Publications by authors named "Sureshkumar Muthupalani"

66 Publications

Hierarchical cell-type-specific functions of caspase-11 in LPS shock and antibacterial host defense.

Cell Rep 2021 Apr;35(3):109012

Department of Immunology, UConn Health School of Medicine, 263 Farmington Ave., Farmington, CT 06030, USA. Electronic address:

Caspase-11 sensing of intracellular lipopolysaccharide (LPS) plays critical roles during infections and sepsis. However, the key cell types that sense intracellular LPS and their contributions to the host responses at the organismal level are not completely clear. Here, we show that macrophage/monocyte-specific caspase-11 plays a dominant role in mediating the pathological manifestations of endotoxemia, including gasdermin D (GSDMD) activation, interleukin (IL)-1β, IL-18, and damage-associated molecular pattern (DAMP) release, tissue damage, and death. Surprisingly, caspase-11 expression in CD11c cells and intestinal epithelial cells (IECs) plays minor detrimental roles in LPS shock. In contrast, caspase-11 expression in neutrophils is dispensable for LPS-induced lethality. Importantly, caspase-11 sensing of intracellular LPS in LyzM myeloid cells and MRP8 neutrophils, but not CD11c cells and IECs, is necessary for bacterial clearance and host survival during intracellular bacterial infection. Thus, we reveal hierarchical cell-type-specific roles of caspase-11 that govern the host-protective and host-detrimental functions of the cytosolic LPS surveillance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2021.109012DOI Listing
April 2021

Cutaneous leiomyosarcoma with visceral metastases in a White Carneau pigeon and literature review.

J Vet Diagn Invest 2021 Feb 5:1040638721992061. Epub 2021 Feb 5.

Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA.

Cutaneous leiomyosarcomas are malignant mesenchymal tumors of smooth muscle origin and are reported occasionally in avian species. A 14-y-old male laboratory White Carneau pigeon () was presented for surgical excision of a cervical soft tissue mass. Ultrasonography with color flow Doppler imaging revealed multiple cavitations of mixed echogenicity within the mass and vascularization. Histologically, the dermis and subcutis were expanded by a densely cellular multinodular mass comprised of fusiform cells forming haphazardly arranged broad streams and short interwoven bundles, often surrounding blood vessels and variably sized cavitations. Neoplastic cells were strongly immunopositive for desmin and α-smooth muscle actin, and negative for pancytokeratin, S100, and von Willebrand factor. Based on histopathology and IHC findings, the cutaneous mass was diagnosed as leiomyosarcoma (LMS). The pigeon died 312 d post-operatively. Postmortem examination revealed masses infiltrating the left and right pulmonary airways and one hepatic nodule, but no regrowth at the surgical site. Histologic and IHC evaluation of the pulmonary and hepatic masses were consistent with LMS, representing metastatic foci from the primary cutaneous LMS. Our case highlights the malignant behavior and histomorphologic features of cutaneous LMS in an avian species.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1040638721992061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120085PMC
February 2021

and infection in a colony of research macaques: characterization and clinical correlates.

J Med Microbiol 2021 Mar 20;70(3). Epub 2021 Jan 20.

The Division of Comparative Medicine, Massachusetts Institute of Technology, 77 Massachusetts Ave, Bldg 16-825, Cambridge, MA, USA.

( type 1) commonly infects nonhuman primates but its clinical importance is in question. To characterize infection in a colony of rhesus macaques () used in cognitive neuroscience research. Inquiries into the nature of in nonhuman primates are required to further define the organism's virulence and the experimental animal's gastric microbiome. Animals with and without clinical signs of vomiting and abdominal pain (=5 and =16, respectively) were evaluated by histology, culture, PCR amplification and sequencing, fluorescent hybridization (FISH) and serology. Three of the five animals with clinical signs, an index case and two others, were evaluated before and after antimicrobial therapy. The index animal had endoscopically visible ulcers and multifocal, moderate, chronic lymphoplasmacytic gastritis with intraglandular and luminal spiral bacteria. Antimicrobial therapy in the index animal achieved histologic improvement, elimination of endoscopically visible ulcers, and evident eradication but clinical signs persisted. In the other treated animals, gastritis scores were not consistently altered, gastric bacteria persisted, but vomiting and abdominal discomfort abated.Nineteen of 21 animals were PCR positive for and five animals were also PCR positive for . Organisms were detected by FISH in 17 of 21 animals: 16S rRNA sequences of two of these were shown to be . Mild to moderate lymphoplasmacytic gastritis was seen in antrum, body and cardia, with antral gastritis more likely to be moderate than that of the body. No clear association between the bacterial numbers of spp. and the degree of inflammation was observed. is prevalent in this colony of but its clinical importance remains unclear. This study corroborates many of the findings in earlier studies of infection in macaques but also identifies at least one animal in which gastritis and endoscopically visible gastric ulcers were strongly associated with infection. In this study, serology was an inadequate biomarker for endoscopic evaluation in diagnosis of infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1099/jmm.0.001315DOI Listing
March 2021

Male-Dependent Promotion of Colitis in 129 Mice Co-Infected with and .

Int J Mol Sci 2020 Nov 24;21(23). Epub 2020 Nov 24.

Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

The prevalence of gastric (Hp) infection is ~50% of the world population. However, how Hp infection influences inflammatory bowel disease in humans is not fully defined. In this study, we examined whether co-infection with Hp influenced (Hh)-induced intestinal pathology in mice. mice of both sexes were infected with Hh, of which a subgroup was followed by infection with Hp two weeks later. Co-infected males, but not females, had significantly higher total colitis index scores in the colon at both 10 and 21 weeks post-Hh infection (WPI) and developed more severe dysplasia at 21 WPI compared with mono-Hh males. There were no significant differences in colonization levels of gastric Hp and colonic Hh between sexes or time-points. In addition, mRNA levels of colonic , , , , , , and , which play important roles in the development and function of proinflammatory innate lymphoid cell groups 1 and 3, were significantly up-regulated in the dually infected males compared with mono-Hh males at 21 WPI. These data suggest that concomitant Hp infection enhances the inflammatory responses in the colon of-Hh-infected males, which results in more severe colitis and dysplasia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21238886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727654PMC
November 2020

Anaplastic nephroblastoma with peritoneal metastasis in an adult female Sprague Dawley rat.

J Toxicol Pathol 2020 Oct 11;33(4):297-302. Epub 2020 Oct 11.

Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Spontaneous nephroblastomas are uncommon tumors of laboratory rats. This report describes a spontaneous nephroblastoma with peritoneal metastasis in an 11-month-old, female Sprague Dawley rat. The rat was part of a breeding program and presented 15 days post parturition with clinical signs including tachypnea, dyspnea and abdominal distension. At necropsy, the right kidney was markedly enlarged by an expansile pale-tan to white multinodular mass with extension into the retroperitoneal space, with multifocal variably sized nodules involving the mesentery, and surface of pancreas, liver, uterus, and ovarian bursa. The rat also had severe bicavitary effusion. Histologically, the renal parenchyma of the affected kidney was replaced by a moderately cellular, poorly-demarcated, non-encapsulated, multilobulated mass that appeared to compress the adjacent renal outer medulla and cortex. Three distinct neoplastic cell populations were identified in this renal tumor: epithelial cells (convoluted and dilated tubules / rare primitive glomeruloid structures), mesenchymal (neoplastic spindle cells in connective tissue), and blastemal cells (primitive neoplastic cells). The extrarenal nodular masses were predominantly composed of neoplastic mesenchymal and pleomorphic blastemal cells. Immunohistochemically, neoplastic epithelial cells in the renal mass were positive for pancytokeratin, and blastemal cells in both renal and extrarenal masses were positive for Wilms' tumor 1 protein (WT1) and vimentin. Neoplastic mesenchymal elements in both renal and extrarenal masses were positive for vimentin. The neoplasm was negative for chromogranin A and S100. The tumor was classified as an anaplastic nephroblastoma with metastasis to the mesentery and peritoneal organs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1293/tox.2020-0030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677621PMC
October 2020

Claudin-18 Loss Alters Transcellular Chloride Flux but not Tight Junction Ion Selectivity in Gastric Epithelial Cells.

Cell Mol Gastroenterol Hepatol 2021 16;11(3):783-801. Epub 2020 Oct 16.

Department of Surgery/Division of General Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts. Electronic address:

Background & Aims: Tight junctions form a barrier to the paracellular passage of luminal antigens. Although most tight junction proteins reside within the apical tight junction complex, claudin-18 localizes mainly to the basolateral membrane where its contribution to paracellular ion transport is undefined. Claudin-18 loss in mice results in gastric neoplasia development and tumorigenesis that may or may not be due to tight junction dysfunction. The aim here was to investigate paracellular permeability defects in stomach mucosa from claudin-18 knockout (Cldn18-KO) mice.

Methods: Stomach tissue from wild-type, heterozygous, or Cldn18-KO mice were stripped of the external muscle layer and mounted in Ussing chambers. Transepithelial resistance, dextran 4 kDa flux, and potential difference (PD) were calculated from the chambered tissues after identifying differences in tissue histopathology that were used to normalize these measurements. Marker expression for claudins and ion transporters were investigated by transcriptomic and immunostaining analysis.

Results: No paracellular permeability defects were evident in stomach mucosa from Cldn18-KO mice. RNAseq identified changes in 4 claudins from Cldn18-KO mice, particularly the up-regulation of claudin-2. Although claudin-2 localized to tight junctions in cells at the base of gastric glands, its presence did not contribute overall to mucosal permeability. Stomach tissue from Cldn18-KO mice also had no PD versus a lumen-negative PD in tissues from wild-type mice. This difference resulted from changes in transcellular Cl permeability with the down-regulation of Cl loading and Cl secreting anion transporters.

Conclusions: Our findings suggest that Cldn18-KO has no effect on tight junction permeability in the stomach from adult mice but rather affects anion permeability. The phenotype in these mice may thus be secondary to transcellular anion transporter expression/function in the absence of claudin-18.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcmgh.2020.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847960PMC
October 2020

Implantable Nanosensors for Human Steroid Hormone Sensing In Vivo Using a Self-Templating Corona Phase Molecular Recognition.

Adv Healthc Mater 2020 11 16;9(21):e2000429. Epub 2020 Sep 16.

Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.

Dynamic measurements of steroid hormones in vivo are critical, but steroid sensing is currently limited by the availability of specific molecular recognition elements due to the chemical similarity of these hormones. In this work, a new, self-templating synthetic approach is applied using corona phase molecular recognition (CoPhMoRe) targeting the steroid family of molecules to produce near infrared fluorescent, implantable sensors. A key limitation of CoPhMoRe has been its reliance on library generation for sensor screening. This problem is addressed with a self-templating strategy of polymer design, using the examples of progesterone and cortisol sensing based on a styrene and acrylic acid copolymer library augmented with an acrylated steroid. The pendant steroid attached to the corona backbone is shown to self-template the phase, providing a unique CoPhMoRE design strategy with high efficacy. The resulting sensors exhibit excellent stability and reversibility upon repeated analyte cycling. It is shown that molecular recognition using such constructs is viable even in vivo after sensor implantation into a murine model by employing a poly (ethylene glycol) diacrylate (PEGDA) hydrogel and porous cellulose interface to limit nonspecific absorption. The results demonstrate that CoPhMoRe templating is sufficiently robust to enable a new class of continuous, in vivo biosensors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/adhm.202000429DOI Listing
November 2020

Identification of a new strain of mouse kidney parvovirus associated with inclusion body nephropathy in immunocompromised laboratory mice.

Emerg Microbes Infect 2020 Dec;9(1):1814-1823

Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA.

Inclusion body nephropathy (IBN) and kidney fibrosis in aged immunodeficient mice and, to lesser extent, in immunocompetent mice have been recently linked to infection of mouse kidney parvovirus (MKPV), also known as murine chapparvovirus (MuCPV). Knowledge about its prevalence and the complete genome sequence of more MKPV strains is essential for understanding phylogenetic relationships and pathogenicity among MKPV strains. In the present study using PCR and genome walking, we determined the complete 4440-nucleotide genome of a new MKPV strain, namely MIT-WI1, which was identified in IBN-affected mice housed in the vivarium at Whitehead Institute for Biomedical Research (WI). The overall nucleotide (>94%) and deduced amino acid sequences (>98%) of p10, p15, NS1 (replicase), NS2 and VP1 (capsid protein) within the MIT-WI1 genome, are closely related to MKPV/MuCPV strains described in laboratory and wild mice. In addition, PCR and qPCR assays using newly designed primers conserved among the known MKPV/MuCPV genomes were developed and utilized to assess MKPV status in selected laboratory mice. MKPV was also detected in immunodeficient (NSG) and immunocompetent (Crl:CD1(ICR), UTX) mouse strains/stocks. The abundance of the MKPV genome copies was significantly correlated with the severity of IBN. Our data indicate that MKPV is present in selected mouse strains/stocks, and provides new insights into the genome evolution of MKPV.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/22221751.2020.1798288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473309PMC
December 2020

Risk and characteristics of gastric carcinoma in the chow chow dog.

Can Vet J 2020 04;61(4):396-400

University College Dublin, Veterinary Hospital, Belfield, Dublin, Ireland (Koterbay); Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA (Muthupalani, Fox); Cummings School of Veterinary Medicine, Tufts University, Grafton, Massachusetts, USA (McNiel).

Gastric carcinoma is not commonly reported in dogs. There is an increased risk, however, in certain breeds such as the Belgian Tervuren. Review of the Veterinary Medical Database (VMDB) established an increase in risk for gastric carcinoma in the chow chow breed. In 106 chow chow dogs signs commenced, on average, 3 weeks before definitive diagnosis. The most common clinical signs were vomiting, loss of appetite, diarrhea, and melena. Most affected dogs were euthanized, without treatment, within 2 weeks of diagnosis. Two dogs which were treated aggressively (surgery and chemotherapy) survived a considerably longer time (12 and 36 months). Histologically, these chow chow dogs comprised a similar histologic type as familial gastric carcinoma in humans; diffuse-type carcinoma that was enriched in the signet ring and mucinous variants. Understanding the pathogenesis of diffuse gastric carcinoma in the chow chow dog may provide insight into the biology of this aggressive cancer in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074117PMC
April 2020

Natural Transmission of Helicobacter saguini Causes Multigenerational Inflammatory Bowel Disease in C57/129 IL-10 Mice.

mSphere 2020 03 25;5(2). Epub 2020 Mar 25.

Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

Cotton-top tamarins (CTTs) are an ideal model of human inflammatory bowel disease (IBD) because these animals develop multigenerational, lower bowel cancer. We previously isolated and characterized a novel enterohepatic species, , from CTTs with IBD and documented that infection in germfree C57BL IL-10 mice recapitulates IBD, suggesting that influences IBD etiopathogenesis. In this study, we utilized a germfree IL-10 model to illustrate that infection can naturally transmit and infect four generations and cause significant intestinal inflammatory pathology. Additionally, whole-genome sequencing of representative isolates from each generation of IL-10 mice revealed gene mutations suggestive of multigenerational evolution. Overall, these results support that specific bacterial species with pathogenic potential, like , are transmissible microorganisms in the etiopathogenesis of IBD in CTTs and reinforces the importance of specific microbiota in the pathogenesis of IBD in humans. While family history is a significant risk factor for developing inflammatory bowel disease (IBD), it is unclear whether the microbiome from parents is a transmissible influence on disease in their offspring. Furthermore, it is unknown whether IBD-associated microbes undergo genomic adaptations during multigenerational transmission and chronic colonization in their hosts. Herein, we show that a single bacterial species, , isolated from a nonhuman primate species with familial IBD, is transmissible from parent to offspring in germfree IL-10 mice and causes multigenerational IBD. Additionally, whole-genome sequence analysis of isolated from different mouse generations identified microevolutions in environmental interaction, nutrient metabolism, and virulence factor genes that suggest that multigenerational transmission may promote adaptations related to colonization and survival in new hosts and chronic inflammatory environments. The findings from our study highlight the importance of specific bacterial species with pathogenic potential, like , as transmissible microorganisms in the etiopathogenesis of IBD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mSphere.00011-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096620PMC
March 2020

antibiotic eradication coupled with a chemically defined diet in INS-GAS mice triggers dysbiosis and vitamin K deficiency resulting in gastric hemorrhage.

Gut Microbes 2020 07 19;11(4):820-841. Epub 2020 Jan 19.

Division of Comparative Medicine, Massachusetts Institute of Technology , Cambridge, MA, USA.

Infection with causes chronic inflammation and is a risk factor for gastric cancer. Antibiotic treatment or increased dietary folate prevents gastric carcinogenesis in male INS-GAS mice. To determine potential synergistic effects, -infected male INS-GAS mice were fed an amino acid defined (AAD) diet with increased folate and were treated with antibiotics after 18 weeks of infection. Antibiotic therapy decreased gastric pathology, but dietary folate had no effect. However, the combination of antibiotics and the AAD diet induced anemia, gastric hemorrhage, and mortality. Clinical presentation suggested hypovitaminosis K potentially caused by dietary deficiency and dysbiosis. Based on current dietary guidelines, the AAD diet was deficient in vitamin K. Phylloquinone administered subcutaneously and via a reformulated diet led to clinical improvement with no subsequent mortalities and increased hepatic vitamin K levels. We characterized the microbiome and menaquinone profiles of antibiotic-treated and antibiotic-free mice. Antibiotic treatment decreased the abundance of menaquinone producers within orders and . PICRUSt predicted decreases in canonical menaquinone biosynthesis genes, and . Reduction of from , and were confirmed in antibiotic-treated mice. The fecal menaquinone profile of antibiotic-treated mice had reduced MK5 and MK6 and increased MK7 and MK11 compared to antibiotic-free mice. Loss of menaquinone-producing microbes due to antibiotics altered the enteric production of vitamin K. This study highlights the role of diet and the microbiome in maintaining vitamin K homeostasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/19490976.2019.1710092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524293PMC
July 2020

Muc5ac null mice are predisposed to spontaneous gastric antro-pyloric hyperplasia and adenomas coupled with attenuated H. pylori-induced corpus mucous metaplasia.

Lab Invest 2019 12 9;99(12):1887-1905. Epub 2019 Aug 9.

Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.

Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide and is strongly associated with chronic Helicobacter pylori (Hp) infection. The ability of Hp to closely adhere to the gastric surface protective mucous layer containing mucins (MUC in humans and Muc in animals), primarily Muc5ac, is integral in the stepwise pathogenesis from gastritis to cancer. To probe the role of Muc5ac in Hp-induced gastric pathology, Muc5ac and Muc5ac (WT) mice were experimentally infected with Hp Sydney strain (SS1). At 16 weeks and 32 weeks post infection (wpi), groups of mice were euthanized and evaluated for the following: gastric histopathological parameters, immunohistochemical expression of mucins (Muc5ac, Muc1, Muc2), Trefoil factor family proteins (Tff1 and Tff2), Griffonia (Bandeiraea) simplicifolia lectin II (GSL II) (mucous metaplasia marker) and Clusterin (Spasmolytic Polypeptide Expressing Metaplasia (SPEM) marker), Hp colonization density by qPCR and gastric cytokine mRNA levels. Our results demonstrate that Muc5ac mice developed spontaneous antro-pyloric proliferation, adenomas and in one case with neuroendocrine differentiation; these findings were independent of Hp infection along with strong expression levels of Tff1, Tff2 and Muc1. Hp-infected Muc5ac mice had significantly lowered gastric corpus mucous metaplasia at 16 wpi and 32 wpi (P = 0.0057 and P = 0.0016, respectively), with a slight reduction in overall gastric corpus pathology. GSII-positive mucous neck cells were decreased in Hp-infected Muc5ac mice compared to WT mice and clusterin positivity was noted within metaplastic glands in both genotypes following Hp infection. Additionally, Hp colonization densities were significantly higher in Muc5ac mice compared to WT at 16 wpi in both sexes (P = 0.05) along with a significant reduction in gastric Tnfα (16 wpi-males and females, P = 0.017 and P = 0.036, respectively and 32 wpi-males only, P = 0.025) and Il-17a (16 wpi-males) (P = 0.025). Taken together, our findings suggest a protective role for MUC5AC/Muc5ac in maintaining gastric antral equilibrium and inhibiting Hp colonization and associated inflammatory pathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41374-019-0293-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927550PMC
December 2019

High-Fat Diet Accelerates Carcinogenesis in a Mouse Model of Barrett's Esophagus via Interleukin 8 and Alterations to the Gut Microbiome.

Gastroenterology 2019 08 15;157(2):492-506.e2. Epub 2019 Apr 15.

Irvine Cancer Research Center, Columbia University, New York, New York.

Background & Aims: Barrett's esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC). Progression from BE to cancer is associated with obesity, possibly due to increased abdominal pressure and gastroesophageal reflux disease, although this pathogenic mechanism has not been proven. We investigated whether environmental or dietary factors associated with obesity contribute to the progression of BE to EAC in mice.

Methods: Tg(ED-L2-IL1RN/IL1B)#Tcw mice (a model of BE, called L2-IL1B mice) were fed a chow (control) or high-fat diet (HFD) or were crossbred with mice that express human interleukin (IL) 8 (L2-IL1B/IL8 mice). Esophageal tissues were collected and analyzed for gene expression profiles and by quantitative polymerase chain reaction, immunohistochemistry, and flow cytometry. Organoids were established from BE tissue of mice and cultured with serum from lean or obese individuals or with neutrophils from L2-IL1B mice. Feces from mice were analyzed by 16s ribosomal RNA sequencing and compared to 16s sequencing data from patients with dysplasia or BE. L2-IL1B were mice raised in germ-free conditions.

Results: L2-IL1B mice fed an HFD developed esophageal dysplasia and tumors more rapidly than mice fed the control diet; the speed of tumor development was independent of body weight. The acceleration of dysplasia by the HFD in the L2-IL1B mice was associated with a shift in the gut microbiota and an increased ratio of neutrophils to natural killer cells in esophageal tissues compared with mice fed a control diet. We observed similar differences in the microbiomes from patients with BE that progressed to EAC vs patients with BE that did not develop into cancer. Tissues from dysplasias of L2-IL1B mice fed the HFD contained increased levels of cytokines that are produced in response to CXCL1 (the functional mouse homolog of IL8, also called KC). Serum from obese patients caused organoids from L2-IL1B/IL8 mice to produce IL8. BE tissues from L2-IL1B mice fed the HFD and from L2-IL1B/IL8 mice contained increased numbers of myeloid cells and cells expressing Cxcr2 and Lgr5 messenger RNAs (epithelial progenitors) compared with mice fed control diets. BE tissues from L2-IL1B mice raised in germ-free housing had fewer progenitor cells and developed less dysplasia than in L2-IL1 mice raised under standard conditions; exposure of fecal microbiota from L2-IL1B mice fed the HFD to L2-IL1B mice fed the control diet accelerated tumor development.

Conclusions: In a mouse model of BE, we found that an HFD promoted dysplasia by altering the esophageal microenvironment and gut microbiome, thereby inducing inflammation and stem cell expansion, independent of obesity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.gastro.2019.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662596PMC
August 2019

Mutagenicity of Helicobacter hepaticus infection in the lower bowel mucosa of 129/SvEv Rag2 Il10 gpt delta mice is influenced by sex.

Int J Cancer 2019 08 7;145(4):1042-1054. Epub 2019 May 7.

Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA.

Inflammatory bowel disease and colonic tumors induced by Helicobacter hepaticus (Hh) infection in susceptible mouse strains are utilized to dissect the mechanisms underlying similar human diseases. In our study, infection with genotoxic cytolethal distending toxin-producing Hh in 129/SvEv Rag2 Il10 gpt delta (RagIl10gpt) mice of both sexes for 21 weeks induced significantly more severe cecal and colonic pathology compared to uninfected controls. The mutation frequencies in the infected RagIl10gpt males were 2.1-fold higher for the cecum and 1.7-fold higher for the colon than male RagIl10gpt controls. In addition, there was a 12.5-fold increase of G:C-to-T:A transversions in the colon of Hh-infected males compared to controls. In contrast, there was no statistical significance in mutation frequencies between infected female Rag2Il10gpt mice and controls. Moreover, Hh infection in RagIl10gpt males significantly up-regulated transcription of Tnfα and iNos, and decreased mRNA levels of cecal Atm compared to the infected females; there was no significant difference in mRNA levels of Il-22, Il-17A, Ifnγ and Atr between the infected males and females. Significantly higher levels of cecal and colonic iNos expression and γH2AX-positive epithelial cells (a biomarker for double-strand DNA breaks [DSB]) in Hh-infected Rag2Il10gpt males vs. Hh-infected females were noted. Finally, Hh infection and associated inflammation increased levels of intestinal mucosa-associated genotoxic colibactin-producing pks+ Escherichia coli. Elevated Tnfα and iNos responses and bacterial genotoxins, in concert with suppression of the DSB repair responses, may have promoted mutagenesis in the lower bowel mucosa of Hh-infected male RagIl10gpt mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.32332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724725PMC
August 2019

Loss of Tight Junction Protein Claudin 18 Promotes Progressive Neoplasia Development in Mouse Stomach.

Gastroenterology 2018 12 7;155(6):1852-1867. Epub 2018 Sep 7.

Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.

Background & Aims: Loss of claudin 18 (CLDN18), a membrane-spanning tight junction protein, occurs during early stages of development of gastric cancer and associates with shorter survival times of patients. We investigated whether loss of CLDN18 occurs in mice that develop intraepithelial neoplasia with invasive glands due to infection with Helicobacter pylori, and whether loss is sufficient to promote the development of similar lesions in mice with or without H pylori infection.

Methods: We performed immunohistochemical analyses in levels of CLDN18 in archived tissues from B6:129 mice infected with H pylori for 6 to 15 months. We analyzed gastric tissues from B6:129S5-Cldn18tm1Lex/Mmucd mice, in which the CLDN18 gene was disrupted in gastric tissues (CLDN18-knockout mice), or from control mice with a full-length CLDN18 gene (CLDN18+/+; B6:129S5/SvEvBrd) or heterozygous disruption of CLDN18 (CLDN18+/-; B6:129S5/SvEvBrd) that were infected with H pylori SS1 or PMSS1 at 6 weeks of age and tissues collected for analysis at 20 and 30 weeks after infection. Tissues from CLDN18-knockout mice and control mice with full-length CLDN18 gene expression were also analyzed without infection at 7 weeks and 2 years after birth. Tissues from control and CLDN18-knockout mice were analyzed by electron microscopy, stained by conventional methods and analyzed for histopathology, prepared by laser capture microdissection and analyzed by RNAseq, and immunostained for lineage markers, proliferation markers, and stem cell markers and analyzed by super-resolution or conventional confocal microscopy.

Results: CLDN18 had a basolateral rather than apical tight junction localization in gastric epithelial cells. B6:129 mice infected with H pylori, which developed intraepithelial neoplasia with invasive glands, had increasing levels of CLDN18 loss over time compared with uninfected mice. In B6:129 mice infected with H pylori compared with uninfected mice, CLDN18 was first lost from most gastric glands followed by disrupted and reduced expression in the gastric neck and in surface cells. Gastric tissues from CLDN18-knockout mice had low levels of inflammation but increased cell proliferation, expressed markers of intestinalized proliferative spasmolytic polypeptide-expressing metaplasia, and had defects in signal transduction pathways including p53 and STAT signaling by 7 weeks after birth compared with full-length CLDN18 gene control mice. By 20 to 30 weeks after birth, gastric tissues from uninfected CLDN18-knockout mice developed intraepithelial neoplasia that invaded the submucosa; by 2 years, gastric tissues contained large and focally dysplastic polypoid tumors with invasive glands that invaded the serosa.

Conclusions: H pylori infection of B6:129 mice reduced the expression of CLDN18 early in gastric cancer progression, similar to previous observations from human gastric tissues. CLDN18 regulates cell lineage differentiation and cellular signaling in mouse stomach; CLDN18-knockout mice develop intraepithelial neoplasia and then large and focally dysplastic polypoid tumors in the absence of H pylori infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.gastro.2018.08.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613545PMC
December 2018

Lung Lobe Torsion in an Adult Male Common Marmoset ().

Comp Med 2018 08 16;68(4):314-318. Epub 2018 Jul 16.

Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

A 6-y-old, intact, pair-housed male common marmoset (Callithrix jacchus) presented with acute onset dyspnea and tachypnea immediately after sedation with alfaxalone; a history of gradual weight loss initiated the examination under sedation. Thoracic radiographs revealed significant right-lung consolidation, with a vesicular gas pattern in the right caudodorsal lung field, pleural effusion, and dorsal displacement of the heart. The marmoset was euthanized due to his unstable condition and poor prognosis. At necropsy, the cranial and middle lobes of the right lung were homogenously dark red-brown, enlarged, edematous, and twisted around the longitudinal axis at the hilus. The left lung lobes were pale pink and slightly edematous. In light of the clinical and gross necropsy findings, acute torsion of the right cranial and middle lung lobes was diagnosed. Predisposing conditions for lung lobe torsion include trauma, neoplasia, pulmonary disease, previous thoracic surgery, and diaphragmatic hernia, but none of these applied to this case. Initial therapy for lung lobe torsion is to stabilize the patient and treat for underlying conditions, with prompt surgical resection as the treatment of choice. To our knowledge, this report is the first description of lung lobe torsion in an experimentally unmanipulated New World NHP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.30802/AALAS-CM-17-000128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6103417PMC
August 2018

Evaluation of Lineage Changes in the Gastric Mucosa Following Infection With and Specified Intestinal Flora in INS-GAS Mice.

J Histochem Cytochem 2019 01 3;67(1):53-63. Epub 2018 Jul 3.

Section of Surgical Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee.

Gastric adenocarcinoma develops in metaplastic mucosa associated with infection in the stomach. We have sought to evaluate the precise lineage changes in the stomachs of insulin-gastrin (INS-GAS) mice infected with and/or intestinal flora (Altered Schaedler's Flora; ASF). Stomachs from groups infected with contained progressive spasmolytic polypeptide-expressing metaplasia (SPEM) compared with germ-free and mice infected with ASF alone. The overall phenotype of the -infected mice was dominated by Ulex europaeus lectin (UEAI)-positive foveolar hyperplasia that was distinct from GSII/CD44v9-positive SPEM. However, in the mice with co-infected with ASF, we identified a subpopulation of UEAI-positive foveolar cells that co-expressed intestinal mucin 4 (MUC4). These regions of foveolar cells were variably positive for CD44v9 as well as TFF3. Interestingly, an intravascular lesion identified in a dual /ASF-infected mouse expressed both UEAI and . Finally, we identified an increase in the number of tuft cells within the mucosa of -infected groups. Our findings suggest that infection promotes foveolar hyperplasia as well as metaplasia, while co-infection may promote progressive foveolar and metaplastic lesions as well as dysplasia. Grading of gastric lesions in mice as preneoplastic requires multiple immunostaining markers to assign lineage derivation and behavior.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1369/0022155418785621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309034PMC
January 2019

Helicobacter pylori-infected C57BL/6 mice with different gastrointestinal microbiota have contrasting gastric pathology, microbial and host immune responses.

Sci Rep 2018 05 22;8(1):8014. Epub 2018 May 22.

Division of Comparative Medicine, the Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.

C57BL/6 (B6) mice from Taconic Sciences (Tac) and the Jackson Laboratory (Jax) were infected with H. pylori PMSS1 (Hp) for 16 week; there was no significant difference in the gastric histologic activity index between Hp infected Tac and Jax B6. However, the degree of gastric mucous metaplasia and Th1-associated IgG2c levels in response to Hp infection were increased in Tac mice over Jax mice, whereas the colonization levels of gastric Hp were higher by 8-fold in Jax B6 compared with Tac B6. Additionally, mRNA expression of gastric Il-1β, Il-17A and RegIIIγ were significantly lower in the infected Tac compared to the infected Jax mice. There were significant differences in the microbial community structures in stomach, colon, and feces between Jax and Tac B6 females. Differences in gastric microbial communities between Jax and Tac B6 females are predicted to affect the metagenome. Moreover, Hp infection perturbed the microbial community structures in the stomach, colon and feces of Jax mice, but only altered the colonic microbial composition of Tac mice. Our data indicate that the GI microbiome of Tac B6 mice is compositionally distinct from Jax B6 mice, which likely resulted in different pathological, immunological, and microbial responses to Hp infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-25927-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964229PMC
May 2018

Adult-onset, chronic, cyclic thrombocytopenia in a Rhesus macaque (Macaca mulatta) after dengue virus vaccination and viral challenge.

Vet Clin Pathol 2017 Jun 18;46(2):238-247. Epub 2017 May 18.

Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA.

An 8-year-old, male Rhesus macaque (Macaca mulatta), previously used for dengue virus (DENV) vaccine research with viral challenge, was presented with adult-onset, chronic, cyclic thrombocytopenia. Platelet number, morphology, and function were evaluated by automated hematology, peripheral blood smears, electron microscopy, flow cytometry, and impedance aggregometry. Bone marrow was evaluated by cytology. Both serum anti-dengue nonstructural protein 1 (NS1) antibodies and anti-platelet antibodies were detected by ELISA. Platelet characterization showed a lack of aggregation to all agonists (ADP, ASP, and collagen), increased activation with increased expression of surface marker (HLA-ABC), and an absence of surface receptor GPIX during clinical episodes of petechiae and ecchymoses, even in the presence of normal platelet counts. Bone marrow aspirates identified potential mild megakaryocytic hypoplasia. All platelet functions and morphologic attributes were within normal limits during clinically normal phases. Presence of anti-dengue NS1 serum antibodies confirmed a positive DENV titer 8 years postvaccination. Based on the history and clinical findings, a primary differential diagnosis for this chronic, cyclic platelet pathology was autoimmune platelet destruction with potential bone marrow involvement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/vcp.12497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5977396PMC
June 2017

Local and Systemic Changes Associated with Long-term, Percutaneous, Static Implantation of Titanium Alloys in Rhesus Macaques ().

Comp Med 2017 Mar;67(2):165-175

Division of Comparative Medicine, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.

Metal alloys are frequently used as implant materials in veterinary medicine. Recent studies suggest that many alloys induce both local and systemic inflammatory responses. In this study, 37 rhesus macaques with long-term skull-anchored percutaneous titanium alloy implants (duration, 0 to 14 y) were evaluated for changes in their hematology, coagulation, and serum chemistry profiles. Negative controls (n = 28) did not have implants. Macaques with implants had higher plasma D-dimer and lower antithrombin III concentrations than nonimplanted animals. In addition, animals with implants had higher globulin and lower albumin and calcium concentrations compared with nonimplanted macaques. Many of these changes were positively correlated with duration of implantation and the number of implants. Chronic bacterial infection of the skin was present around many of the implant sites and within deeper tissues. Representative histopathology around the implant site of 2 macaques revealed chronic suppurative to pyogranulomatous inflammation extending from the skin to the dura mater. X-ray fluorescence microscopy of tissue biopsies from the implant site of the same 2 animals revealed significantly higher levels of free metal ions in the tissue, including titanium and iron. The higher levels of free metal ions persisted in the tissues for as long as 6 mo after explantation. These results suggest that long-term skull-anchored percutaneous titanium alloy implants can be associated with localized inflammation, chronic infection, and leaching of metal ions into local tissues.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5402736PMC
March 2017

Helicobacter hepaticus cytolethal distending toxin promotes intestinal carcinogenesis in 129Rag2-deficient mice.

Cell Microbiol 2017 07 20;19(7). Epub 2017 Feb 20.

Division of Comparative Medicine, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA02139, USA.

Multiple pathogenic Gram-negative bacteria produce the cytolethal distending toxin (CDT) with activity of DNase I; CDT can induce DNA double-strand breaks (DSBs), G2/M cell cycle arrest, and apoptosis in cultured mammalian cells. However, the link of CDT to in vivo tumorigenesis is not fully understood. In this study, 129/SvEv Rag2 mice were gavaged with wild-type Helicobacter hepatics 3B1(Hh) and its isogenic cdtB mutant HhcdtBm7, followed by infection for 10 and 20 weeks (WPI). HhCDT deficiency did not affect cecal colonization levels of HhcdtBm7, but attenuated severity of cecal pathology in HhcdtBm7-infected mice. Of importance, preneoplasic dysplasia was progressed to cancer from 10 to 20 WPI in the Hh-infected mice but not in the HhcdtBm7-infected mice. In addition, the loss of HhCDT significantly dampened transcriptional upregulation of cecal Tnfα and Il-6, but elevated Il-10 mRNA levels when compared to Hh at 10 WPI. Furthermore, the presence of HhCDT increased numbers of lower bowel intestinal γH2AX-positive epithelial cells (a marker of DSBs) at both 10 and 20 WPI and augmented phospho-Stat3 foci intestinal crypts (activation of Stat3) at 20 WPI. Our findings suggest that CDT promoted Hh carcinogenesis by enhancing DSBs and activation of the Tnfα/Il-6-Stat3 signaling pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cmi.12728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5469717PMC
July 2017

Novel Helicobacter species H.japonicum isolated from laboratory mice from Japan induces typhlocolitis and lower bowel carcinoma in C57BL/129 IL10-/- mice.

Carcinogenesis 2016 Dec 21;37(12):1190-1198. Epub 2016 Sep 21.

Division of Comparative Medicine,

A novel Helicobacter species Helicobacter japonicum was isolated from the stomach and intestines of clinically normal mice received from three institutes from Japan. The novel Helicobacter sp. was microaerobic, grew at 37°C and 42°C, was catalase and oxidase positive, but urease negative. It is most closely related to the 16S rRNA gene of H.muridarum (98.6%); to the 23S rRNA gene of H.hepaticus (97.9%); to the hsp60 gene of H.typhlonius (87%). The novel Helicobacter sp. has in vitro cytolethal distending toxin (CDT) activity; its cdtB gene sequence has 83.8% identity with that of H.hepaticus The whole genome sequence of H.japonicum MIT 01-6451 has a 2.06-Mb genome length with a 37.5% G + C content. When the organism was inoculated into C57BL/129 IL10 mice, it was cultured from the stomach, colon and cecum of infected mice at 6 and 10 weeks post-infection. The cecum had the highest H.japonicum colonization levels by quantitative PCR. The histopathology of the lower bowel was characterized by moderate to severe inflammation, mild edema, epithelial defects, mild to severe hyperplasia, dysplasia and carcinoma. Inflammatory cytokines IFNγ, TNFα and IL17a, as well as iNOS were significantly upregulated in the cecal tissue of infected mice. These results demonstrate that the novel H.japonicum can induce inflammatory bowel disease and carcinoma in IL10 mice and highlights the importance of identifying novel Helicobacter spp. especially when they are introduced from outside mouse colonies from different geographic locations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/carcin/bgw101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5137264PMC
December 2016

Parp1 protects against Aag-dependent alkylation-induced nephrotoxicity in a sex-dependent manner.

Oncotarget 2016 Jul;7(29):44950-44965

Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.

Nephrotoxicity is a common toxic side-effect of chemotherapeutic alkylating agents. Although the base excision repair (BER) pathway is essential in repairing DNA alkylation damage, under certain conditions the initiation of BER produces toxic repair intermediates that damage healthy tissues. We have shown that the alkyladenine DNA glycosylase, Aag (a.k.a. Mpg), an enzyme that initiates BER, mediates alkylation-induced whole-animal lethality and cytotoxicity in the pancreas, spleen, retina, and cerebellum, but not in the kidney. Cytotoxicity in both wild-type and Aag-transgenic mice (AagTg) was abrogated in the absence of Poly(ADP-ribose) polymerase-1 (Parp1). Here we report that Parp1-deficient mice expressing increased Aag (AagTg/Parp1-/-) develop sex-dependent kidney failure upon exposure to the alkylating agent, methyl methanesulfonate (MMS), and suffer increased whole-animal lethality compared to AagTg and wild-type mice. Macroscopic, histological, electron microscopic and immunohistochemical analyses revealed morphological kidney damage including dilated tubules, proteinaceous casts, vacuolation, collapse of the glomerular tuft, and deterioration of podocyte structure. Moreover, mice exhibited clinical signs of kidney disease indicating functional damage, including elevated blood nitrogen urea and creatinine, hypoproteinemia and proteinuria. Pharmacological Parp inhibition in AagTg mice also resulted in sensitivity to MMS-induced nephrotoxicity. These findings provide in vivo evidence that Parp1 modulates Aag-dependent MMS-induced nephrotoxicity in a sex-dependent manner and highlight the critical roles that Aag-initiated BER and Parp1 may play in determining the side-effects of chemotherapeutic alkylating agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.10440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5216697PMC
July 2016

Lamellipodin-Deficient Mice: A Model of Rectal Carcinoma.

PLoS One 2016 5;11(4):e0152940. Epub 2016 Apr 5.

Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, United States of America.

During a survey of clinical rectal prolapse (RP) cases in the mouse population at MIT animal research facilities, a high incidence of RP in the lamellipodin knock-out strain, C57BL/6-Raph1tm1Fbg (Lpd-/-) was documented. Upon further investigation, the Lpd-/- colony was found to be infected with multiple endemic enterohepatic Helicobacter species (EHS). Lpd-/- mice, a transgenic mouse strain produced at MIT, have not previously shown a distinct immune phenotype and are not highly susceptible to other opportunistic infections. Predominantly male Lpd-/- mice with RP exhibited lesions consistent with invasive rectal carcinoma concomitant to clinically evident RP. Multiple inflammatory cytokines, CD11b+Gr1+ myeloid-derived suppressor cell (MDSC) populations, and epithelial cells positive for a DNA damage biomarker, H2AX, were elevated in affected tissue, supporting their role in the neoplastic process. An evaluation of Lpd-/- mice with RP compared to EHS-infected, but clinically normal (CN) Lpd-/- animals indicated that all of these mice exhibit some degree of lower bowel inflammation; however, mice with prolapses had significantly higher degree of focal lesions at the colo-rectal junction. When Helicobacter spp. infections were eliminated in Lpd-/- mice by embryo transfer rederivation, the disease phenotype was abrogated, implicating EHS as a contributing factor in the development of rectal carcinoma. Here we describe lesions in Lpd-/- male mice consistent with a focal inflammation-induced neoplastic transformation and propose this strain as a mouse model of rectal carcinoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0152940PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4821566PMC
August 2016

Neural innervation stimulates splenic TFF2 to arrest myeloid cell expansion and cancer.

Nat Commun 2016 Feb 4;7:10517. Epub 2016 Feb 4.

Division of Digestive and Liver Disease, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA.

CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs) expand in the spleen during cancer and promote progression through suppression of cytotoxic T cells. An anti-inflammatory reflex arc involving the vagus nerve and memory T cells is necessary for resolution of acute inflammation. Failure of this neural circuit could promote procarcinogenic inflammation and altered tumour immunity. Here we show that splenic TFF2, a secreted anti-inflammatory peptide, is released by vagally modulated memory T cells to suppress the expansion of MDSCs through CXCR4. Splenic denervation interrupts the anti-inflammatory neural arc, resulting in the expansion of MDSCs and colorectal cancer. Deletion of Tff2 recapitulates splenic denervation to promote carcinogenesis. Colorectal carcinogenesis could be suppressed through transgenic overexpression of TFF2, adenoviral transfer of TFF2 or transplantation of TFF2-expressing bone marrow. TFF2 is important to the anti-inflammatory reflex arc and plays an essential role in arresting MDSC proliferation. TFF2 offers a potential approach to prevent and to treat cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms10517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742920PMC
February 2016

Systemic Coronaviral Disease in 5 Ferrets.

Comp Med 2015 Dec;65(6):508-16

Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

The prevalence of reported systemic coronaviral disease in ferrets (Mustela putorius furo), which resembles the dry form of feline infectious peritonitis, has been increasing in the literature since its initial diagnosis and characterization approximately 10 y ago. Here we describe the clinical signs, pathologic findings, and diagnosis by immunohistochemistry using an FIPV3-70 monoclonal antibody of systemic coronaviral disease in 5 ferrets, 2 of which were strictly laboratory-housed; the remaining 3 were referred from veterinary private practices. This case report illustrates the importance of considering FRSCV infection as a differential diagnosis in young, debilitated ferrets with abdominal masses and other supporting clinical signs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4681245PMC
December 2015

Helicobacter pylori Infection Induces Anemia, Depletes Serum Iron Storage, and Alters Local Iron-Related and Adult Brain Gene Expression in Male INS-GAS Mice.

PLoS One 2015 17;10(11):e0142630. Epub 2015 Nov 17.

Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.

Iron deficiency anemia (IDA) affects > 500 million people worldwide, and is linked to impaired cognitive development and function in children. Helicobacter pylori, a class 1 carcinogen, infects about half of the world's population, thus creating a high likelihood of overlapping risk. This study determined the effect of H. pylori infection on iron homeostasis in INS-GAS mice. Two replicates of INS-GAS/FVB male mice (n = 9-12/group) were dosed with H. pylori (Hp) strain SS1 or sham dosed at 6-9 weeks of age, and were necropsied at 27-29 weeks of age. Hematologic and serum iron parameters were evaluated, as was gene expression in gastric and brain tissues. Serum ferritin was lower in Hp SS1-infected mice than uninfected mice (p < 0.0001). Infected mice had a lower red blood cell count (p<0.0001), hematocrit (p < 0.001), and hemoglobin concentration (p <0.0001) than uninfected mice. Relative expression of gastric hepcidin antimicrobial peptide (Hamp) was downregulated in mice infected with Hp SS1 compared to sham-dosed controls (p<0.001). Expression of bone morphogenic protein 4 (Bmp4), a growth factor upstream of hepcidin, was downregulated in gastric tissue of Hp SS1-infected mice (p<0.001). Hp SS1-infected mice had downregulated brain expression of tyrosine hydroxylase (Th) (p = 0.02). Expression of iron-responsive genes involved in myelination (myelin basic protein (Mbp) and proteolipid protein 2 (Plp2)) was downregulated in infected mice (p = 0.001 and p = 0.02). Expression of synaptic plasticity markers (brain derived neurotrophic factor 3 (Bdnf3), Psd95 (a membrane associated guanylate kinase), and insulin-like growth factor 1 (Igf1)) was also downregulated in Hp SS1-infected mice (p = 0.09, p = 0.04, p = 0.02 respectively). Infection of male INS-GAS mice with Hp SS1, without concurrent dietary iron deficiency, depleted serum ferritin, deregulated gastric and hepatic expression of iron regulatory genes, and altered iron-dependent neural processes. The use of Hp SS1-infected INS-GAS mice will be an appropriate animal model for further study of the effects of concurrent H. pylori infection and anemia on iron homeostasis and adult iron-dependent brain gene expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0142630PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4648568PMC
June 2016

Male Syrian Hamsters Experimentally Infected with Helicobacter spp. of the H. bilis Cluster Develop MALT-Associated Gastrointestinal Lymphomas.

Helicobacter 2016 Jun 8;21(3):201-17. Epub 2015 Sep 8.

Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA.

Background: Aged hamsters naturally infected with novel Helicobacter spp. classified in the H. bilis cluster develop hepatobiliary lesions and typhlocolitis.

Methods: To determine whether enterohepatic H. spp. contribute to disease, Helicobacter-free hamsters were experimentally infected with H. spp. after suppression of intestinal bacteria by tetracycline treatment of dams and pups. After antibiotic withdrawal, weanlings were gavaged with four H. bilis-like Helicobacter spp. isolated from hamsters or H. bilis ATCC 43879 isolated from human feces and compared to controls (n = 7 per group).

Results: Helicobacter bilis 43879-dosed hamsters were necropsied at 33 weeks postinfection (WPI) due to the lack of detectable infection by fecal PCR; at necropsy, 5 of 7 were weakly PCR positive but lacked intestinal lesions. The remaining hamsters were maintained for ~95 WPI; chronic H. spp. infection in hamsters (6/7) was confirmed by PCR, bacterial culture, fluorescent in situ hybridization, and ELISA. Hamsters had mild-to-moderate typhlitis, and three of the male H. spp.-infected hamsters developed small intestinal lymphoma, in contrast to one control. Of the three lymphomas in H. spp.-infected hamsters, one was a focal ileal mucosa-associated lymphoid tissue (MALT) B-cell lymphoma, while the other two were multicentric small intestinal large B-cell lymphomas involving both the MALT and extra-MALT mucosal sites with lymphoepithelial lesions. The lymphoma in the control hamster was a diffuse small intestinal lymphoma with a mixed population of T and B cells.

Conclusions: Results suggest persistent H. spp. infection may augment risk for gastrointestinal MALT origin lymphomas. This model is consistent with H. pylori/heilmannii-associated MALT lymphoma in humans and could be further utilized to investigate the mechanisms of intestinal lymphoma development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/hel.12265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4783298PMC
June 2016

Inflammation-induced cell proliferation potentiates DNA damage-induced mutations in vivo.

PLoS Genet 2015 Feb 3;11(2):e1004901. Epub 2015 Feb 3.

Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America; Singapore-MIT Alliance for Research and Technology, Singapore.

Mutations are a critical driver of cancer initiation. While extensive studies have focused on exposure-induced mutations, few studies have explored the importance of tissue physiology as a modulator of mutation susceptibility in vivo. Of particular interest is inflammation, a known cancer risk factor relevant to chronic inflammatory diseases and pathogen-induced inflammation. Here, we used the fluorescent yellow direct repeat (FYDR) mice that harbor a reporter to detect misalignments during homologous recombination (HR), an important class of mutations. FYDR mice were exposed to cerulein, a potent inducer of pancreatic inflammation. We show that inflammation induces DSBs (γH2AX foci) and that several days later there is an increase in cell proliferation. While isolated bouts of inflammation did not induce HR, overlap between inflammation-induced DNA damage and inflammation-induced cell proliferation induced HR significantly. To study exogenously-induced DNA damage, animals were exposed to methylnitrosourea, a model alkylating agent that creates DNA lesions relevant to both environmental exposures and cancer chemotherapy. We found that exposure to alkylation damage induces HR, and importantly, that inflammation-induced cell proliferation and alkylation induce HR in a synergistic fashion. Taken together, these results show that, during an acute bout of inflammation, there is a kinetic barrier separating DNA damage from cell proliferation that protects against mutations, and that inflammation-induced cell proliferation greatly potentiates exposure-induced mutations. These studies demonstrate a fundamental mechanism by which inflammation can act synergistically with DNA damage to induce mutations that drive cancer and cancer recurrence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1004901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4372043PMC
February 2015

Gremlin 1 identifies a skeletal stem cell with bone, cartilage, and reticular stromal potential.

Cell 2015 Jan;160(1-2):269-84

Department of Medicine and Irving Cancer Research Center, Columbia University, New York, NY 10032, USA.

The stem cells that maintain and repair the postnatal skeleton remain undefined. One model suggests that perisinusoidal mesenchymal stem cells (MSCs) give rise to osteoblasts, chondrocytes, marrow stromal cells, and adipocytes, although the existence of these cells has not been proven through fate-mapping experiments. We demonstrate here that expression of the bone morphogenetic protein (BMP) antagonist gremlin 1 defines a population of osteochondroreticular (OCR) stem cells in the bone marrow. OCR stem cells self-renew and generate osteoblasts, chondrocytes, and reticular marrow stromal cells, but not adipocytes. OCR stem cells are concentrated within the metaphysis of long bones not in the perisinusoidal space and are needed for bone development, bone remodeling, and fracture repair. Grem1 expression also identifies intestinal reticular stem cells (iRSCs) that are cells of origin for the periepithelial intestinal mesenchymal sheath. Grem1 expression identifies distinct connective tissue stem cells in both the bone (OCR stem cells) and the intestine (iRSCs).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2014.11.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4436082PMC
January 2015
-->