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The incidence of obesity and type 2 diabetes (T2DM) in the Western world has increased dramatically during the recent decades. According to the American Cancer Society, pancreatic cancer (PC) is the fourth leading cause of cancer‐related death in the United States. The relationship among obesity, T2DM and PC is complex. Due to increase in obesity, diabetes, alcohol consumption and sedentary lifestyle, the mortality due to PC is expected to rise significantly by year 2040. The underlying mechanisms by which diabetes and obesity contribute to pancreatic tumorigenesis are not well understood. Furthermore, metabolism and microenvironment within the pancreas can also modulate pancreatic carcinogenesis. The risk of PC on a population level may be reduced by modifiable lifestyle risk factors. In this review, the interactions of diabetes and obesity to PC development were summarized, and novel strategies for the prevention and treatment of diabetes and PC were discussed.

Background Patients with metastatic uveal melanoma (MUM) in the liver usually die within 1 year. The development of new treatments for MUM has been limited by the lack of diverse MUM cell lines and appropriate animal models. We previously reported that orthotopic xenograft mouse models established by direct injection of MUM cells into the liver were useful for the analysis associated with tumor microenvironment in the liver. However, considering that patients with UM metastasize to the liver hematogenously, direct liver injection model might not be suitable for investigation on various mechanisms of liver metastasis. Here, we aim to establish new orthotopic xenograft models via hematogenous dissemination of tumor cells to the liver, and to compare their characteristics with the hepatic injection model. We also determine if hepatic tumors could be effectively monitored with non-invasive live imaging. Methods tdtTomate-labeled, patient-derived MUM cells were injected into the liver, spleen or tail vein of immunodeficient NSG mice. Tumor growth was serially assessed with In Vivo Imaging System (IVIS) images once every week. Established hepatic tumors were evaluated with CT scan and then analyzed histologically. Results We found that splenic injection could consistently establish hepatic tumors. Non-invasive imaging showed that the splenic injection model had more consistent and stronger fluorescent intensity compared to the hepatic injection model. There were no significant differences in tumor growth between splenic injection with splenectomy and without splenectomy. The splenic injection established hepatic tumors diffusely throughout the liver, while the hepatic injection of tumor cells established a single localized tumor. Long-term monitoring of tumor development showed that tumor growth, tumor distribution in the liver, and overall survival depended on the number of tumor cells injected to the spleen. Conclusion We established a new orthotopic hepatic metastatic xenograft mouse model by splenic injection of MUM cells. The growth of orthotopic hepatic tumors could be monitored with non-invasive IVIS imaging. Moreover, we evaluated the therapeutic effect of a MEK inhibitor by using this model. Our findings suggest that our new orthotopic liver metastatic mouse model may be useful for preclinical drug screening experiments and for the analysis of liver metastasis mechanisms.

The propensity of uveal melanoma to metastasize to the liver hinders the accrual of micro-metastatic and end-stage disease tissue samples and restricts the investigation of metastatic uveal melanoma (MUM). Pre-clinical experimental animal models of MUM can help elucidate the pathophysiology of metastatic lesions and provide a tool for designing new therapeutic approaches for MUM. Here, we present an advanced model of hepatic metastases that enables quantitatively visualizing the development of individual hepatic tumor clones and estimating their growth kinetics and colonization efficiency. Similar to clinically observed liver metastases, these models enable the assessment of growth kinetics of the liver micro-metastases and the testing of therapeutic approaches for the treatment of MUM. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Experimental patient-derived xenograft mouse model of metastatic uveal melanoma Basic Protocol 2: Experimental liver micro-metastatic mouse model using splenic injection of metastatic uveal melanoma cells.

Diabetes mellitus (DM), one of the metabolic diseases which is characterized by sustained hyperglycemia, is a life-threatening disease. The global prevalence of DM is on the rise, mainly in low- and middle-income countries. Diabetes is a major cause of blindness, heart attacks, kidney failure, stroke, and lower limb amputation. Type 2 diabetes mellitus (T2DM) is a form of diabetes that is characterized by high blood sugar and insulin resistance. T2DM can be prevented or delayed by a healthy diet, regular physical activity, maintaining normal body weight, and avoiding alcohol and tobacco use. Ethanol and its metabolites can cause differentiation defects in stem cells and promote inflammatory injury and carcinogenesis in several tissues. Recent studies have suggested that diabetes can be treated, and its consequences can be avoided or delayed with proper management. DM has a greater risk for several cancers, such as breast, colorectal, endometrial, pancreatic, gallbladder, renal, and liver cancer. The incidence of cancer is significantly higher in patients with DM than in those without DM. In addition to DM, alcohol abuse is also a risk factor for many cancers. We present a review of the recent studies investigating the association of both DM and alcohol abuse with cancer incidence.

// Bao Quoc Lam 1, 2, * , Lu Dai 1, 2, 3, * , Li Li 2 , Jing Qiao 3 , Zhen Lin 4 , Zhiqiang Qin 1, 2, 3 1 Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA 2 Louisiana Cancer Research Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA 3 Department of Pediatrics, Research Center for Translational Medicine and Key Laboratory of Arrhythmias, East Hospital, Tongji University School of Medicine, Shanghai 200120, China 4 Department of Pathology, Tulane University Health Sciences Center, Tulane Cancer Center, New Orleans, LA 70112, USA * These authors have contributed equally to this work Correspondence to: Zhen Lin, email: zlin@tulane.edu Zhiqiang Qin, email: zqin@lsuhsc.edu Keywords: KSHV, primary effusion lymphoma, c-MET, Plexin-B1, SNV Received: December 06, 2016 Accepted: January 21, 2017 Published: February 17, 2017 ABSTRACT The oncogenic Kaposi’s sarcoma–associated herpesvirus (KSHV) is a principal causative agent of primary effusion lymphoma (PEL), which is mostly seen in immunosuppressed patients. PEL is a rapidly progressing malignancy with a median survival time of approximately 6 months even under the conventional chemotherapy. We recently report that the hepatocyte growth factor (HGF)/c-MET pathway is highly activated in PEL cells and represents a promising therapeutic target ( Blood. 2015;126(26):2821-31 ). However, the underlying mechanisms of c-MET activation within PEL cells remain largely unknown. To solve this puzzle, here we have utilized the next generation sequencing (NGS) based bioinformatics approach to investigate the genomic landscape of the c-MET gene and we found that there’s no single nucleotide variations (SNVs) occurred in the c-MET genomic regions in a cohort of PEL samples. Consistently, Sanger sequencing analysis of frequently mutated exons such as exon 10, 14 and 19 shows no mutation of these c-MET exons in PEL cell-lines, which further supports the notion that mutations are not the major mechanism responsible for c-MET activation in PEL. Further, we found that a transmembrane receptor protein, Plexin-B1, is expressed in PEL cell-lines, which is required for c-MET-mediated PEL cell survival via direct protein interaction.

Alterations in transcriptional programs promote tumor development and progression and are targetable by bromodomain and extraterminal (BET) protein inhibitors. However, in a multi‐site clinical trial testing the novel BET inhibitor, PLX51107, in solid cancer patients, liver metastases of uveal melanoma (UM) patients progressed rapidly following treatment. Mechanisms of resistance to BET inhibitors in UM are unknown. We show that fibroblast growth factor 2 (FGF2) rescued UM cells from growth inhibition by BET inhibitors, and FGF2 effects were reversible by FGF receptor (FGFR) inhibitors. BET inhibitors also increased FGFR protein expression in UM cell lines and in patient tumor samples. Hepatic stellate cells (HSCs) secrete FGF2, and HSC‐conditioned medium provided resistance of UM cells to BET inhibitors. PLX51107 was ineffective in vivo, but the combination of a FGFR inhibitor, AZD4547, and PLX51107 significantly suppressed the growth of xenograft UM tumors formed from subcutaneous inoculation of UM cells with HSCs and orthotopically in the liver. These results suggest that co‐targeting of FGFR signaling is required to increase the responses of metastatic UM to BET inhibitors.

Inappropriate activation of c-mesenchymal-epithelial transition (MET), the receptor tyrosine kinase (RTK) for hepatocyte growth factor (HGF), has been implicated in tumorigenesis and represented a promising therapeutic target for developing anticancer agents. In contrast to other solid tumors, there are limited data describing the functional role of HGF/c-MET signaling pathway in lymphoma. In the current review, we summarize recent findings about the expression, cellular mechanisms/functions, and therapeutic application of HGF/c-MET in different types of lymphoma, especially B cell lymphoma, T and NK cell lymphoma, and Hodgkin lymphoma. We also discuss the existing problems and future directions about studying the HGF/c-MET pathway in lymphoma cells.

Introduction: Metastatic uveal melanoma (MUM) is resistant to currently available treatments and overall prognosis is poor. MUM is an “immune cold” tumor and immune checkpoint blockades have only a marginal effect on this tumor. To bring immune cells to the tumor site and change the tumor microenvironment, we developed Chimeric Antigen Receptor (CAR)-NK cells targeting high molecular weight melanoma associated antigen (HMW-MAA/CPSG4). Methods: NK92 cell line derived from NK cell lymphoma was obtained from the American Type Culture Collection (ATCC). NK92 cells were transfected with retroviral pBMN-I vector co-expressing Green Fluorescent Protein (GFP) and anti-HMW-MAA-CD28-CD3z CAR construct. The efficacy of CAR construct transfection was confirmed by expression of His-Tag and F(ab)2 by using BD FACS Celesta flow cytometry. MUM cell line, TJU-UM001, was established from a hepatic metastasis of a uveal melanoma patient in our institution. TJU-UM001 cells have approximately 37,000 HMW-MAA molecules on their surface and are sensitive to NK92 cell killing. Tdtomato-transfected TJU-UM001 cells (106 cells) were intra-hepatically implanted into NOD-scid IL2Rgammanull (NSG) mice. Once establishment of hepatic tumor was confirmed by IVIS 200 imaging system (PerkinElmer) at Red Fluorescent Protein (RFP) excitation 535nm, 3 x 106 CAR-NK92 cells or NK92 cells without CAR constructs were injected into the spleen. Accumulations of GFP+ NK92 cells in the TJU-UM001 tumors in the liver were analyzed under fluorescence microscopy. In a separate experiment, 107 TJU-UM001 cells were subcutaneously implanted into NSG mice. The size of subcutaneous tumor was measured by Caliper. Once tumor became palpable (7-10 mm), 3 x 106 CAR- or non-CAR NK92 cells were directly injected to the MUM tumors. Forty thousand units of human IL-2 were intra-peritoneally injected into mouse once daily for 4 consecutive days after NK92 cell injections. Results: There were expressions of both His-tag and F(ab)2 on CAR-GFP NK92 cells. GFP and CD54 (ICAM-1) were expressed on 95% and 90% of CAR-GFP NK92 cells, respectively. There was no cross-expression of GFP or human CD54 on mouse cells. Therefore, GFP and CD54 were confirmed to be reliable markers for tracking CAR-GFP NK92 cells in mice. Both CAR- and non-CAR NK92 cells exhibited suppression of TJU-UM001 cell proliferation in in vitro assay. Direct injections of both CAR- and non-CAR NK92 cells showed anti-tumor growth effects on subcutaneously implanted TJU-UM001 tumors. More importantly, via splenic injection, CAR-NK92 cells accumulated selectively in the MUM tumors in the liver, while non-CAR NK92 cells were randomly distributed to normal liver tissue and the MUM tumors. These results support the rationale for hepatic arterial infusion of CAR-NK cells as treatment for uveal melanoma patients with hepatic metastasis. Citation Format: Bao Quoc Lam, Takahito Sugase, Mizue Terai, Meggie Danielson, Nadezhda Anikeyeva, Melissa A. Wilson, Yuri Sykulev, Takami Sato. Accumulation and anti-tumor effect of chimeric antigen receptor (CAR) NK cells in metastasis uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2319.

A total of 89 blood samples collected from HIV-infected infants and children from provinces of southern Vietnam who were hospitalized at Children's Hospital 1, Ho Chi Minh City, during the 1-year period from October 2004 to September 2005 were submitted to serological screening for IgG, IgA, and IgM antibodies against Chlamydophila pneumoniae (C. pneumoniae). The presence of this microorganism was also evaluated by PCR. The results showed that 64 % of the samples were positive for anti-C. pneumoniae IgG, 31.5 % were positive for IgA, and 3.4 % were positive for IgM. The highest prevalences of IgG and IgA positivity, 75 % and 66.7 %, respectively, were noted in the 1- to 2-year-old age group. However, all the samples were negative for C. pneumoniae by PCR. The study revealed a high seroprevalence of C. pneumoniae in Vietnamese infants and children with HIV/AIDS.

A molecular epidemiological study was conducted on 104 HIV-1 strains isolated from HIV-infected children hospitalized in Children Hospital 1 in Ho Chi Minh City, Vietnam during 2004-2005. Genetic subtyping based on env C2/V3 sequences revealed that CRF01-AE was the sole circulating recombinant form found in this study. Sequence analysis of the V3 loop showed that GPGQ tetramer was the most common V3 loop core motif identified in the HIV-1 strains studied (89.5%). The findings raise great concern about HIV-infected children in Vietnam and provide up-to-date molecular epidemiological information of HIV-1 circulating in Vietnam during the study period.

Anti-HIV drugs have recently become available for the treatment of children infected with HIV in Vietnam; however, the genetic background of HIV-1 drug resistance in antiretroviral-naive children has yet to be studied. Of the 104 HIV-1 CRF01-AE subtype strains that were previously isolated from antiretroviral-naive children from the provinces of southern Vietnam and hospitalized in Children Hospital 1 in Ho Chi Minh City from 2004 to 2005, 79 strains were used for amplification and sequence analyses of the protease and reverse transcriptase (RT) genes. Minor mutations were found in the protease gene, including L10I, I13V, G16E, M36I, D60E, I62V, I64V, L63P, H69K, V82I, and I93L. Of these mutations, M36I and H69K were detected in all of the strains that were studied. However, all of the amino acid changes in the protease gene were considered to be polymorphisms. In the RT gene, three major mutations were detected in six strains: the V75M mutation in one strain, the Y181C mutation in two strains, and the M184I mutation in three strains. The prevalence of primary or transmitted HIV drug resistance to all of the drugs and drug classes that were evaluated in this study was 7.6%. These findings provide a useful background for antiretroviral therapy in Vietnam and contribute reference data for the surveillance of HIV drug resistance around the world. This study suggests that the prevalence of HIVDR in Vietnam may have recently increased. The monitoring of HIV drug resistance in Vietnam is necessary.

s for the 29th Annual Congress of Japanese Society / Journal of Reproductive Immunology 106 (2014) 1–20 17 LPS stimulation induced a significant increase of transcript levels of matrix metalloproteinase (MMP)-1, MMP-3, and MMP-9, while P4 treatment significantly attenuated LPSinduced increase of transcript levels of these MMPs. Conclusions: Our preliminary results suggest that P4 might prevent spontaneous preterm labor by inhibiting cervical remodeling, particularly through the attenuation of ECM degradation by inhibiting MMPs production. http://dx.doi.org/10.1016/j.jri.2014.09.040 Analysis of miRNA–mRNA expression profiles in decidual natural killer cells during early pregnancy D. Zhao1,∗, B. Than Naing1, K. Inada2, T. Shima2, S. Saito2, T. Takeshita3, T. Takizawa1 1 Department of Molecular Medicine & Anatomy, Nippon Medical School, Tokyo, Japan 2 Department of Obstetrics and Gynecology, University of Toyama, Toyama, Japan 3 Department of Obstetrics and Gynecology, Nippon Medical School, Tokyo, Japan Objective: Decidual natural killer (dNK) cells play an important role in the maintenance of early pregnancy. However, the expression profiles and functions of miRNAs within dNK cells remain to be clarified.We investigated the miRNA–mRNAexpressionprofiles in dNK cells during early pregnancy. Methods:Decidual tissue and peripheral blood samples from patients who gave informed consent were aseptically obtained after legal abortions (at 6–7 weeks of gestation, n=3). We compared miRNA-mRNA expression patterns between dNK and peripheral NK (pNK) cells. The expression levels of miRNAs were examined by real-time PCR using a TaqMan microRNA Assay, and gene expression profiling was conducted using an Agilent microarray. Networks, functions, and pathways analyses were generated using Ingenuity Pathway Analysis (IPA). Results and conclusions: Among the 750 miRNAs examined, 199 miRNAs were significantly up-regulated in dNK cells compared with pNK cells. We detected some placenta-specific miRNAs derived from the chromosome 19 microRNA cluster in dNK cells. Among the 34,127 transcripts examined, 534 genes were significantly downregulated in dNK cells compared with pNK cells; the down-regulated gene expression profile exhibited low cytotoxicity in dNK cells. Some of the up-regulated miRNAs in dNK cells were the miRNAs potentially targeting the above cytotoxicity-associated genes. These data suggest that dNKcells have auniquemiRNA-mRNA interaction network for the maintenance of early pregnancy. http://dx.doi.org/10.1016/j.jri.2014.09.041 Frequent Chlamydophila pneumoniae infection in vertically HIV-infected children in Vietnam Q.D. Trinh ∗, N.T. Pham, N.T. Le Nguyen, B.Q. Lam, K.T. Le Phan, K.H. Truong, T.Q. Le, H.T. Nguyen, T.C. Tang, Y. Izumi, S. Komine-Aizawa, H. Ushijima, S. Hayakawa Division of Microbiology, Department of Pathology and Microbiology, Nihon University School of Medicine, Japan Objective: Chlamydophila pneumoniae (C. pneumoniae) is an intracellular pathogen and often cause fatal respiratory symptoms in HIV/AIDS patients. However, its frequency in children with vertical HIV infection is so far unknown. Methods: A total of 89 blood samples collected from HIV-infected infants and children from provinces of southern Vietnam who were hospitalized at Children’s Hospital 1, Ho Chi Minh City, during the 1-year period fromOctober 2004 to September 2005 were submitted to serological screening for IgG, IgA, and IgM antibodies against C. pneumoniae. The presence of this microorganism was also evaluated by PCR. Age matched control enrolled HIV negative 91 children with other infectious disorders. Results: The results showed that 64% of the samples were positive for anti-C. pneumoniae IgG, 31.5% were positive for IgA, and 3.4% were positive for IgM. The highest prevalences of IgG and IgA positivity, 75% and 66.7%, respectively, were noted in the 1to 2-year-old age group. In control patients, IgG and IgA positivitywere 7.7 and 4.4% respectively. No patients showed positive PCR results. Conclusions: Our study revealed a high seroprevalence of C. pneumoniae in Vietnamese infants and children with HIV/AIDS by vertical transmission. http://dx.doi.org/10.1016/j.jri.2014.09.042 Porphyromonas gingivalis inhibits trophoblast invasion N. Hirohata ∗, S. Komine-Aizawa, S. Hayakawa Division of Microbiology, Department of Pathology and Microbiology, Nihon University School of Medicine, Japan Objective: Periodontitis has been regarded as a risk factor of pregnancy complications including preterm birth, intrauterine growth retardation and preeclampsia. However protective roles of dental intervention during pregnancyon fetal/maternal outcomes are controversial. In this study, we investigated in vitro effects of a periodontal bacteria Porphyromonas gingivalis on cultured trophoblasts and mucosal natural killer cells to mimic in vivo phenomena at the feto-maternal interface. Methods: 2×109 of P. gingivalis (ATCC33277)were cultured at 37 ◦C, 10% CO2 in BHIB media supplemented with 0.005mgml−1 hemin and 0.0005mgml−1 menadione for