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- Chemoquiescence for ideal cancer treatment and prevention: where are we now? [Journal Article, Review]
- J Cancer Prev 2014 Jun; 19(2):89-6.
Cellular quiescence is a state of reversible cell cycle arrest and is associated with a low metabolic state featured with decreased glycolysis, reduced translation rates, and activation of autophagy, fundamentally to provide nutrients for cell survival similar as seen in hybernation. As signal for quiescence, inactivating the target of rapamycin kinase and resulting reduced cell growth and biosynthesis are essential, but cellular quiescence is not always associated with reduced metabolism since it is also possible to achieve a state of cellular quiescence in which glucose uptake, glycolysis and flux through central carbon metabolism are not reduced. However, in cancer cells, overcoming intrinsic and acquired resistance of cancer stem or cancer dormancy cells to current clinical treatments can be reversed with the acquisition of chemoquiesence. The development of new drug combinations or strategy to treat the highly aggressive and metastatic cancers including relapsed leukaemias, melanoma and head and neck, brain, lung, breast, ovary, prostate, pancreas as well as gastrointestinal cancers which remain incurable in the clinic in spite of aggressive therapies, can be accelerated with the introduction of chemoquiescence agent, for which cancer stem cells or tumor dormancy should be eradicated or removed. Recently potential applications of metformin or chloroquine as well as the potential drugs under investigation such as proton pump inhibitor, sonic hedgehog inhibitor, and Akt inhibitor, are actively investigated in this field of chemoquiescence to achieve cancer cure far beyond those of chemoprevention. In this review article, the evolving concept of chemoquiescence or cancer dormancy will be introduced accompanied by a description of novel target drug development.
- F-18 FDG hypermetabolism in mass-forming focal pancreatitis and old hepatic schistosomiasis with granulomatous inflammation misdiagnosed by PET/CT imaging. [Journal Article]
- Int J Clin Exp Pathol 2014; 7(9):6339-44.
We report the case of a 59-year-old male patient who presented with space-occupying lesions in the pancreas and liver suggestive of metastatic pancreatic cancer.Whole-body F-18 fluorodeoxyglucose (FDG) PET/CT imaging and enhanced CT imaging of the lesions were performed in addition to abdominal ultrasound, ERCP, and MRCP. Tumor markers, including CA199 and AFP, were also evaluated.PET/CT imaging showed a soft tissue mass with indistinct boundaries in the head of the pancreas with a maximum SUV of 4.39. A less dense shadow was also found in the left lobe of the liver with an indistinct boundary and a maximum SUV of 4.13. Enhanced CT revealed an enhancing mass in the head of the pancreas on arterial phase imaging as well as a mildly enhancing focus in the left lobe of the liver. The patient was diagnosed with a space-occupying lesion of the uncinate process of the pancreas suggestive of pancreatic cancer with metastasis to the liver. However, serum tumor markers were normal. Postoperative pathology was consistent with chronic pancreatitis and old hepatic schistosomiasis associated with granulomatous inflammation of the liver.This case of mass-forming pancreatitis and granulomatous inflammation in old hepatic schistosomiasis mimicked metastatic pancreatic cancer on PET/CT. Such false positive lesions have not been reported before, and further exploration and investigation are needed.
- Neuroendocrine liver metastasis in gastric mixed adenoneuroendocrine carcinoma with trilineage cell differentiation: a case report. [Journal Article]
- Int J Clin Exp Pathol 2014; 7(9):6333-8.
Mixed adenoneuroendocrine carcinoma (MANEC) is a rare disease, which mostly occurs in the gastroin testinal tract and pancreas. Here we report a case of gastric MANEC with tri-lineage differentiation in which only the neuroendocrine component had metastasized to the liver. Liver and gastric masses were detected by abdominal computed tomography, and the preoperative relationship between liver and gastric masses was unknown. The histopathological analysis after operation confirmed the gastric mass to be MANEC, whereas the liver mass was actually the metastatic neuroendocrine component of the gastric MANEC. In the pathologic diagnosis, tri-lineage differentiation, including tubular adenocarcinoma, neuroendocrine carcinoma and squamous cell carcinoma was observed in the gastric MANEC tissues. The mitotic and Ki-67 labeling indexes of the resected tumor tissue were high, and thus, the tumor was classified as a grade G3 neuroendocrine carcinoma, which has a poor prognosis. Multiple low-density masses were found in the right lobe of the liver 2.5 months after operation.
- MUC1 Promoter-driven DTA as a Targeted Therapeutic Strategy against Pancreatic Cancer. [JOURNAL ARTICLE]
- Mol Cancer Res 2014 Oct 21.
Mucin1 (MUC1) is overexpressed in pancreatic ductal adenocarcinoma (PDA) and is associated with tumor aggressiveness, suggesting that MUC1 is a promising therapeutic target for promoterdriven diphtheria toxin A (DTA). Endogenous MUC1 transcript levels were analyzed by quantitative PCR (qPCR) in multiple PDA cells (Capan1, HPAFII, Su.86.86, Capan2, Hs766T, MiaPaCa2, and Panc1). Expression levels were correlated with luciferase activity and cell death after transfection with MUC1 promoter-driven luciferase and DTA constructs. MUC1-positive (+) cells had significantly elevated MUC1 mRNA expression compared to MUC1-negative (-) cells. Luciferase activity was significantly higher in MUC1+ cells when transfected with MUC1 promoter-driven luciferase and MUC1+ cells underwent enhanced cell death after transfection with a single dose of MUC1 promoter-driven DTA. Interferon gamma (IFN-γ) pre-treatment enhanced MUC1 expression in MUC1- cells and induced sensitivity to MUC1-DTA therapy. Matched primary and metastatic tumor lesions from clinical specimens revealed similar MUC1 immunohistochemistry (IHC) labeling patterns, and a tissue microarray of human PDA biopsies revealed increased immunolabeling with a combination of MUC1 and mesothelin (MSLN) antibodies, compared to either antibody alone. Combining MUC1 with MSLN targeted DTA enhanced drug efficacy in an in vitro model of heterogeneous PDA. These data demonstrate that MUC1 promoter-driven DTA preferentially kills MUC1-expressing PDA cells and drugs that enhance MUC1 expression sensitize PDA cells with low MUC1 expression. Implications: MUC1 expression in primary and metastatic lesions provides a rational for the development of a systemic MUC1 promoter-driven DTA therapy that may be further enhanced by combination with other promoter driven DTA constructs.
- MANAGEMENT OF ENDOCRINE DISEASE: Cystic fibrosis-related diabetes: novel pathogenic insights opening new therapeutic avenues. [JOURNAL ARTICLE]
- Eur J Endocrinol 2014 Oct 21.
Cystic fibrosis (CF) is a recessive genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR). CFTR is primarily present in epithelial cells of the airways, intestine and in cells with exocrine and endocrine functions. Mutations in the gene encoding the channel protein complex (CFTR) cause alterations in the ionic composition of secretions from the lung, gastrointestinal tract, liver but also the pancreas. Cystic Fibrosis-Related Diabetes (CFRD), the most common complication of CF, has a major detrimental impact on pulmonary function, nutrition and survival. Glucose derangements in CF seem to start from early infancy and, even when the pathophysiology is multifactorial, insulin insufficiency is clearly a major component. Consistently, recent evidence confirms that CFTR is an important regulator of insulin secretion by islet beta-cells. In addition, several other mechanisms were also recognized from cellular and animals models also contributing to either beta-cell mass reduction or beta-cell malfunction. Understanding such mechanisms is crucial to the development of the so-called "transformational" therapies in CF, including the preservation of insulin secretion. Innovative therapeutic approaches aim to modify specific CFTR mutant proteins or positively modulate their function. CFTR modulators recently showed in vitro capacity to enhance insulin secretion and thereby potential clinical utility in CFDR, including synergistic effects between corrector and potentiator drugs. The introduction of incretins and the optimization of exocrine pancreatic replacement complete the number of therapeutic options of CFRD besides early diagnosis and implementation of insulin therapy. This review focuses on the recently identified pathogenic mechanisms leading to CFRD relevant for the development of novel pharmacological avenues in CFRD therapy.
- The fetal liver as cell source for the regenerative medicine of liver and pancreas. [Journal Article, Review]
- Ann Transl Med 2013 Jul; 1(2):13.
Patients affected by liver diseases and diabetes mellitus are in need for sources of new cells to enable a better transition into clinic programs of cell therapy and regenerative medicine. In this setting, fetal liver is becoming the most promising and available source of cells. Fetal liver displays unique characteristics given the possibility to isolate cell populations with a wide spectrum of endodermal differentiation and, the co-existence of endodermal and mesenchymal-derived cells. Thus, the fetal liver is a unique and highly available cell source contemporarily candidate for the regenerative medicine of both liver and pancreas. The purpose of this review is to revise the recent literature on the different stem cells populations isolable from fetal liver and candidate to cell therapy of liver diseases and diabetes and to discuss advantages and limitation with respect to other cell sources.
- Role of NKG2D in Obesity-Induced Adipose Tissue Inflammation and Insulin Resistance. [JOURNAL ARTICLE]
- PLoS One 2014; 9(10):e110108.
The early events that initiate inflammation in the adipose tissue during obesity are not well defined. It is unclear whether the recruitment of CD8 T cells to the adipose tissue during onset of obesity occurs through antigen-dependent or -independent processes. We have previously shown that interaction between NKG2D (natural-killer group 2, member D) and its ligand Rae-1ε is sufficient to recruit cytotoxic T lymphocytes to the pancreas and induce insulitis. Here, we tested whether NKG2D-NKG2D ligand interaction is also involved in obesity-induced adipose tissue inflammation and insulin resistance. We observed a significant induction of NKG2D ligand expression in the adipose tissue of obese mice, especially during the early stages of obesity. However, mice lacking NKG2D developed similar levels of insulin resistance and adipose tissue inflammation compared to control mice when placed on a high-fat diet. Moreover, overexpression of Rae-1ε in the adipose tissue did not increase immune cell infiltration to the adipose tissue either in the setting of a normal or high-fat diet. These results indicate that, unlike in the pancreas, NKG2D-NKG2D ligand interaction does not play a critical role in obesity-induced inflammation in the adipose tissue.
- 22. TESTICULAR INVOLVEMENT IN SYSTEMIC DISEASES. [JOURNAL ARTICLE]
- Pediatr Dev Pathol 2014 Oct 21.
Abstract Normal testicular physiology requires appropriate function of endocrine glands and other tissues. Testicular lesions have been described in disorders involving the hypothalamus-hypophysis, thyroid glands, adrenal glands, pancreas, liver, kidney, and gastrointestinal tract. Testicular abnormalities can also associate with chronic anemia, obesity, and neoplasia. Although many of the disorders that affect the above-mentioned glands and tissues are congenital, acquired lesions may result in hypogonadism in children and adolescents.
- Select Biomarkers for Tumors of the Gastrointestinal Tract: Present and Future. [JOURNAL ARTICLE]
- Arch Pathol Lab Med 2014 Oct 21.
Context .- Advances in molecular biomarkers of the gastrointestinal tract have contributed to a decline in the incidence of and mortality from these diseases. The discovery and clinical validation of new biomarkers are important to personalized cancer therapy, and numerous clinical trials are currently ongoing to help identify individualized therapy affecting these biomarkers and molecular mechanisms they represent. Distinct molecular pathways leading to cancers of the colorectum, esophagus, stomach, small bowel, and pancreas have been identified. Using biomarkers in these pathways to direct patient care, including selection of proper molecular testing for identification of actionable mutations and reporting the results of these biomarkers to guide clinicians and genetic counselors, is paramount. Objective .- To examine and review select clinically actionable biomarkers of the colon, esophagus, stomach, small bowel, and pancreas, including present and future biomarkers with relevant clinical trials. Data Sources .- Extensive literature review and practical and consultation experience of the authors. Conclusions .- Although numerous biomarkers have been identified and are currently guiding patient therapy, few have shown evidence of clinical utility in the management of patients with gastrointestinal cancers. Inconsistent results and discordant proposed algorithms for testing were identified throughout the literature; however, the potential for biomarkers to improve outcomes for patients with gastrointestinal cancer remains high. Continued advances through high-quality studies are needed.
- Author Index. [JOURNAL ARTICLE]
- Pancreas 2014 Nov; 43(8):1430-1435.