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pancreatic cancer metabolism

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https://www.readbyqxmd.com/read/28418859/serum-metabolomics-differentiating-pancreatic-cancer-from-new-onset-diabetes
#1
Xiangyi He, Jie Zhong, Shuwei Wang, Yufen Zhou, Lei Wang, Yongping Zhang, Yaozong Yuan
To establish a screening strategy for pancreatic cancer (PC) based on new-onset diabetic mellitus (NO-DM), serum metabolomics analysis and a search for the metabolic pathways associated with PC related DM were performed. Serum samples from patients with NO-DM (n = 30) and patients with pancreatic cancer and NO-DM were examined by liquid chromatography-mass spectrometry. Data were analyzed using principal components analysis (PCA) and orthogonal projection to latent structures (OPLS) of the most significant metabolites...
March 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28414315/the-emt-activator-zeb1-is-a-key-factor-for-cell-plasticity-and-promotes-metastasis-in-pancreatic-cancer
#2
Angela M Krebs, Julia Mitschke, María Lasierra Losada, Otto Schmalhofer, Melanie Boerries, Hauke Busch, Martin Boettcher, Dimitrios Mougiakakos, Wilfried Reichardt, Peter Bronsert, Valerie G Brunton, Christian Pilarsky, Thomas H Winkler, Simone Brabletz, Marc P Stemmler, Thomas Brabletz
Metastasis is the major cause of cancer-associated death. Partial activation of the epithelial-to-mesenchymal transition program (partial EMT) was considered a major driver of tumour progression from initiation to metastasis. However, the role of EMT in promoting metastasis has recently been challenged, in particular concerning effects of the Snail and Twist EMT transcription factors (EMT-TFs) in pancreatic cancer. In contrast, we show here that in the same pancreatic cancer model, driven by Pdx1-cre-mediated activation of mutant Kras and p53 (KPC model), the EMT-TF Zeb1 is a key factor for the formation of precursor lesions, invasion and notably metastasis...
April 17, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28400627/molecular-subtypes-in-cancers-of-the-gastrointestinal-tract
#3
REVIEW
Maarten F Bijlsma, Anguraj Sadanandam, Patrick Tan, Louis Vermeulen
Malignancies of the gastrointestinal tract are among the most common human cancers. The distinct tissues of origin give rise to a diverse set of diseases, such as colorectal cancer, pancreatic carcinoma and gastric cancers, with each associating with specific clinical features. Genomic and transcriptomic analyses have further defined the heterogeneity that occurs within these cancers by identifying so-called molecular subtypes. These subtypes are characterized by specific genetic aberrations and expression signatures that suggest important biological differences...
April 12, 2017: Nature Reviews. Gastroenterology & Hepatology
https://www.readbyqxmd.com/read/28396056/connecting-the-metabolic-and-immune-responses-to-cancer
#4
REVIEW
Thomas R Flint, Douglas T Fearon, Tobias Janowitz
Separate research fields have advanced our understanding of, on the one hand, cancer immunology and, on the other hand, cachexia, the fatal tumor-induced wasting syndrome. A link between the host's immune and metabolic responses to cancer remained unexplored. Emerging work in preclinical models of colorectal and pancreatic cancer has unveiled tumor-induced reprogramming of liver metabolism in cachexia that leads to suppression of antitumor immunity and failure of immunotherapy. As research efforts in metabolism and immunology in cancer are rapidly expanding, it is timely to discuss the metabolic and immunological determinants of the cancer-host interaction...
April 7, 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/28383714/a-systems-approach-identifies-time-dependent-associations-of-multimorbidities-with-pancreatic-cancer-risk
#5
P Gomez-Rubio, V Rosato, M Marquez, C Bosetti, E Molina-Montes, M Rava, J Piñero, C W Michalski, A Farré, X Molero, M Löhr, L Ilzarbe, J Perea, W Greenhalf, M O'Rorke, A Tardón, T Gress, V M Barberà, T Crnogorac-Jurcevic, L Muñoz-Bellvís, E Domínguez-Muñoz, A Gutiérrez-Sacristán, J Balsells, E Costello, C Guillén-Ponce, J Huang, M Iglesias, J Kleeff, B Kong, J Mora, L Murray, D O'Driscoll, P Peláez, I Poves, R T Lawlor, A Carrato, M Hidalgo, A Scarpa, L Sharp, L I Furlong, F X Real, C La Vecchia, N Malats
Background: HASH(0x33a3e10) Pancreatic ductal adenocarcinoma (PDAC) is usually diagnosed in late adulthood; therefore, many patients suffer or have suffered from other diseases. Identifying disease-patterns associated with PDAC risk may enable a better characterization of high-risk patients. Methods: HASH(0x339b400) Multimorbidity patterns (MPs) were assessed from 17 self-reported conditions using hierarchical clustering, principal component, and factor analyses in 1705 PDAC cases and 1084 controls from a European population...
April 5, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28373363/re-engineering-the-pancreas-tumor-microenvironment-a-regenerative-program-hacked
#6
EDITORIAL
Gerard I Evan, Nasun Hah, Trevor D Littlewood, Nicole M Sodir, Tania Campos, Michael Downes, Ronald M Evans
The "hallmarks" of pancreatic ductal adenocarcinoma (PDAC) include proliferative, invasive, and metastatic tumor cells and an associated dense desmoplasia comprised of fibroblasts, pancreatic stellate cells, extracellular matrix, and immune cells. The oncogenically activated pancreatic epithelium and its associated stroma are obligatorily interdependent, with the resulting inflammatory and immunosuppressive microenvironment contributing greatly to the evolution and maintenance of PDAC. The peculiar pancreas-specific tumor phenotype is a consequence of oncogenes hacking the resident pancreas regenerative program, a tissue-specific repair mechanism regulated by discrete super enhancer networks...
April 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28373361/pancreatic-cancer-a-riddle-wrapped-in-a-mystery-inside-an-enigma
#7
EDITORIAL
Erkut Borazanci, Chi V Dang, Robert W Robey, Susan E Bates, John A Chabot, Daniel D Von Hoff
Pancreatic ductal adenocarcinoma (PDAC) is one of the most difficult-to-treat cancers. With an increasing incidence and inability to make major progress, it represents the very definition of unmet medical need. Progress has been made in understanding the basic biology-systematic genomic sequencing has led to the recognition that PDAC is not typically a heavily mutated tumor, although there are exceptions. The most consistently mutated genes are KRAS, CDKN2A, TP53, and SMAD4/DPC4 Study of familial PDAC has led to the recognition that a variety of defects in DNA repair genes can be associated with the emergence of pancreatic cancer...
April 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28368405/connexin-43-channels-are-a-pathway-for-discharging-lactate-from-glycolytic-pancreatic-ductal-adenocarcinoma-cells
#8
T H Dovmark, M Saccomano, A Hulikova, F Alves, P Swietach
Glycolytic cancer cells produce large quantities of lactate that must be removed to sustain metabolism in the absence of oxidative phosphorylation. The only venting mechanism described to do this at an adequate rate is H(+)-coupled lactate efflux on monocarboxylate transporters (MCTs). Outward MCT activity is, however, thermodynamically inhibited by extracellular acidity, a hallmark of solid tumours. This inhibition would feedback unfavourably on metabolism and growth, raising the possibility that other venting mechanisms become important in under-perfused tumours...
April 3, 2017: Oncogene
https://www.readbyqxmd.com/read/28363942/usp49-negatively-regulates-tumorigenesis-and-chemoresistance-through-fkbp51-akt-signaling
#9
Kuntian Luo, Yunhui Li, Yujiao Yin, Lei Li, Chenming Wu, Yuping Chen, Somaira Nowsheen, Qi Hu, Lizhi Zhang, Zhenkun Lou, Jian Yuan
The AKT pathway is a fundamental signaling pathway that mediates multiple cellular processes, such as cell proliferation and survival, angiogenesis, and glucose metabolism. We recently reported that the immunophilin FKBP51 is a scaffolding protein that can enhance PHLPP-AKT interaction and facilitate PHLPP-mediated dephosphorylation of AKT at Ser473, negatively regulating AKT activation. However, the regulation of FKBP51-PHLPP-AKT pathway remains unclear. Here we report that a deubiquitinase, USP49, is a new regulator of the AKT pathway...
March 31, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28361035/mitochondrial-and-oxidative-stress-mediated-activation-of-protein-kinase-d1-and-its-importance-in-pancreatic-cancer
#10
REVIEW
Heike Döppler, Peter Storz
Due to alterations in their metabolic activity and decreased mitochondrial efficiency, cancer cells often show increased generation of reactive oxygen species (ROS), but at the same time, to avoid cytotoxic signaling and to facilitate tumorigenic signaling, have mechanism in place that keep ROS in check. This requires signaling molecules that convey increases in oxidative stress to signal to the nucleus to upregulate antioxidant genes. Protein kinase D1 (PKD1), the serine/threonine kinase, is one of these ROS sensors...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28356294/exocytosis-proteins-as-novel-targets-for-diabetes-prevention-and-or-remediation
#11
Arianne Aslamy, Debbie C Thurmond
Diabetes remains one of the leading causes of morbidity and mortality worldwide, affecting an estimated 422 million adults. In the U.S. it is predicted that 1 in every 3 children born as of 2000 will suffer from diabetes in their lifetime. Type 2 diabetes results from combinatorial defects in pancreatic beta cell glucose-stimulated insulin secretion and in peripheral glucose uptake. Both processes, insulin secretion and glucose uptake, are mediated by exocytosis proteins, SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complexes, Sec1/Munc18 (SM), and Double C2-domain protein B (DOC2B)...
March 29, 2017: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
https://www.readbyqxmd.com/read/28351381/the-role-of-stromal-cancer-associated-fibroblasts-in-pancreatic-cancer
#12
REVIEW
Dagny von Ahrens, Tushar D Bhagat, Deepak Nagrath, Anirban Maitra, Amit Verma
Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer generally refractory to conventional treatments. Cancer-associated fibroblasts (CAFs) are cellular components of the desmoplastic stroma characteristic to the tumor that contributes to this treatment resistance. Various markers for CAFs have been explored including palladin and CD146 that have prognostic and functional roles in the pathobiology of PDAC. Mechanisms of CAF-tumor cell interaction have been described including exosomal transfer and paracrine signaling mediated by cytokines such as GM-CSF and IL-6...
March 28, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28350132/a-new-facet-of-ndrg1-in-pancreatic-ductal-adenocarcinoma-suppression-of-glycolytic-metabolism
#13
Wensheng Liu, Bo Zhang, Qiangsheng Hu, Yi Qin, Wenyan Xu, Si Shi, Chen Liang, Qingcai Meng, Jinfeng Xiang, Dingkong Liang, Shunrong Ji, Jiang Liu, Pengfei Hu, Liang Liu, Chen Liu, Jiang Long, Quanxing Ni, Xianjun Yu, Jin Xu
N-myc downstream-regulated gene 1 (NDRG1) is known as tumor/metastasis suppressor in a variety of cancers including pancreas, being involved in angiogenesis, cancer growth and metastasis. However, the precise molecular mechanism how NDRG1 exerts its inhibitory function in pancreatic cancer remains unclear. In this investigation, we demonstrated that K-Ras plays a vital role in modulating NDRG1 protein level in PDAC cancer cells in vitro, which is mediated through ERK signaling. Noteworthy, K-Ras downstream Akt/mTOR signaling is inhibited upon NDRG1 overexpression, resulting in decease of HIF1α level...
March 28, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28348075/computational-and-structural-evidence-for-neurotransmitter-mediated-modulation-of-the-oligomeric-states-of-human-insulin-in-storage-granules
#14
Vladimír Palivec, Cristina M Viola, Mateusz Kozak, Timothy R Ganderton, Květoslava Křížková, Johan P Turkenburg, Petra Halušková, Lenka Žáková, Jiří Jiráček, Pavel Jungwirth, Andrzej M Brzozowski
Human insulin is a pivotal protein hormone controlling metabolism, growth and ageing, and whose malfunctioning underlies diabetes, some cancers and neuro-degeneration. Despite its central position in human physiology, the in vivo oligomeric state and conformation of insulin in its storage granules in the pancreas are not known. In contrast, many in vitro structures of hexamers of this hormone are available, which fall into three conformational states: T6, T3Rf3 and R6. As there is strong evidence for accumulation of neurotransmitters, such as serotonin and dopamine, in insulin storage granules in pancreatic β-cells, we probed by molecular dynamics (MD) and protein crystallography (PC) if these endogenous ligands affect and stabilize insulin oligomers...
March 27, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28348045/stratification-of-pancreatic-ductal-adenocarcinoma-combinatorial-genetic-stromal-and-immunological-markers
#15
Erik Knudsen, Paris Vail, Uthra Balaji, Hoai Ngo, Ihab W Botros, Vladimir Makarov, Nadeem Riaz, Vinod P Balachandran, Steven D Leach, Debrah M Thompson, Timothy A Chan, Agnieszka K Witkiewicz
PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is associated with an immunosuppressive milieu that supports immune system evasion and disease progression. Here, we interrogated genetic, stromal, and immunological features of PDAC to delineate impact on prognosis and to more effectively employ immunotherapy. EXPERIMENTAL DESIGN: A cohort of 109 PDAC cases annotated for overall survival was utilized as a primary discovery cohort. Gene expression analysis defined immunological subtypes of PDAC that were confirmed in the Cancer Genome Atlas data set...
March 27, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28346693/using-a-novel-nqo1-bioactivatable-drug-beta-lapachone-arq761-to-enhance-chemotherapeutic-effects-by-metabolic-modulation-in-pancreatic-cancer
#16
Muhammad Shaalan Beg, Xiumei Huang, Molly A Silvers, David E Gerber, Joyce Bolluyt, Venetia Sarode, Farjana Fattah, Ralph J Deberardinis, Matthew E Merritt, Xian-Jin Xie, Richard Leff, Daniel Laheru, David A Boothman
Novel, tumor-selective therapies are needed to increase the survival rate of pancreatic cancer patients. K-Ras-mutant-driven NAD(P)H:quinone oxidoreductase 1 (NQO1) is over-expressed in pancreatic tumor versus associated normal tissue, while catalase expression is lowered compared to levels in associated normal pancreas tissue. ARQ761 undergoes a robust, futile redox cycle in NQO1+ cancer cells, producing massive hydrogen peroxide (H2 O2 ) levels; normal tissues are spared by low NQO1 and high catalase expression...
March 27, 2017: Journal of Surgical Oncology
https://www.readbyqxmd.com/read/28346394/engineered-resistant-starch-ers-diet-shapes-colon-microbiota-profile-in-parallel-with-the-retardation-of-tumor-growth-in-in-vitro-and-in-vivo-pancreatic-cancer-models
#17
Concetta Panebianco, Kaarel Adamberg, Signe Adamberg, Chiara Saracino, Madis Jaagura, Kaia Kolk, Anna Grazia Di Chio, Paolo Graziano, Raivo Vilu, Valerio Pazienza
BACKGROUND/AIMS: Pancreatic cancer (PC) is ranked as the fourth leading cause of cancer-related deaths worldwide. Despite recent advances in treatment options, a modest impact on the outcome of the disease is observed so far. We have previously demonstrated that short-term fasting cycles have the potential to improve the efficacy of chemotherapy against PC. The aim of this study was to assess the effect of an engineered resistant-starch (ERS) mimicking diet on the growth of cancer cell lines in vitro, on the composition of fecal microbiota, and on tumor growth in an in vivo pancreatic cancer mouse xenograft model...
March 27, 2017: Nutrients
https://www.readbyqxmd.com/read/28344661/liposomal-irinotecan-in-gemcitabine-refractory-metastatic-pancreatic-cancer-efficacy-safety-and-place-in-therapy
#18
REVIEW
Emma Kipps, Kate Young, Naureen Starling
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. The majority of patients are diagnosed with locally advanced or metastatic disease with a prognosis of short months. Therapeutic options are limited and until recently, there was no standard second-line chemotherapy option. Liposomal constructs have been engineered to encapsulate chemotherapy thereby preventing premature metabolism, improving distribution and minimizing toxicity. Favourable preclinical data on liposomal irinotecan and early phase trials, led to a recently published phase III trial of liposomal irinotecan in combination with fluorouracil and folinic acid in patients with metastatic PDAC, who progressed after gemcitabine-based chemotherapy...
March 2017: Therapeutic Advances in Medical Oncology
https://www.readbyqxmd.com/read/28343174/mirna-analysis-in-pancreatic-cancer-the-dartmouth-experience
#19
REVIEW
Francine B de Abreu, Xiaoying Liu, Gregory J Tsongalis
Pancreatic cancer is considered one of the most lethal cancers being the fourth leading cause of cancer deaths in adults in the United States because of the lack of early signs and symptoms and the lack of early detection. Pancreatic ductal adenocarcinoma (PDAC) is the most common histological type among pancreatic cancers, representing 80%-90% of all solid tumors of the pancreas. The majority of PDAC develops from three precursor lesions: pancreatic intraepithelial neoplasia, intraductual papillary mucinous neoplasm and mucinous cystic neoplasm...
May 1, 2017: Clinical Chemistry and Laboratory Medicine: CCLM
https://www.readbyqxmd.com/read/28340556/innovative-substance-2250-as-a-highly-promising-anti-neoplastic-agent-in-malignant-pancreatic-carcinoma-in-vitro-and-in-vivo
#20
M Buchholz, B Majchrzak-Stiller, S Hahn, D Vangala, R W Pfirrmann, W Uhl, C Braumann, A M Chromik
BACKGROUND: Former studies already revealed the anti-neoplastic properties of the anti-infective agent Taurolidine (TRD) against many tumor species in vitro and in vivo. Its anti-proliferative and cell death inducing capacity is largely due to its main derivative Taurultam (TRLT). In this study it could be demonstrated, that substance 2250 - a newly defined innovative structural analogue of TRLT - exhibits an anti-neoplastic effect on malignant pancreatic carcinoma in vitro and in vivo...
March 24, 2017: BMC Cancer
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