Publications by authors named "Shi-he Liu"

53 Publications

CT Radiomics Model for Predicting the Ki-67 Index of Lung Cancer: An Exploratory Study.

Front Oncol 2021 11;11:743490. Epub 2021 Oct 11.

The Affiliated Hospital of Qingdao University, Qingdao, China.

Objective: To establish a radiomics signature and a nomogram model based on enhanced CT images to predict the Ki-67 index of lung cancer.

Methods: From January 2014 to December 2018, 282 patients with lung cancer who had undergone enhanced CT scans and Ki-67 examination within 2 weeks were retrospectively enrolled and analyzed. The clinical data of the patients were collected, such as age, sex, smoking history, maximum tumor diameter and serum tumor markers. Our primary cohort was randomly divided into a training group (n=197) and a validation group (n=85) at a 7:3 ratio. A Ki-67 index ≤ 40% indicated low expression, and a Ki-67 index > 40% indicated high expression. In total, 396 radiomics features were extracted using AK software. Feature reduction and selection were performed using the lasso regression model. Logistic regression analysis was used to establish a multivariate predictive model to identify high and low Ki-67 expression in lung cancer. A nomogram integrating the radiomics score was established based on multiple logistic regression analysis. Area under the curve (AUC) was used to evaluate the prediction efficiency of the radiomics signature and nomogram.

Results: The AUC,sensitivity, specificity and accuracy of the radiomics signature in the training and validation groups were 0.88 (95% CI: 0.82~0.93),79.2%,84.3%,81.2% and 0.86 (95% CI: 0.78~0.94),74.6%,88.1%,79.8%, respectively. A nomogram combining radiomics features and clinical risk factors (smoking history and NSE) was developed. The AUC, sensitivity, specificity and accuracy were 0.87 (95% CI: 0.80~0.95), 75.0%, 90.2% and 83.5% in the validation group, respectively.

Conclusion: The radiomics signature and nomogram based on enhanced CT images provide a way to predict the Ki-67 expression level in lung cancer.
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http://dx.doi.org/10.3389/fonc.2021.743490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8542688PMC
October 2021

Emerging Kinase Therapeutic Targets in Pancreatic Ductal Adenocarcinoma and Pancreatic Cancer Desmoplasia.

Int J Mol Sci 2020 Nov 21;21(22). Epub 2020 Nov 21.

Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA.

Kinase drug discovery represents an active area of therapeutic research, with previous pharmaceutical success improving patient outcomes across a wide variety of human diseases. In pancreatic ductal adenocarcinoma (PDAC), innovative pharmaceutical strategies such as kinase targeting have been unable to appreciably increase patient survival. This may be due, in part, to unchecked desmoplastic reactions to pancreatic tumors. Desmoplastic stroma enhances tumor development and progression while simultaneously restricting drug delivery to the tumor cells it protects. Emerging evidence indicates that many of the pathologic fibrotic processes directly or indirectly supporting desmoplasia may be driven by targetable protein tyrosine kinases such as Fyn-related kinase (FRK); B lymphoid kinase (BLK); hemopoietic cell kinase (HCK); ABL proto-oncogene 2 kinase (ABL2); discoidin domain receptor 1 kinase (DDR1); Lck/Yes-related novel kinase (LYN); ephrin receptor A8 kinase (EPHA8); FYN proto-oncogene kinase (FYN); lymphocyte cell-specific kinase (LCK); tec protein kinase (TEC). Herein, we review literature related to these kinases and posit signaling networks, mechanisms, and biochemical relationships by which this group may contribute to PDAC tumor growth and desmoplasia.
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http://dx.doi.org/10.3390/ijms21228823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700673PMC
November 2020

Kinome Array Profiling of Patient-Derived Pancreatic Ductal Adenocarcinoma Identifies Differentially Active Protein Tyrosine Kinases.

Int J Mol Sci 2020 Nov 17;21(22). Epub 2020 Nov 17.

Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA.

Pancreatic cancer remains one of the most difficult malignancies to treat. Minimal improvements in patient outcomes and persistently abysmal patient survival rates underscore the great need for new treatment strategies. Currently, there is intense interest in therapeutic strategies that target tyrosine protein kinases. Here, we employed kinome arrays and bioinformatic pipelines capable of identifying differentially active protein tyrosine kinases in different patient-derived pancreatic ductal adenocarcinoma (PDAC) cell lines and wild-type pancreatic tissue to investigate the unique kinomic networks of PDAC samples and posit novel target kinases for pancreatic cancer therapy. Consistent with previously described reports, the resultant peptide-based kinome array profiles identified increased protein tyrosine kinase activity in pancreatic cancer for the following kinases: epidermal growth factor receptor (EGFR), fms related receptor tyrosine kinase 4/vascular endothelial growth factor receptor 3 (FLT4/VEGFR-3), insulin receptor (INSR), ephrin receptor A2 (EPHA2), platelet derived growth factor receptor alpha (PDGFRA), SRC proto-oncogene kinase (SRC), and tyrosine kinase non receptor 2 (TNK2). Furthermore, this study identified increased activity for protein tyrosine kinases with limited prior evidence of differential activity in pancreatic cancer. These protein tyrosine kinases include B lymphoid kinase (BLK), Fyn-related kinase (FRK), Lck/Yes-related novel kinase (LYN), FYN proto-oncogene kinase (FYN), lymphocyte cell-specific kinase (LCK), tec protein kinase (TEC), hemopoietic cell kinase (HCK), ABL proto-oncogene 2 kinase (ABL2), discoidin domain receptor 1 kinase (DDR1), and ephrin receptor A8 kinase (EPHA8). Together, these results support the utility of peptide array kinomic analyses in the generation of potential candidate kinases for future pancreatic cancer therapeutic development.
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http://dx.doi.org/10.3390/ijms21228679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698519PMC
November 2020

Transcriptome sequencing analysis reveals unique and shared antitumor effects of three statins in pancreatic cancer.

Oncol Rep 2020 12 15;44(6):2569-2580. Epub 2020 Oct 15.

Department of Surgery, College of Medicine and Life Sciences, University of Toledo, Toledo, OH 43614, USA.

Statins, a class of commonly prescribed cholesterol‑lowering medications, have been revealed to influence the risk of multiple types of cancer. However, the antitumor effects of statins on pancreatic cancer and their differential efficacy among a variety of statins are not currently well‑defined. The aim of the present study was therefore to identify and compare the genes and related biological pathways that were affected by each individual statin on pancreatic cancer. Two human pancreatic cancer cell lines, MiaPaCa2 and PANC1, were exposed to three statins, lovastatin, fluvastatin and simvastatin. The inhibitory effect of statins on pancreatic cancer cell proliferation was first validated. Next, RNA‑seq analysis was used to determine the gene expression alterations in either low (2 µM) or high (20 µM) statin concentration‑treated cancer cells. Marked differences in gene transcription profiles of both pancreatic cancer cell lines exposed to high concentration statins were observed. Notably, the high concentration statins significantly suppressed core‑gene CCNA2‑associated cell cycle and DNA replication pathways and upregulated genes involved in ribosome and autophagy pathways. However, the low concentration statin‑induced gene expression alterations were only detected in MiaPaCa2 cells. In conclusion, a marked difference in the intra and inter cell‑type performance of pancreatic cancer cells exposed to a variety of statins at low or high concentrations was reported herein, which may provide insights for the potential clinical use of statins in future pancreatic cancer therapeutics.
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http://dx.doi.org/10.3892/or.2020.7810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7640361PMC
December 2020

Repurposing metformin, simvastatin and digoxin as a combination for targeted therapy for pancreatic ductal adenocarcinoma.

Cancer Lett 2020 10 21;491:97-107. Epub 2020 Aug 21.

Department of Surgery, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA; Department of Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA.

Patients with pancreatic adenocarcinoma (PDAC) have a 5-year survival rate of 8%, the lowest of any cancer in the United States. Traditional chemotherapeutic regimens, such as gemcitabine- and fluorouracil-based regimens, often only prolong survival by months. Effective precision targeted therapy is therefore urgently needed to substantially improve survival. In an effort to expedite approval and delivery of targeted therapy to patients, we utilized a platform to develop a novel combination of FDA approved drugs that would target pancreaticoduodenal homeobox1 (PDX1) and baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5) utilizing super-promoters of the target genes to interrogate an FDA approved drug library. We identified and selected metformin, simvastatin and digoxin (C3) as a novel combination of FDA approved drugs, which were shown to effectively target PDX1 and BIRC5 in human PDAC tumors in mice with no toxicity.
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http://dx.doi.org/10.1016/j.canlet.2020.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8766172PMC
October 2020

A retrospective analysis of the risk factors associated with systemic air embolism following percutaneous lung biopsy.

Exp Ther Med 2020 Jan 18;19(1):347-352. Epub 2019 Nov 18.

Department of Radiology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266100, P.R. China.

In the present study, the risk factors for systemic air embolism as a complication of percutaneous CT-guided lung biopsy were explored. Data from 2,026 percutaneous CT-guided lung biopsy procedures were retrospectively analyzed. All cases were divided into a concurrent air embolism group and a control group, depending on whether air embolism occurred during the puncture process. A systemic air embolism was confirmed when CT values <-200 Hounsfield units were observed in two sequential images. A total of 19 cases (0.9%) of air embolism were detected among the 2,026 patients subjected to percutaneous CT-guided lung biopsy procedures. The most frequently detected embolism site was the left ventricle (89.5%). Only 3 cases (15.8%) were accompanied by obvious clinical symptoms. The results indicated that a puncture location above the level of the left atrium and coughing during the procedure significantly altered the likelihood of embolism developing (P=0.002 and P=0.014 vs. control, respectively). In conclusion, a puncture lesion above the level of the left atrium and coughing during the procedure may be risk factors for air embolism development.
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http://dx.doi.org/10.3892/etm.2019.8208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6909561PMC
January 2020

BIRC5 is a target for molecular imaging and detection of human pancreatic cancer.

Cancer Lett 2019 08 3;457:10-19. Epub 2019 May 3.

Department of Surgery, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA; Department of Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA. Electronic address:

Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer mortality with a dismal overall survival rate and an urgent need for detection of minute tumors. Current diagnostic modalities have high sensitivity and specificity for larger tumors, but not for minute PDAC. In this study, we test the feasibility of a precision diagnostic platform for detecting and localizing minute human PDAC in mice. This platform includes: 1) defining BIRC5 as an early PDAC-upregulated gene and utilizing an enhanced BIRC5 super-promoter to drive expression of dual Gaussia luciferase (GLuc) and sr39 thymidine kinase (sr39TK) reporter genes exponentially and specifically in PDAC; 2) utilizing a genetically-engineered AAV to ensure targeted delivery of GLuc and sr39TK specifically to PDAC; 3) using serologic GLuc and sr39TK microPET/CT imaging to detect and localize minute human PDAC in mice. The study demonstrates feasibility of a precision diagnostic platform using an integrated technology through a multiple-stage amplification strategy of dual reporter genes to enhance the specificity and sensitivity of detection and localization of minute PDAC tumors and currently undetectable disease.
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http://dx.doi.org/10.1016/j.canlet.2019.04.036DOI Listing
August 2019

A novel synthetic human insulin super promoter for targeting PDX-1-expressing pancreatic cancer.

Cancer Lett 2018 04 6;418:75-83. Epub 2018 Jan 6.

Department of Surgery, University of Toledo College of Medicine & Life Sciences, Toledo OH, USA. Electronic address:

Our previous studies have shown that a rat insulin promoter II fragment (RIP) was used to effectively target pancreatic adenocarcinoma (PDAC) and insulinoma that over-express pancreatic and duodenal homeobox-1 (PDX-1). To enhance the activity and specificity of the human insulin promoter, we engineered a synthetic human insulin super-promoter (SHIP). Reporter assay demonstrated that SHIP1 was the most powerful promoter among all of the SHIPs and had far greater activity than the endogenous human insulin promoters and RIP in PDAC expressing PDX-1. Over-expression, knockdown and competitive inhibition of PDX-1 expression assay proved that PDX-1 is a critical transcript factor to regulate the activity of SHIP1. SHIP1-driven viral thymidine kinase followed by ganciclovir (SHIP1-TK/GCV) resulted in cytotoxicity to PDAC cells in vitro. Systemic delivery of SHIP1-TK/GCV in PDAC xenograft mice significantly suppressed PANC-1 tumor growth in vivo greater than RIP-TK/GCV and CMV-TK/GCV controls (p < .05). These preclinical data suggest that SHIP1 is a powerful novel promoter that can be used to target human PDAC expressing PDX-1 in clinical trials. Furthermore, this novel strategy of engineering synthetic super-promoters could be used for other cancer targets.
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http://dx.doi.org/10.1016/j.canlet.2018.01.007DOI Listing
April 2018

PDX1 associated therapy in translational medicine.

Ann Transl Med 2016 Jun;4(11):214

1 Division of General Surgery, Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, CA, USA ; 2 Mary Crowley Cancer Research Center, Dallas, TX, USA ; 3 Division of Digestive Diseases, Department of Medicine, CURE: Digestive Diseases Research Center, David Geffen School of Medicine and Molecular Biology Institute, University of California at Los Angeles, Los Angeles, CA, USA.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extremely poor prognosis and a low median survival due to lack of the early and reliable detection and effective therapeutic options, despite improvements observed for many other cancers in last decade. Pancreatic and duodenal homeobox 1 (PDX1), which is a homeodomain-containing transcription factor and a key regulator for insulin gene expression, β cell maturation and proper β cell function maintenance in the pancreas. Our previous studies revealed that PDX1 promotes tumorigenesis and it is a promising therapeutic target for PDAC. For translational purposes, we developed three therapeutic platforms utilizing RNA interference (RNAi), gene therapy and small inhibitory drug targeting PDX1, and further validated them in PDAC preclinical models both in vitro and in vivo. These PDX1 targeted therapies significantly inhibited PDX1 expression in PDAC cells, ablated PDX1-expressing human PDAC xenograft tumor growth, and prolonged survival in the PDAC mouse models. The data from these preclinical studies proved the translational potentials of PDX1 targeted therapies in PDAC and suggest that the strategy of developing PDX1 targeted therapies would permit a rapid bench-to-bedside translation of other relevant gene therapies, which would eventually benefit the patients suffering from this deadly disease.
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http://dx.doi.org/10.21037/atm.2016.03.51DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916355PMC
June 2016

Pancreatic cancer actionable genes in precision medicine and personalized surgery.

Surgeon 2017 Feb 28;15(1):24-29. Epub 2016 Jun 28.

Division of General Surgery, Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, CA, USA. Electronic address:

Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with an overall 5-year survival rate less than 5% due to the poor early diagnosis and lack of effective therapeutic options. The most effective therapy remains surgery, however post-operative survival could be enhanced with effective adjuvant therapy. The massive information gained from Omics techniques on PDAC at the beginning of the 21st century is a remarkable accomplishment. However, the information gained from the omics data, including next generation sequencing data, has yet to successfully affect care of patients suffering with PDAC. Therefore, we propose the development of an actionable genomic platform that matches a patient's PDAC clinically actionable genes with potential targeted adjuvant therapies. Using this platform, PDX1 has been identified as a potential actionable gene for PDAC, therefore, RNAi therapy, gene therapy and small inhibitory drugs, all targeting PDX1, serve as potential targeted adjuvant therapies. Preclinical studies support the hypothesis that identification of PDAC actionable genes could permit translation of a patient's genomic information into precision targeted adjuvant therapy for PDAC.
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http://dx.doi.org/10.1016/j.surge.2016.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5195911PMC
February 2017

Effect of lipiodol and methylene blue on the thoracoscopic preoperative positioning.

Int J Clin Exp Med 2015 15;8(5):7569-76. Epub 2015 May 15.

Department of Thoracic surgery, Affiliated Hospital of Qingdao University Qingdao 266101, Shandong, People's Republic of China.

The aim of this study was to compare and analyze the site-specific accuracy of mixture of lipiodol and methylene blue (MLM) (0.6 ml, 1:5) and pure methylene blue (0.5 ml) on the rabbit lungs. In this study, CT-guided percutaneous injection of MLM and methylene blue. Compare the staining degree by biopsy of lung tissue. Use 4 points system to evaluate the site-specific accuracy at 6h and 24 h after injection. For MLM, evaluate its radiopacity by radiation. When evaluate the positioning, 2 points mean acceptable, 3 points mean excellent. The results indicated that the staining range of MLM is obvious less than that of methylene blue (0.6 vs. 1.0 cm, P<0.01), but the staining capacity of MLM is higher than that of methylene blue (2.8 vs. 2.2, P = 0.01). About the staining abilities which are evaluated as excellent, MLM group accounts for 81%, methylene blue group accounts for 38% (P = 0.011). About the radiopacity which are evaluated as acceptable or excellent, MLM group accounts for 62%. With good direct vision, the suitable positioning rate of MLM can be 100%, which is better than that of methylene blue. In conclusion, percutaneous injection of MLM can be used to lung positioning. The result shows that use MLM is better than only using methylene blue. But it is necessary to do the investigation in human beings in order to confirm the feasibility of its clinical application.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4509246PMC
July 2015

Liposomal insulin promoter-thymidine kinase gene therapy followed by ganciclovir effectively ablates human pancreatic cancer in mice.

Cancer Lett 2015 Apr 14;359(2):206-10. Epub 2015 Jan 14.

David Geffen School of Medicine, UCLA, Los Angeles, CA, USA. Electronic address:

PDX1 is overexpressed in pancreatic cancer, and activates the insulin promoter (IP). Adenoviral IP-thymidine kinase and ganciclovir (TK/GCV) suppresses human pancreatic ductal carcinoma (PDAC) in mice, but repeated doses carry significant toxicity. We hypothesized that multiple cycles of liposomal IP-TK/GCV ablate human PDAC in SCID mice with minimal toxicity compared to adenoviral IP-TK/GCV. SCID mice with intraperitoneal human pancreatic cancer PANC-1 tumor implants were given a single cycle of 35 µg iv L-IP-TK, or four cycles of 1, 10, 20, 30, or 35 µg iv L-IP-TK (n = 20 per group), followed by intraperitoneal GCV. Insulin and glucose levels were monitored in mice treated with four cycles of 35 µg iv L-IP-TK. We found that four cycles of 10-35 µg L-IP-TK/GCV ablated more PANC-1 tumor volume compared to a single cycle with 35 µg. Mice that received four cycles of 10 µg L-IP-TK demonstrated the longest survival (P < 0.05), with a median survival of 126 days. In comparison, mice that received a single cycle of 35 µg L-IP-TK/GCV or GCV alone survived a median of 92 days and 68.7 days, respectively. There were no significant changes in glucose or insulin levels following treatment. In conclusion, multiple cycles of liposomal IP-TK/GCV ablate human PDAC in SCID mice with minimal toxicity, suggesting non-viral vectors are superior to adenoviral vectors for IP-gene therapy.
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http://dx.doi.org/10.1016/j.canlet.2015.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336837PMC
April 2015

Down-regulation of pancreatic and duodenal homeobox-1 by somatostatin receptor subtype 5: a novel mechanism for inhibition of cellular proliferation and insulin secretion by somatostatin.

Front Physiol 2014 25;5:226. Epub 2014 Jun 25.

Division of General Surgery, Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, CA, USA ; CURE: Digestive Disease Research Center, David Geffen School of Medicine at University of California Los Angeles, CA, USA.

Somatostatin (SST) is a regulatory peptide and acts as an endogenous inhibitory regulator of the secretory and proliferative responses of target cells. SST's actions are mediated by a family of seven transmembrane domain G protein-coupled receptors that comprise five distinct subtypes (SSTR1-5). SSTR5 is one of the major SSTRs in the islets of Langerhans. Homeodomain-containing transcription factor pancreatic and duodenal homeobox-1 (PDX-1) is essential for pancreatic development, β cell differentiation, maintenance of normal β cell functions in adults and tumorigenesis. Recent studies show that SSTR5 acts as a negative regulator for PDX-1 expression and that SSTR5 mediates somatostatin's inhibitory effect on cell proliferation and insulin expression/excretion through down-regulating PDX-1 expression. SSTR5 exerts its inhibitory effect on PDX-1 expression at both the transcriptional level by down-regulating PDX-1 mRNA and the post-translational level by enhancing PDX-1 ubiquitination. Identification of PDX-1 as a transcriptional target for SSTR5 may help in guiding the choice of therapeutic cancer treatments.
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http://dx.doi.org/10.3389/fphys.2014.00226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4069483PMC
July 2014

Cell surface lactate receptor GPR81 is crucial for cancer cell survival.

Cancer Res 2014 Sep 13;74(18):5301-10. Epub 2014 Jun 13.

Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

The mechanisms that allow cancer cells to adapt to the typical tumor microenvironment of low oxygen and glucose and high lactate are not well understood. GPR81 is a lactate receptor recently identified in adipose and muscle cells that has not been investigated in cancer. In the current study, we examined GPR81 expression and function in cancer cells. We found that GPR81 was present in colon, breast, lung, hepatocellular, salivary gland, cervical, and pancreatic carcinoma cell lines. Examination of tumors resected from patients with pancreatic cancer indicated that 94% (148 of 158) expressed high levels of GPR81. Functionally, we observed that the reduction of GPR81 levels using shRNA-mediated silencing had little effect on pancreatic cancer cells cultured in high glucose, but led to the rapid death of cancer cells cultured in conditions of low glucose supplemented with lactate. We also observed that lactate addition to culture media induced the expression of genes involved in lactate metabolism, including monocarboxylase transporters in control, but not in GPR81-silenced cells. In vivo, GPR81 expression levels correlated with the rate of pancreatic cancer tumor growth and metastasis. Cells in which GPR81 was silenced showed a dramatic decrease in growth and metastasis. Implantation of cancer cells in vivo was also observed to lead to greatly elevated levels of GPR81. These data support that GPR81 is important for cancer cell regulation of lactate transport mechanisms. Furthermore, lactate transport is important for the survival of cancer cells in the tumor microenvironment. Cancer Res; 74(18); 5301-10. ©2014 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-14-0319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4167222PMC
September 2014

Notch1 activation up-regulates pancreatic and duodenal homeobox-1.

Genes (Basel) 2013 Jul 19;4(3):358-74. Epub 2013 Jul 19.

Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA.

Transcription factor pancreatic and duodenal homeobox-1 (PDX-1) plays an essential role in pancreatic development, β-cell differentiation, maintenance of normal β-cell function and tumorigenesis. PDX-1 expression is tightly controlled through a variety of mechanisms under different cellular contexts. We report here that overexpression of Notch1 intracellular domain (NICD), an activated form of Notch1, enhanced PDX-1 expression in both PDX-1 stable HEK293 cells and mouse insulinoma β-TC-6 cells, while NICD shRNA inhibited the enhancing effect. NICD-enhanced PDX-1 expression was accompanied by increased insulin expression/secretion and cell proliferation in β-TC-6 cells, which was reversed by NICD shRNA. Cre activation-induced specific expression of NICD in islet β cells of transgenic βNICD+/+ mice induced increased expression of PDX-1, insulin and proliferating cell nuclear antigen (PCNA) and decreased expression of p27 with accompanied fasting hyperinsulinemia and hypoglycemia and altered responses to intraperitoneal glucose tolerance test. Systemically delivered NICD shRNA suppressed islet expression of PDX-1 and reversed the hypoglycemia and hyperinsulinemia. Moreover, expression levels of NICD were correlated with those of PDX-1 in human pancreatic neuroendocrine tumor. Thus, Notch1 acts as a positive regulator for PDX-1 expression, cooperates with PDX-1 in the development of insulin overexpression and islet cell neoplasia and represents a potential therapeutic target for islet neoplasia.
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http://dx.doi.org/10.3390/genes4030358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3924823PMC
July 2013

PDX-1 is a therapeutic target for pancreatic cancer, insulinoma and islet neoplasia using a novel RNA interference platform.

PLoS One 2012 8;7(8):e40452. Epub 2012 Aug 8.

Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, United States of America.

Pancreatic and duodenal homeobox-1 (PDX-1) is a transcription factor that regulates insulin expression and islet maintenance in the adult pancreas. Our recent studies demonstrate that PDX-1 is an oncogene for pancreatic cancer and is overexpressed in pancreatic cancer. The purpose of this study was to demonstrate that PDX-1 is a therapeutic target for both hormonal symptoms and tumor volume in mouse models of pancreatic cancer, insulinoma and islet neoplasia. Immunohistochemistry of human pancreatic and islet neoplasia specimens revealed marked PDX-1 overexpression, suggesting PDX-1 as a "drugable" target within these diseases. To do so, a novel RNA interference effector platform, bifunctional shRNA(PDX-1), was developed and studied in mouse and human cell lines as well as in mouse models of pancreatic cancer, insulinoma and islet neoplasia. Systemic delivery of bi-shRNA(humanPDX-1) lipoplexes resulted in marked reduction of tumor volume and improved survival in a human pancreatic cancer xenograft mouse model. bi-shRNA(mousePDX-1) lipoplexes prevented death from hyperinsulinemia and hypoglycemia in an insulinoma mouse model. shRNA(mousePDX-1) lipoplexes reversed hyperinsulinemia and hypoglycemia in an immune-competent mouse model of islet neoplasia. PDX-1 was overexpressed in pancreatic neuroendocrine tumors and nesidioblastosis. These data demonstrate that PDX-1 RNAi therapy controls hormonal symptoms and tumor volume in mouse models of pancreatic cancer, insulinoma and islet neoplasia, therefore, PDX-1 is a potential therapeutic target for these pancreatic diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0040452PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3414490PMC
February 2013

Negative regulation of pancreatic and duodenal homeobox-1 by somatostatin receptor subtype 5.

Mol Endocrinol 2012 Jul 5;26(7):1225-34. Epub 2012 Jun 5.

Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, California 90095, USA.

Somatostatin receptor subtype 5 (SSTR5) mediates the inhibitory effect of somatostatin and its analogs on insulin expression/secretion and islet cell proliferation. We provide biochemical and genetic evidence that SSTR5 exerted its physiological actions via down-regulating pancreatic and duodenal homeobox-1 (PDX-1), a β-cell-specific homeodomain-containing transcription factor. Cotransfection of SSTR5 with PDX-1 resulted in dose-dependent inhibition of PDX-1 expression in human embryonic kidney 293 cells. SSTR5 agonist RPL-1980 inhibited PDX-1 expression and abolished glucagon-like peptide 1-stimulated PDX-1 expression in mouse insulinoma β-TC-6 cells. SSTR5 knockdown by short hairpin RNA led to increased PDX-1 expression that was accompanied by enhanced insulin secretion stimulated by high glucose in β-TC6 cells and alternated expressions of cell cycle proteins that favor cell proliferation in mouse insulinoma MIN6 cells. Quantitative RT-PCR analysis showed that cotransfected SSTR5 inhibited PDX-1 mRNA expression, whereas knockdown of SSTR5 increased PDX-1 mRNA expression. In addition, we found that cotransfected wild-type SSTR5 increased PDX-1 ubiquitination in human embryonic kidney 293 cells, whereas SSTR5 P335L, a hypofunctional single nucleotide polymorphism of SSTR5, inhibited PDX-1 ubiquitination. SSTR5 knockout resulted in increased expression of PDX-1, insulin, and proliferating cell nuclear antigen in the islets of sstr(-/-) mice. Immunohistochemistry analysis showed that SSTR5 P335L was associated with elevated expression of PDX-1 in human pancreatic neuroendocrine tumor. Taken together, our studies demonstrated that SSTR5 is a negative regulator for PDX-1 expression and that SSTR5 may mediate the inhibitory effects of somatostatin and its analogs on insulin expression/secretion and cell proliferation via down-regulating PDX-1 at both transcriptional and posttranslational levels.
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http://dx.doi.org/10.1210/me.2012-1095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3385795PMC
July 2012

SSTR5 P335L monoclonal antibody differentiates pancreatic neuroendocrine neuroplasms with different SSTR5 genotypes.

Surgery 2011 Dec;150(6):1136-42

Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA.

Background: Somatostatin receptor type 5 (SSTR5) P335L is a hypofunctional, single nucleotide polymorphism of SSTR5 with implications in the diagnostics and therapy of pancreatic neuroendocrine neoplasms. The purpose of this study is to determine whether a SSTR5 P335L-specific monoclonal antibody could sufficiently differentiate pancreatic neuroendocrine neoplasms (PNENs) with different SSTR5 genotypes.

Methods: Cellular proliferation rate, SSTR5 mRNA level, and SSTR5 protein level were measured by performing MTS assay, a quantitative reverse transcription polymerase chain reaction study, Western blot analysis, and immunohistochemistry, respectively. SSTR5 genotype was determined with the TaqMan SNP Genotyping assay (Applied Biosystems, Foster City, CA).

Results: We found that the SSTR5 analogue RPL-1980 inhibited cellular proliferation of CAPAN-1 cells more than that of PANC-1 cells. Only PANC-1 (TT) cells, but not CAPAN-1 (CC) cells expressed SSTR5 P335L. In 29 white patients with PNENs, 38% had a TT genotype for SSTR5 P335L, 24% had a CC genotype for WT SSTR5, and 38% hada CT genotype for both SSTR5 P335L and WT SSTR5. Immunohistochemistry using SSTR5 P335L monoclonal antibody detected immunostaining signals only from the neuroendocrine specimens with TT and CT genotypes, but not those with CC genotypes.

Conclusion: A SSTR5 P335L monoclonal antibody that specifically recognizes SSTR5 P335L but not WT SSTR5 could differentiate PNENs with different SSTR5 genotypes, thereby providing a potential tool for the clinical diagnosis of PNEN.
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http://dx.doi.org/10.1016/j.surg.2011.09.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3233698PMC
December 2011

Somatostatin receptor 1 and 5 double knockout mice mimic neurochemical changes of Huntington's disease transgenic mice.

PLoS One 2011 2;6(9):e24467. Epub 2011 Sep 2.

Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada.

Background: Selective degeneration of medium spiny neurons and preservation of medium sized aspiny interneurons in striatum has been implicated in excitotoxicity and pathophysiology of Huntington's disease (HD). However, the molecular mechanism for the selective sparing of medium sized aspiny neurons and vulnerability of projection neurons is still elusive. The pathological characteristic of HD is an extensive reduction of the striatal mass, affecting caudate putamen. Somatostatin (SST) positive neurons are selectively spared in HD and Quinolinic acid/N-methyl-D-aspartic acid induced excitotoxicity, mimic the model of HD. SST plays neuroprotective role in excitotoxicity and the biological effects of SST are mediated by five somatostatin receptor subtypes (SSTR1-5).

Methods And Findings: To delineate subtype selective biological responses we have here investigated changes in SSTR1 and 5 double knockout mice brain and compared with HD transgenic mouse model (R6/2). Our study revealed significant loss of dopamine and cAMP regulated phosphoprotein of 32 kDa (DARPP-32) and comparable changes in SST, N-methyl-D-aspartic acid receptors subtypes, calbindin and brain nitric oxide synthase expression as well as in key signaling proteins including calpain, phospho-extracellular-signal-regulated kinases1/2, synapsin-IIa, protein kinase C-α and calcineurin in SSTR1/5(-/-) and R6/2 mice. Conversely, the expression of somatostatin receptor subtypes, enkephalin and phosphatidylinositol 3-kinases were strain specific. SSTR1/5 appears to be important in regulating NMDARs, DARPP-32 and signaling molecules in similar fashion as seen in HD transgenic mice.

Conclusions: This is the first comprehensive description of disease related changes upon ablation of G- protein coupled receptor gene. Our results indicate that SST and SSTRs might play an important role in regulation of neurodegeneration and targeting this pathway can provide a novel insight in understanding the pathophysiology of Huntington's disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0024467PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3166321PMC
December 2011

Personalized cancer approach: using RNA interference technology.

World J Surg 2011 Aug;35(8):1700-14

Mary Crowley Cancer Research Centers, 1700 Pacific Avenue, Suite 1100, Dallas, TX, USA.

Normal cellular survival is dependent on the cooperative expression of genes' signaling through a broad array of DNA patterns. Cancer, however, has an Achilles' heel. Its altered cellular survival is dependent on a limited subset of signals through mutated DNA, possibly as few as three. Identification and control of these signals through the use of RNA interference (RNAi) technology may provide a unique clinical opportunity for the management of cancer that employs genomic-proteomic profiling to provide a molecular characterization of the cancer, leading to targeted therapy customized to an individual cancer signal. Such an approach has been described as "personalized therapy." The present review identifies unique developing technology that employs RNAi as a method to target, and therefore block, signaling from mutated DNA and describes a clinical pathway toward its development in cancer therapy.
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http://dx.doi.org/10.1007/s00268-011-1100-0DOI Listing
August 2011

Serum response factor expression is enriched in pancreatic β cells and regulates insulin gene expression.

FASEB J 2011 Aug 27;25(8):2592-603. Epub 2011 Apr 27.

Michael E. DeBakey VA Medical Center, 2002 Holcombe Blvd., Houston, TX 77030, USA.

Serum response factor (SRF) is an essential regulator of myogenic and neurogenic genes and the ubiquitously expressed immediate-early genes. The purpose of this study is to determine SRF expression pattern in murine pancreas and examine the role of SRF in pancreatic gene expression. Immunohistochemical analysis of wild-type pancreas and LacZ staining of pancreas from SRF LacZ knock-in animals showed that SRF expression is restricted to β cells. SRF bound to the rat insulin promoter II (RIP II) serum response element, an element conserved in both rat I and murine I and II insulin promoters. SRF activated RIP II, and SRF binding to RIP II and the exon 5-encoded 64-aa subdomain of SRF was required for this activation. Transient or stable knockdown of SRF leads to down-regulation of insulin gene expression, suggesting that SRF is required for insulin gene expression. Further, SRF physically interacted with the pancreas and duodenum homeobox-1 (Pdx-1) and synergistically activated RIP II. Elevated glucose concentration down-regulated SRF binding to RIP II SRE, and this down-regulation was associated with decreased RIP II activity and increased SRF phosphorylation on serine 103. Together, our results demonstrate that SRF is a glucose concentration-sensitive regulator of insulin gene expression.
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http://dx.doi.org/10.1096/fj.10-173757DOI Listing
August 2011

Multiple treatment cycles of liposome-encapsulated adenoviral RIP-TK gene therapy effectively ablate human pancreatic cancer cells in SCID mice.

Surgery 2011 Apr 5;149(4):484-95. Epub 2011 Feb 5.

Michael E. DeBakey Department of Surgery, Elkins Pancreas Center, Baylor College of Medicine, Houston, TX 77030, USA.

Background: Adenoviral gene therapy has been applied widely for cancer therapy; however, transient gene expression as result of humoral immunoneutralization response to adenovirus limits its effect. The purpose of this study is to determine whether DOTAP:cholesterol liposome could shield adenovirus from neutralizing antibody and permit the use of multiple cycles of intravenous liposome encapsulated serotype 5 adenoviral rat insulin promoter directed thymidine kinase (L-A-5-RIP-TK) with ganciclovir (GCV) to enhance its effect.

Methods: The effect of multiple cycles of systemic L-A-5-RIP-TK/GCV therapy was evaluated in grouped PANC-1 SCID mice treated with different numbers of cycles. Humoral immune response to A-5-RIP-TK or L-A-5-RIP-TK was assessed using C57/B6J mice challenged with adenovirus or liposome adenovirus complex.

Results: The minimal residual tumor burden (3.2 ± 0.6 mm(3)) and greatest survival time (153.0 ± 6 days) were obtained in the mice receiving 4 and 3 cycles of therapy, respectively. Toxicity to islet cells associated with RIP-TK/GCV therapy was observed after 4 cycles. DOTAP:chol-encapsulated adenovectors were able to protect adenovectors from the neutralization of high titer of anti-adenoviral antibodies induced by itself.

Conclusion: Multiple treatment cycles of L-A-5-RIP-TK/GCV ablate human PANC-1 cells effectively in SCID mice; however, the mice become diabetic and have substantial mortality after the 4th cycle. Liposome-encapsulated adenovirus is functionally resistant to the neutralizing effects of anti-adenoviral antibodies, suggesting feasibility of multiple cycles of therapy. Liposome encapsulation of the adenovirus may be a promising strategy for repeated delivery of systemic adenoviral gene therapy.
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http://dx.doi.org/10.1016/j.surg.2010.11.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3072061PMC
April 2011

Defining the cancer master switch.

World J Surg 2011 Aug;35(8):1738-45

Michael E. DeBakey Veterans Affairs Hospital, Houston, TX, USA.

Background: Recent research has focused on signaling cascades and their interactions yielding considerable insight into which genetic pathways are targeted and how they tend to be altered in tumors. Therapeutic interventions now can be designed based on the knowledge of pathways vital to tumor growth and survival. These critical targets for intervention, master switches for cancer, are termed so because the tumor attempts to "flip the switch" in a way that promotes its survival, whereas molecular therapy aims to "switch off" signals important for tumor-related processes.

Methods: Literature review.

Conclusions: Defining useful targets for therapy depends on identifying pathways that are crucial for tumor growth, survival, and metastasis. Because not all signaling cascades are created equal, selecting master switches or targets for intervention needs to be done in a systematic fashion. This discussion proposes a set of criteria to define what it means to be a cancer master switch and provides examples to illustrate their application.
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http://dx.doi.org/10.1007/s00268-010-0941-2DOI Listing
August 2011

The hypofunctional effect of P335L single nucleotide polymorphism on SSTR5 function.

World J Surg 2011 Aug;35(8):1715-24

Michael E. DeBakey Department of Surgery, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.

Background: Somatostatin receptor subtype 5 (SSTR5) mediates the inhibitory effect of somatostatin on insulin expression/secretion and cell proliferation. A number of single nucleotide polymorphisms (SNPs) of SSTR5 have been identified, including P335L, a nonsynonymous SNP located in the protein C-terminal region and encrypted by the codon CCG (proline) or the codon CTG (leucine). In the present study we sought to determine the distribution of the SSTR5 P335L SNP in a cohort of pancreatic cancer patients and whether the P335L SNP affected cellular function of SSTR5 in human pancreatic cancer.

Methods: The P335L germline genotype of 246 patients with pancreatic cancer (213 Caucasians, 16 Hispanics, and 17 African Americans) and 17 human pancreatic cell lines was determined with the TaqMan SNP Genotyping assay. Human SSTR5 leucine variant (L335) was generated by performing site-directed mutagenesis using SSTR5 proline variant (P335) as a template. Transient transfections were performed in HEK293, Mia PaCa-2, and β-TC-6 cells using Lipofectamine 2000. The expression of SSTR5 L335 was determined with a mouse monoclonal anti-SSTR5 L335 antibody generated in our laboratory. The cell proliferation rate was measured by performing MTS assays. Insulin concentration was measured by performing ELISA assays.

Results: Genotyping of the patients' blood indicated that the frequency of the T allele (CT and TT genotypes) in codon 335 of SSTR5 in Caucasians, Hispanics, and African Americans was 52, 69, and 35%, respectively, which was race-dependent. Statistical analysis indicated that association between the frequency of the T allele and the existence of pancreatic cancer in each race missed significance perhaps due to limited sample size. In 17 tested human pancreatic cancer cell lines, 5 (Capan-2, HPAF-II, Panc03.27, Panc-1, and -3) were homozygous (TT genotype) and 9, including Mia PaCa-2, were heterozygous (CT genotype). Overexpression of SSTR5 L335 in Mia PaCa-2 cells enhanced cell proliferation compared to overexpression of SSTR5 P335. Overexpression of SSTR5 P335 enhanced the inhibitory effect of SSTR5 agonist RPL-1980 on cell proliferation of Mia PaCa-2 cells and glucose-stimulated insulin secretion from mouse insulinoma cells, while overexpression of SSTR5 L335 blocked the inhibitory effect of RPL-1980. Overexpression of SSTR5 L335 enhanced PDX-1 expression in Mia PaCa-2 cells. A specific monoclonal antibody was generated to detect SSTR5 P335L.

Conclusion: SSTR5 P335L SNP widely exists in the human population, in patients with pancreatic cancer, and is race-dependent. The SNP is also present in selected human pancreatic cancer cell lines. In contrast to SSTR5 P335, overexpression of the SSTR5 L335 variant resulted in cellular proliferation and PDX-1 overexpression in human pancreatic cancer cells. Its overexpression blocked the inhibitory effect of an SSTR5-specific analog on human pancreatic cancer cell proliferation and on glucose-stimulated insulin secretion from mouse insulinoma cells. These data suggest that SSTR5 P335L is a hypofunctional protein with a potentially harmful effect on function, as well as potential latent effect, and therefore it could affect the clinical response to somatostatin analog therapy for patients with pancreatic cancer.
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http://dx.doi.org/10.1007/s00268-010-0939-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4137969PMC
August 2011

PDX-1: demonstration of oncogenic properties in pancreatic cancer.

Cancer 2011 Feb 30;117(4):723-33. Epub 2010 Sep 30.

Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, USA.

Background: Pancreatic-duodenal homeobox 1 (PDX-1) is a transcription factor that regulates embryologic pancreas development and insulin expression in the adult islet; however, it is overexpressed in many types of cancer, including pancreatic cancer. The purpose of this study was to investigate the role of PDX-1 in tumorigenesis in human cells.

Methods: In vitro cell proliferation, invasion, and transformation were performed in human embryonic kidney cell line (HEK 293), pancreatic cancer cell line MIA PaCa2, and human pancreatic ductal epithelial (HPDE) cells transiently or stably expressing PDX-1 or green fluorescent protein (GFP) PDX-1, with or without cotransfection of PDX-1 short hairpin RNA (shRNA). In vivo tumor formation was carried out in severe combined immunodeficiency (SCID) mice with subcutaneous injection of HEK 293 and MIA PaCa2 stably transfected cells. Cell cycle was analyzed by Western blot or immunostaining. Microarray of RNA from pancreatic adenocarcinoma cells with and without PDX-1 shRNA was performed and analyzed.

Results: Transient and stable expressing PDX-1 significantly increased cell proliferation and invasion in HEK 293, human pancreatic ductal epithelial (HPDE), and MIA PaCa2 cells versus controls (P < .05), human PDX-1 shRNA reversed these effects. Expression of PDX-1 significantly increased colony formation in HEK 293, HPDE, and MIA PaCa2 cells versus controls in vitro (P < .05). PDX-1 promoted HEK 293 and MIA PaCa2 tumor formation in SCID mice as compared with that of control (P < .05). PDX-1 overexpression disrupted cell cycles proteins. PDX-1 expression was confirmed by Western blot and tracked by viewing of GFP-PDX-1 expression. Microarray data support an oncogenic role of PDX-1 in pancreas cancer cells.

Conclusions: PDX-1 induced increased cell proliferation, invasion, and colony formation in vitro, and resulted in markedly increased HEK 293 and MIA PaCa2 tumor formation in SCID mice. These data suggest that PDX-1 is a potential oncogene that regulates tumorigenesis.
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http://dx.doi.org/10.1002/cncr.25629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3017729PMC
February 2011

Myocardial bridging on dual-source computed tomography: degree of systolic compression of mural coronary artery correlating with length and depth of the myocardial bridge.

Clin Imaging 2010 Mar-Apr;34(2):83-8

Shandong Medical Imaging Research Institute, Shandong University, Road Jing-Wu, No. 324, Jinan, 250021, PR China.

Objective: To investigate the correlation between the degree of systolic compression of mural coronary artery (MCA) and the length and depth of myocardial bridging (MB) with dual-source computed tomography (DSCT).

Methods: The length and depth of MB were measured from diastolic phase. All datasets were reconstructed in 5% steps of R-R interval. The optimum phases were chosen where the maximal and minimal diameters were shown. The degree of systolic compression of MCA was calculated. The correlation between length and depth of MB and the degree of systolic compression of MCA were analyzed by Pearson test.

Results: The minimal diameters were found in 27 sites (90.0%) from 30% to 35% R-R interval, and the maximal diameters were found in 27 sites (90.0%) from 70% to 80% R-R interval. The correlation between systolic compression of MCA and length of MB was not significant (r=0.096, P=.613); however, the correlation between systolic compression of MCA and the depth of MB was significant (r=0.675, P<.01).

Conclusion: The minimal and maximal diameters of MCA are usually demonstrated in 30-35% and 70-80% R-R reconstruction interval, respectively. The degree of systolic compression of MCA correlates well with the depth of MB.
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http://dx.doi.org/10.1016/j.clinimag.2009.05.010DOI Listing
June 2010

Microarray analysis of somatostatin receptor 5-regulated gene expression profiles in murine pancreas.

World J Surg 2009 Apr;33(4):630-7

The Michael E. DeBakey Department of Surgery, Baylor College of Medicine, 1709 Dryden Street, Suite 1500, Houston, TX 77030, USA.

Background: We previously demonstrated that somatostatin receptor type 5 (SSTR5) gene ablation results in alterations in insulin secretion and glucose metabolism, accompanied by morphologic alterations in the islets of Langerhans. The underlying mechanism(s) by which SSTR5 exerts its cellular functions remain(s) unknown. We hypothesized that SSTR5 mediates the inhibitory effect of somatostatin (SST) on insulin secretion and islet proliferation by regulating a specific set of pancreatic genes.

Methods: To identify SSTR5-regulated pancreatic genes, gene expression microarray analysis was performed on the whole pancreas of 1- and 3-month-old wild-type (WT) and SSTR5 knockout (SSTR5-/-) male mice. Real-time RT-PCR and immunofluorescence were performed to validate selected differentially expressed genes.

Results: A set of 143 probes were identified to be differentially expressed in the pancreas of 1-month-old SSTR5-/- mice, 72 of which were downregulated and 71 upregulated. At 3 months of age, SSTR5 gene ablation resulted in downregulation of a set of 30 probes and upregulation of a set of 37 probes. Among these differentially expressed genes, there were 15 and 5 genes that were upregulated and downregulated, respectively, in mice at both 1 and 3 months of age. Three genes, PAP/INGAP, ANG, and TDE1, were selected to be validated by real-time RT-PCR and immunofluorescence.

Conclusions: A specific set of genes linked to a wide range of cellular functions such as islet proliferation, apoptosis, angiogenesis, and tumorigenesis were either upregulated or downregulated in SSTR5-deficient male mice compared with their expression in wild-type mice. Therefore, these genes are potential SSTR5-regulated genes during normal pancreatic development and functional maintenance.
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http://dx.doi.org/10.1007/s00268-008-9893-1DOI Listing
April 2009

Transcription factor PDX-1 in human colorectal adenocarcinoma: a potential tumor marker?

World J Gastroenterol 2008 Oct;14(38):5823-6

The Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA.

Aim: To examine the expression of pancreatic duodenal homeobox-1 (PDX-1) transcription factor in human colorectal cancer.

Methods: RT-PCR, Western blotting, and immuno-histochemistry were performed to determine the expression pattern of transcription factor PDX-1 in primary colorectal tumor, hepatic metastasis, and benign colon tissue from a single patient.

Results: The highest PDX-1 transcription levels were detected in the metastasis material. Lower levels of PDX-1 were found to be present in the primary tumor, while normal colon tissue failed to express detectable levels of PDX-1. Western blot data revealed a PDX-1 expression pattern identical to that of mRNA expression. Immunohistochemistry confirmed high metastasis PDX-1 expression, lower levels in the primary tumor, and the presence of only traces of PDX-1 in normal colon tissue.

Conclusion: These data argue for further evaluation of PDX-1 as a biomarker for colorectal cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2751891PMC
http://dx.doi.org/10.3748/wjg.14.5823DOI Listing
October 2008

[Chromosomal structural changes in patients with myelodysplastic syndrome].

Zhonghua Yi Xue Za Zhi 2007 Oct;87(38):2693-7

Institute of Hematology, State Key Laboratory of Experiment Hematology, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.

Objective: To study the clinical and laboratory features of myelodysplastic syndromes (MDS) with chromosomal structural changes.

Methods: Among 584 MDS cases with cytogenetic data, 50 patients with chromosomal structural changes, 34 males and 16 females, aged 50.5 (9 approximately 77), were reclassified according to the WHO criteria, and their clinical and laboratory features were analyzed retrospectively.

Results: The incidence of chromosomal structural changes in the MDS patients was 7.4%. i (17) (q10), t (1; 3) (p36; q21), der (1; 7) (q10; p10), and der (22) occurred frequently. The chromosomal structural changes in 13 cases were reported in the literatures for the first time. The patients with i (17) (q10) were characterized by moderate to severe anemia and a poor prognosis. Predominant dysgranulocytopoiesis and dysmegakaryocytopoiesis, including a nuclear shift to the left, pseudo-Pelger-Hüet anomaly, hypogranularity, and increased micromegakaryocytes. The patients with t (1; 3) (p36; q21) revealed macrocytic anemia, obvious dysmegakaryocytopoiesis, and dysgranulocytopoiesis, accompanied by defective differentiation and monocytosis. The bone marrow cells from the MDS patients with t (1; 3) (p36; q21) mainly or only expressed MEL1. The initial symptom of the patients with der (1; 7) (q10; p10) was infection. These patients showed macrocytic or normocytic anemia. Trilineage dysplasia was found in the bone marrow smears. The patients had short median survival. The patients with der (22) revealed anemia, and normal or elevated platelet counts. Hypogranularity and pseudo-Pelger-Hüet anomaly were present in all cases with der (22). The megakaryocytes were small and generally contained one or two nuclei. A translocation involvement of 22q11 was frequently found in the patients with der (22).

Conclusion: MDS patients with i (17) (q10), t (1; 3) (p36; q21), and der (1; 7) (q10; p10) may be a new unique clinical-pathologic subsets. Whether the MDS patients with der (22) can be considered as a new unique subject remains to be confirmed by future studies.
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October 2007

[Clinical and laboratory investigation of hematological malignancy patients carrying 3q21q26 rearrangement].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2007 Dec;24(6):696-8

Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300020 PR China.

Objective: To investigate the clinical and laboratory characteristics of various hematopoietic malignant patients with t(3;3)(q21;q26) or inv(3) (q21q26).

Methods: Bone marrow samples were collected at presentation, prepared by short-time unstimulated culture and R-binding, and karyotyped by conventional cytogenetical assay (CCA); megalokaryocytes were detected by Streptavidin-AKP (SAP); immunotype of the leukemia cells was tested by flow cytometric anylysis of surface antigens (FACS).

Results: All of the 9 hematopoietic malignant patients with t(3;3)(q21;q26) or inv(3) (q21q26) manifested myelodysplasia and poor treatment response. One of them relapsed shortly after allogenic hemotopoietic stem cell transplantation (allo-HSCT).

Conclusion: Patients with 3q21q26 rearrangement can be found in various hematopoietic malignances and demonstrate an unique entity. These patients show poor treatment response and have extremely poor prognosis.
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December 2007
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