesan Velmurugan, Allen J Freddy, Sivakumar Anusha, Tharmarajan Ramprasath, Karuppusamy V Karthik, Shanmugarajan Suresh, Prerna Kulshrestha, Gilles Mithieux, Alexander R Lyon, Govindan Sadasivam Selvam, Subbiah Ramasamy
Caramel colours are the preferential food colouring agent globally, reaches wide age groups through eatables. Colas, a sweetened carbonated drink are most common caramel coloured beverage and its consumption is linked with diabetes, obesity, pancreatic cancer and other endocrine disorders. A major by-product produced during caramelization is 4-methylimidazole (4-MEI) that is detected in noteworthy concentrations in colas and other beverages. Previous studies revealed the neurotoxic and carcinogenic potential of 4-MEI in animals at higher doses but the effect of 4-MEI at theoretical maximum daily intake dose on glucose homeostasis is unexplored...
November 19, 2018: Scientific Reports
Qiqing Sun, Bo Zhang, Qiangsheng Hu, Yi Qin, Wenyan Xu, Wensheng Liu, Xianjun Yu, Jin Xu
Pancreatic ductal adenocarcinoma (PDAC) constitutes one of the most challenging lethal tumors and has a very poor prognosis. In addition to cancer cells, the tumor microenvironment created by a repertoire of resident and recruited cells and the extracellular matrix also contribute to the acquisition of hallmarks of cancer. Among these factors, cancer-associated fibroblasts (CAFs) are critical components of the tumor microenvironment. CAFs originate from the activation of resident fibroblasts and pancreatic stellate cells, the differentiation of bone marrow-derived mesenchymal stem cells and epithelial-to-mesenchymal transition...
2018: Theranostics
Ling Qian, Shulin Yu, Zhen Chen, Zhiqiang Meng, Shenglin Huang, Peng Wang
Pancreatic cancer is one of the most aggressive human malignancies and is associated with a dismal prognosis, which can be contributed to its atypical symptoms, metastatic propensity, and significant chemoresistance. Emerging evidence shows that pancreatic cancer cell-derived exosomes (PEXs) play critical roles in tumorigenesis and tumor development, as they are involved in drug resistance, immune evasion and metabolic reprograming, and distant metastasis of pancreatic cancer. Their numerous differentially expressed and functional contents make PEXs promising screening tools and therapeutic targets, which require further exploration...
November 9, 2018: Biochimica et biophysica acta. Reviews on cancer
Hans G Beger, Benjamin Mayer, Bertram Poch
BACKGROUND: Parenchyma-sparing, local pancreatic head resection, but not pancreaticoduodenectomy (PD) preserves tissue and maintains the pancreatic metabolic functions. METHODS: PubMed/Medline, Embase, and Cochrane library collections were systematically searched. Twenty-six cohort studies with 523 cumulative patients, who underwent duodenum-sparing pancreatic head resection (DPPHR), were retrieved. The meta-analysis was based on 14 controlled studies. RESULTS: In total, 338 patients suffered cystic neoplasms and 59 PNETs, IPMN-174, MCN-43 and SPN-23 patients...
October 16, 2018: American Journal of Surgery
Priscilla Cascetta, Alessandro Cavaliere, Geny Piro, Lorena Torroni, Raffaela Santoro, Giampaolo Tortora, Davide Melisi, Carmine Carbone
Cancer and obesity are the two major epidemics of the 21st century. Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of death, with a five-year overall survival rate of only 8%. Its incidence and mortality have increased in recent years, and this cancer type is expected to be among the top five leading causes of cancer-related death by 2030 in the United States (US). In the last three decades, the prevalence of overweight people has boosted with a consequent increase in obesity-related diseases...
October 25, 2018: International Journal of Molecular Sciences
Melissa C Holt, Zahra Assar, Reza Beheshti Zavareh, Lin Lin, Justin Anglin, Oksana Mashadova, Daniel Haldar, Edouard Mullarky, Daniel M Kremer, Lewis C Cantley, Alec C Kimmelman, Adam J Stein, Luke L Lairson, Costas A Lyssiotis
Pancreatic cancer cells are characterized by deregulated metabolic programs that facilitate growth and resistance to oxidative stress. Among these programs, pancreatic cancers preferentially utilize a metabolic pathway through the enzyme aspartate aminotransferase 1 [also known as glutamate oxaloacetate transaminase 1 (GOT1)] to support cellular redox homeostasis. As such, small molecule inhibitors that target GOT1 could serve as starting points for the development of new therapies for pancreatic cancer. We ran a high-throughput screen for inhibitors of GOT1 and identified a small molecule, iGOT1-01, with in vitro GOT1 inhibitor activity...
November 12, 2018: Biochemistry
De-Hai Wu, Hao Liang, Shou-Nan Lu, Hao Wang, Zhi-Lei Su, Lei Zhang, Jian-Qun Ma, Mian Guo, Sheng Tai, Shan Yu
BACKGROUND/AIMS: Increasing evidence shows that reprogramming of energy metabolism is a hallmark of cancer. Considering the emergence of microRNAs as crucial modulators of cancer, this study aimed to better understand the molecular mechanisms of miR-124 in regulating glycolysis in human pancreatic cancer. METHODS: RT-PCR was used to investigate the expression of monocarboxylate transporters (MCTs) in pancreatic ductal adenocarcinoma (PDAC) patient samples and the PANC-1 cell line...
2018: Cellular Physiology and Biochemistry
B S Ankit, Ritvik Agrawal, Ajeet Gadhwal, Chitresh Chahar, R P Agrawal
Objectives: Diabetes mellitus has been claimed to be a risk factor for the development of pancreatic carcinoma. CA 19-9 has a great sensitivity in detection of pancreatic adenocarcinoma. Metformin exhibits a strong and consistent antiproliferative action on several cancer cell lines including pancreatic cancer. We aim to determine the influence of metformin on CA 19-9 levels in type 2 diabetes mellitus patients. Methods: Total 193 patients with type 2 diabetes mellitus were registered for a single centre, cross-sectional study...
March 2018: Journal of the Association of Physicians of India
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