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486. Epidemiology of Carbapenem-ResistantPseudomonas aeruginosaIdentified through the Emerging Infections program (EIP), United States, 2016–2018

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Open Forum Infectious Diseases 2019年第SUPPLEMENT_2期6卷 S238–S238页

作者： Grass, Julian E Bulens, Sandra N Bamberg, Wendy M Janelle, Sarah J Schutz, Kyle Jacob, Jesse T Bower, Chris W Blakney, Rebekah Wilson, Lucy E Vaeth, Elisabeth Li, Linda Lynfield, Ruth Snippes Vagnone, Paula Dobbins, Ginette Phipps, Erin C Hancock, Emily B Dumyati, Ghinwa Tsay, Rebecca Cassidy, P Maureen West, Nicole Kainer, Marion A Mounsey, Jacquelyn Stanton, Richard A McAllister, Gillian A Campbell, Davina Lutgring, Joseph D Karlsson, Maria Walters, Maroya S Division of Healthcare Quality Promotion Centers for Disease Control and Prevention Atlanta Georgia Colorado Department of Public Health and Environment Denver Colorado Emory University Atlanta Georgia Georgia Emerging Infections Program Decatur Georgia University of Maryland Baltimore County Baltimore Maryland Maryland Department of Health Baltimore Maryland Minnesota Department of Health Saint Paul Minnesota Minnesota Department of Health Laboratory St. Paul Minnesota University of New Mexico Albuquerque New Mexico New York Rochester Emerging Infections Program at the University of Rochester Medical Center Rochester New York Oregon Health Authority Portland Oregon Tennessee Department of Health Nashville Tennessee Centers for Disease Control and Prevention Atlanta Georgia

BackgroundPseudomonas aeruginosais intrinsically resistant to many commonly used antimicrobials, and carbapenems are often required to treat infections. We describe the crude incidence, epidemiology, and molecular cha...

Background Pseudomonas aeruginosa is intrinsically resistant to many commonly used antimicrobials, and carbapenems are often required to treat infections. We describe the crude incidence, epidemiology, and molecular characteristics of carbapenem-resistant P. aeruginosa (CRPA) in the EIP catchment area. Methods From August 1, 2016 through July 31, 2018, we conducted laboratory- and population-based surveillance for CRPA in selected areas in eight sites. We defined a case as the first isolate of P. aeruginosa resistant to imipenem, meropenem, or doripenem from the lower respiratory tract, urine, wounds, or normally sterile sites identified from a resident of the EIP catchment area in a 30-day period. Patient charts were reviewed. Analysis excluded cystic fibrosis patients. A random sample of isolates was collected. Real-time PCR to detect carbapenemase genes and whole-genome sequencing are in progress. Results We identified 4,209 cases in 3373 patients. The annual incidence was 14.50 (95% CI, 14.07–14.94) per 100,000 persons and varied among sites from 4.89 in OR to 25.21 in NY. The median age of patients was 66 years (range: < 1–101), 42.1% were female, and nearly all (97.5%) had an underlying condition. Most cases were identified from urine (42.8%) and lower respiratory tract (35.7%) cultures. Nearly all (93.3%) occurred in patients with inpatient healthcare facility stay, surgery, chronic dialysis, or indwelling devices in the prior year; death occurred in 7.2%. Among 937 isolates tested, 847 (90.4%) underwent PCR; six (0.7%) harbored a carbapenemase, from four sites (CO, MD, NY, and OR): bla VIM (3), bla KPC (2), and bla IMP (1). Of 612 (65.3%) isolates sequenced, the most common ST types were ST235 (9.2%) and ST298 (4.9%). Conclusion Carbapenemases were rarely the cause of carbapenem resistance but were found at EIP sites with high and low CRPA incidence. The emergence of mobile carbapenemases in P. aeruginosa has the potential to increase the incidence of CRPA.

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507. Epidemiology of Community-Associated Carbapenemase + Producing Carbapenem-Resistant Enterobacteriacae Identified from the Emerging Infections program, 2012–2017

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Open Forum Infectious Diseases 2019年第SUPPLEMENT_2期6卷 S246–S246页

作者： See, Isaac Ansari, Uzma Reses, Hannah Grass, Julian E Epson, Erin Nadle, Joelle Bamberg, Wendy M Janelle, Sarah J Bower, Chris W Jacob, Jesse T Vaeth, Elisabeth Wilson, Lucy E Lynfield, Ruth VonBank, Brittany Snippes Vagnone, Paula Hancock, Emily B Phipps, Erin C Dumyati, Ghinwa Tsay, Rebecca Cassidy, Maureen Kainer, Marion A Mounsey, Jacquelyn Muleta, Daniel Bulens, Sandra N Karlsson, Maria Duffy, Nadezhda Lutgring, Joseph Centers for Disease Control and Prevention Atlanta Georgia Division of Healthcare Quality Promotion Centers for Disease Control and Prevention Atlanta Georgia California Department Of Public Health Richmond California California Emerging Infections Program Oakland California Colorado Department of Public Health and Environment Denver Colorado Georgia Emerging Infections Program Decatur Georgia Emory University Atlanta Georgia Maryland Department of Health Baltimore Maryland University of Maryland Baltimore County Baltimore Maryland Minnesota Department of Health Saint Paul Minnesota Minnesota Department of Health Laboratory St. Paul Minnesota University of New Mexico Albuquerque New Mexico New York Rochester Emerging Infections Program at the University of Rochester Medical Center Rochester New York Oregon Health Authority Portland Oregon Tennessee Department of Health Nashville Tennessee

BackgroundCarbapenemase-producing (CP-) carbapenem-resistant Enterobacteriaceae (CRE) have been almost exclusively linked to extensive healthcare exposure and are of significant concern due to limited treatment option...

Background Carbapenemase-producing (CP-) carbapenem-resistant Enterobacteriaceae (CRE) have been almost exclusively linked to extensive healthcare exposure and are of significant concern due to limited treatment options and potential for plasmid-mediated spread of resistance. We report on CP-CRE in community-dwelling individuals. Methods We used 2012–2017 active, laboratory and population-based surveillance data for CRE from CDC’s Emerging Infections program sites (9 sites by 2017). Cases were the first isolation of Escherichia coli , Klebsiella spp., or Enterobacter spp. from a normally sterile body specimen or urine in a surveillance site resident meeting a CRE phenotype (figure) in a 30 day period. Epidemiologic data were obtained from chart review. Cases were community-associated (CA) if not isolated after the first three days of a hospital stay; without inpatient healthcare, dialysis, or surgery in the year prior; and without indwelling medical devices within two days prior to culture. A convenience sample of isolates was tested at CDC by real-time PCR to detect bla KPC , bla NDM , bla OXA-48-like , bla VIM , or bla IMP . Results Of 4023 CRE cases, 699 (17%) were CA, from which 297 isolates were tested; 20 (7%) were CP-CRE, from 18 patients (2 had repeat isolation of the same gene/species). The median age was 68 years (range: 33–91), and 14 (78%) were female. Patients were from 7 sites (range: 1–4/site). Their CP-CRE (10 bla KPC , 6 bla NDM , and 2 bla OXA-48-like ) were from three species (10 K. pneumoniae , 6 E. coli , 2 E. cloacae ) and isolated from urine ( n = 16) and blood ( n = 2). Among those with CP-CRE from urine, 12 (75%) had clinical diagnoses of urinary tract infections and the rest had no infection documented. Overall, 7 (39%) were admitted to a hospital within 30 days of culture; none died during hospitalization. Most ( n = 13; 72%) had underlying medical comorbidities, most commonly urinary tract abnormalities ( n = 5; 28%) and diabetes mellitus

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1211. Increasing Incidence of Invasive Methicillin-Resistant and Methicillin-SensitiveS. aureusInfections Among Persons Who Inject Drugs, 2014–2017

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Open Forum Infectious Diseases 2018年第SUPPL_1期5卷 S367–S367页

作者： Felsen, Christina B Gellert, Anita See, Isaac Dumyati, Ghinwa NY Emerging Infections Program Center for Community Health and Prevention University of Rochester Medical Center Rochester New York Division of Healthcare Quality Promotion Centers for Disease Control and Prevention Atlanta Georgia

BackgroundIn 2011, persons who inject drugs (PWID) were estimated to be 2.6% of the US population 13 years of age and older. Infectious endocarditis (IE) and hepatitis C infections among PWID are increasing. We descri...

Background In 2011, persons who inject drugs (PWID) were estimated to be 2.6% of the US population 13 years of age and older. Infectious endocarditis (IE) and hepatitis C infections among PWID are increasing. We describe trends in invasive Staphylococcus aureus (iSA) infections among PWID. Methods Population-based surveillance for invasive (from normally sterile site) methicillin-resistant S. aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) has been conducted in Monroe County, NY (2010 Census population: 744,344) as part of the CDC’s Emerging Infections program since September 2014. Cases are county residents with an iSA infection; iSA incidence was calculated as cases/100,000 census population. Results During September 2014–August 2017, 1,460 iSA cases were identified; 150 (10%) in PWID. The incidence of PWID-associated iSA doubled among 18–49 year olds during years 1–3 (Table 1). The proportion of cases occurring in PWID increased among both MRSA (7% to 20%) and MSSA (6% to 11%). PWID were significantly younger ( P < 0.0001) than noninjection drug users, and more often White ( P = 0.003) and non-Hispanic (p = 0.004). Among PWID with iSA, 45% had IE. Almost all PWID with iSA used other illicit drugs ( n = 112, 91% of 123 unique cases); 89% (110) were smokers, and 46% (56) had chronic liver disease. PWID with iSA had a longer mean length of stay (26 days [SD 22] vs. 21 [37], P = 0.01); PWID with MRSA were more likely to have septic shock (22% vs. 8%, P = 0.03) and pneumonia (9% vs. 1%, P = 0.04) when compared with PWID with MSSA. Among iSA, a history of recurrent skin abscess/boil (24% vs. 8%, P = 0.02) was more common in PWID with MRSA; fewer PWID with MRSA were obese (2% vs. 15%, p = 0.02). Conclusion The increasing incidence of invasive MRSA/MSSA among PWID, frequently accompanied by concurrent chronic liver disease, polysubstance use, and need for extended hospital stays, poses an increasing challenge to the public health and clinical communities. This h

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Author Correction: Multiplexed CRISPR-based microfluidic platform for clinical testing of respiratory viruses and identification of SARS-CoV-2 variants

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Nature medicine 2024年第1期30卷 307页

作者： Nicole L Welch Meilin Zhu Catherine Hua Juliane Weller Marzieh Ezzaty Mirhashemi Tien G Nguyen Sreekar Mantena Matthew R Bauer Bennett M Shaw Cheri M Ackerman Sri Gowtham Thakku Megan W Tse Jared Kehe Marie-Martine Uwera Jacqueline S Eversley Derek A Bielwaski Graham McGrath Joseph Braidt Jeremy Johnson Felecia Cerrato Gage K Moreno Lydia A Krasilnikova Brittany A Petros Gabrielle L Gionet Ewa King Richard C Huard Samantha K Jalbert Michael L Cleary Nicholas A Fitzgerald Stacey B Gabriel Glen R Gallagher Sandra C Smole Lawrence C Madoff Catherine M Brown Matthew W Keller Malania M Wilson Marie K Kirby John R Barnes Daniel J Park Katherine J Siddle Christian T Happi Deborah T Hung Michael Springer Bronwyn L MacInnis Jacob E Lemieux Eric Rosenberg John A Branda Paul C Blainey Pardis C Sabeti Cameron Myhrvold Broad Institute of MIT and Harvard Cambridge MA USA. nicole_welch@g.harvard.edu. Harvard Program in Virology Division of Medical Sciences Harvard Medical School Boston MA USA. nicole_welch@g.harvard.edu. Broad Institute of MIT and Harvard Cambridge MA USA. Department of Biological Engineering Massachusetts Institute of Technology Cambridge MA USA. Division of Infectious Diseases Department of Medicine Massachusetts General Hospital Boston MA USA. Wellcome Sanger Institute Wellcome Genome Campus Hinxton UK. Harvard Program in Biological and Biomedical Sciences Harvard Medical School Boston MA USA. Division of Health Sciences and Technology Harvard Medical School and Massachusetts Institute of Technology Cambridge MA USA. Department of Organismic and Evolutionary Biology Harvard University Cambridge MA USA. Harvard/Massachusetts Institute of Technology MD-PhD Program Harvard Medical School Boston MA USA. Department of Systems Biology Harvard Medical School Boston MA USA. State Health Laboratories Rhode Island Department of Health Providence RI USA. Massachusetts Department of Public Health Boston MA USA. Influenza Division National Center for Immunization and Respiratory Diseases Centers for Disease Control and Prevention Atlanta GA USA. African Centre of Excellence for Genomics of Infectious Diseases Redeemer's University Ede Nigeria. Department of Biological Sciences College of Natural Sciences Redeemer's University Ede Nigeria. Molecular Biology Department and Center for Computational and Integrative Biology Massachusetts General Hospital Boston MA USA. Department of Immunology and Infectious Disease Harvard T.H. Chan School of Public Health Harvard University Boston MA USA. Department of Pathology Massachusetts General Hospital and Harvard Medical School Boston MA USA. Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology Cambridge MA USA. Broad Institute of MIT and Harvard Cambridge MA USA. pardis

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An Analysis of Infant Mortality in the City of Cincinnati, Ohio

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Annals of Epidemiology 2018年第9期28卷 665-665页

作者： Lindsay M. Prescod Maryse Amin Camille Jones Jennifer Mooney Alexander Evans Public Health Associate Program Center for State Tribal Local and Territorial Support (proposed) Centers for Disease Control and Prevention Cincinnati Health Department

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513. Transmission of Carbapenem-Resistant Enterobacteriaceae in a Community-Based, Residential Care Setting: Nevada, 2018

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Open Forum Infectious Diseases 2019年第SUPPLEMENT_2期6卷 S248–S248页

作者： Gomes, Danica Bardossy, Ana Gorzalski, Andrew Holmstadt, Heather Larson, Sandra Halpin, Alison L Chen, Lei Causey, Kimisha Njoku, Chidinma V Stone, Nimalie D Ogundimu, Abimbola Moulton-Meissner, Heather McAllister, Gillian A Gable, Paige Vlachos, Nick Walters, Maroya S Epstein, Lauren Forero, Adrian Centers for Disease Control and Prevention Atlanta Georgia Nevada State Public Health Lab Reno New Jersey Washoe County Health District Reno Nevada Nevada Department of Health and Human Services Las Vegas Nevada Retired Epidemiology Program Manager Washoe County Health District Reno Nevada Nevada Disivion of Public and Behavioral Health Las Vegas Nevada Office of Public Health Investigations and Epidemiology Las Vegas Nevada CDC Atlanta Georgia Division of Healthcare Quality Promotion Centers for Disease Control and Prevention Atlanta Georgia Office of Public Health Informatics and Epidemiology Las Vegas Nevada

BackgroundKlebsiella pneumoniaecarbapenemase-producing organisms (KPCOs) are often multidrug-resistant, and the KPC resistance determinant can be transmitted between bacteria. KPCOs are associated with healthcare faci...

Background Klebsiella pneumoniae carbapenemase-producing organisms (KPCOs) are often multidrug-resistant, and the KPC resistance determinant can be transmitted between bacteria. KPCOs are associated with healthcare facility exposures; identification in community-based, residential care settings is uncommon. In September 2018, the Washoe County Health District was notified of a KPC-producing Escherichia coli from a group home (GH) resident. We investigated the source of this KPCO and evaluated transmission in the GH. Methods A case was defined as detection of KPCO from a GH resident or staff from June 1 to November 30, 2018. Staff included caregivers who provided daily care (including toileting, bathing, feeding) and visiting healthcare workers. Residents and staff were offered KPCO screening to assess colonization status. Exposures were assessed by medical record review and interviews. Genetic relatedness of KPCOs was evaluated by whole-genome sequencing (WGS). Infection prevention and control (IPC) practices were reviewed. Results Overall, six cases were identified, including the index, two of seven staff screened and three of six residents screened. Three residents with KPCOs had recent hospitalizations and shared a bathroom in the GH; one overlapped on the same hospital unit as a patient with KPC-producing Klebsiella oxytoca . Staff with KPCOs were caregivers who had extensive contact with residents and their environment and no IPC training. Gaps in hand hygiene and environmental cleaning were observed. Organism was recovered from 4 positive screening tests as well as from blood cultures from the index case; all were KPC-producing E. coli . WGS showed that the five E. coli isolates were closely related, consistent with transmission, and harbored the same KPC variant as the K. oxytoca . No new cases occurred after IPC was improved. Conclusion A GH resident likely acquired KPCOs during a recent hospitalization, and extensive transmission among GH residents and staf

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1292. HIV Pre-Exposure Prophylaxis (PrEP) Implementation at Silom Community Clinic in Bangkok, Thailand, 2016–2018

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Open Forum Infectious Diseases 2018年第SUPPL_1期5卷 S394–S395页

作者： Kung, Vanessa Pattanasin, Sarika Ungsedhapand, Chaiwat Wimonsate, Wipas Thigpen, Michael Dunne, Eileen Department of Medicine University of Wisconsin School of Medicine and Public Health Madison Wisconsin HIV/STD Research Program Thailand Ministry of Public Health – U.S. Centers for Disease Control and Prevention Collaboration Nonthaburi Thailand Division of HIV/AIDS Prevention U.S. Centers for Disease Control and Prevention Atlanta Georgia

BackgroundSince 2014, the Thailand National Guidelines have recommended pre-exposure prophylaxis (PrEP) to prevent HIV among persons at risk. In March 2016, Silom Community Clinic (SCC) began PrEP provision to men who...

Background Since 2014, the Thailand National Guidelines have recommended pre-exposure prophylaxis (PrEP) to prevent HIV among persons at risk. In March 2016, Silom Community Clinic (SCC) began PrEP provision to men who have sex with men (MSM) and transgender women (TGW) in Bangkok, Thailand. Methods SCC staff routinely counseled MSM and TGW attending HIV voluntary counseling and testing about PrEP. If clients believed that they were at substantial risk of HIV and were interested in PrEP, they could receive PrEP after screening that included HIV and renal function testing. Eligible clients received a 30-day supply of daily oral tenofovir-emtricitabine costing 800 Baht (30 USD), and completed a baseline computer-assisted self-interview (CASI) on knowledge and behaviors. At every 3-month follow-up, PrEP clients had a CASI on adherence; if they were interested in discontinuation of PrEP, they completed a CASI that included reasons for discontinuation. We conducted a descriptive analysis of baseline and follow-up CASI results. Results From March 2016 to February 2018, 192 clients were prescribed PrEP, and 80 (42%) continued PrEP for at least 6 months. The median age of clients starting PrEP was 31 years (range, 17–67 years), and 98% were MSM. Overall, most (77%) reported at least 1 of four risk behaviors in the last 3 months; among the 148, 120 (81%) had a sex partner with unknown or positive HIV status, 99 (67%) had anal sex without a condom, 22 (15%) reported an STI, and 16 (11%) received money or goods in exchange for sex. Among the 166 clients who returned for at least one follow-up visit, 135 (81%) completed the CASI at the last follow-up visit; of those, 106 (78%) reported 100% adherence to daily PrEP in the last 7 days, and 126 (93%) reported ≥80% adherence in the last 30 days. Of the 36 clients who discontinued PrEP and completed CASI, 33% reported the reason for discontinuation was no current HIV risk (33%); most (69%) reported that they would consider PrEP in t

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837. Prior Hospitalizations Among Cases of Community-Associated Clostridioides difficile Infection—10 US States, 2014–2015

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Open Forum Infect Dis 2019年第SUPPL 2期6卷 S9-S9页

作者： Kelly M Hatfield James Baggs Lisa Gail Winston Erin Parker Helen Johnston Geoff Brousseau Danyel M Olson Scott Fridkin Lucy Wilson Rebecca Perlmuter Stacy Holzbauer Erin C Phipps Emily B Hancock Ghinwa Dumyati Valerie Ocampo Marion A Kainer Lauren C Korhonen John A Jernigan L Clifford McDonald Alice Guh Centers for Disease Control and Prevention (CDC) Atlanta Georgia Centers for Disease Control and Prevention Atlanta Georgia University of California San Francisco San Francisco California California Emerging Infections Program Oakland California Colorado Department of Public Health and Environment Denver Colorado Yale School of Public Health New Haven Connecticut Emory University and Emory Healthcare Atlanta Georgia University of Maryland Baltimore County Baltimore Maryland Maryland Department of Health Baltimore Maryland University of New Mexico Albuquerque New Mexico New York Rochester Emerging Infections Program at the University of Rochester Medical Center Rochester New York Oregon Health Authority Portland Oregon Tennessee Department of Health Nashville Tennessee Division of Healthcare Quality Promotion CDC Atlanta Georgia

BackgroundDespite overall progress in preventingClostridioides difficileInfection (CDI), community-associated (CA) infections have been steadily increasing. Although the incubation period of CDI is thought to be relat...

Background Despite overall progress in preventing Clostridioides difficile Infection (CDI), community-associated (CA) infections have been steadily increasing. Although the incubation period of CDI is thought to be relatively short, gastrointestinal microbial disruption from remote healthcare exposures (e.g., inpatient antibiotic use) may be associated with CA-CDI. To assess this potential association, we linked CA-CDI infections identified through CDC’s Emerging Infections program (EIP) to Medicare claims data to describe prior healthcare utilization. Methods We defined an EIP CA-CDI case as a positive C. difficile test collected in 2014–2015 from an outpatient or inpatient within 3 days of hospital admission, provided there was no positive test in the prior 8 weeks and no admission to a healthcare facility in the prior 12 weeks. We linked EIP CA-CDI cases aged ≥65 years to a Medicare beneficiary using unique combinations of birthdate, sex, and zip code. Cases were included if they maintained continuous fee-for-service coverage for 1 year prior to the event date. To calculate exposure odds ratios for previous hospitalizations, each case was matched to 5 control beneficiaries on age, sex, and county of residence. We used logistic regression to calculate adjusted matched odds ratios (amOR) that controlled for chronic conditions. Results We successfully linked 2,287/3,367 (68%) EIP CA-CDI cases. Of these, 1,236 cases met inclusion criteria; the median age was 77 years and 63% were female. We identified 69 (5.6%) cases with misclassification of prior healthcare exposures, most of whom (48, 70%) were hospitalized in the 12 weeks prior to their event. Among the 1,167 true CA-CDI cases, 33% were hospitalized in the prior 12 weeks to 1 year. The median number of weeks from prior hospitalization to CDI was 27 (IQR 18–38, Figure 1). Cases had a higher risk of hospitalization than matched controls in the prior 3–6 months (amOR: 2.33, 95% CI: 1.87, 2.90) and 6–12 months (amOR:

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Author Correction: Risk-stratified treatment for drug-susceptible pulmonary tuberculosis

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Nature communications 2025年第1期16卷 4438页

作者： Vincent K Chang Marjorie Z Imperial Patrick P J Phillips Gustavo E Velásquez Payam Nahid Andrew Vernon Ekaterina V Kurbatova Susan Swindells Richard E Chaisson Susan E Dorman John L Johnson Marc Weiner Amina Jindani Thomas Harrison Erin E Sizemore William Whitworth Wendy Carr Kia E Bryant Deron Burton Kelly E Dooley Melissa Engle Pheona Nsubuga Andreas H Diacon Nguyen Viet Nhung Rodney Dawson Radojka M Savic Department of Bioengineering and Therapeutic Sciences University of California San Francisco San Francisco CA USA. UCSF Center for Tuberculosis University of California San Francisco San Francisco CA USA. Division of Pulmonary and Critical Care Medicine University of California San Francisco San Francisco CA USA. Division of HIV Infectious Diseases and Global Medicine University of California San Francisco San Francisco CA USA. Centers for Disease Control and Prevention Atlanta GA USA. University of Nebraska Medical Center Omaha NE USA. Center for Tuberculosis Research Johns Hopkins University School of Medicine Baltimore MA USA. Medical University of South Carolina Charleston SC USA. Case Western Reserve University University Hospitals Cleveland Medical Center Cleveland OH USA. Uganda-Case Western Reserve University Research Collaboration Kampala Uganda. University of Texas Health Science Center at San Antonio and the South Texas Veterans Health Care System San Antonio TX USA. St. George's University of London London UK. Division of Infectious Diseases Vanderbilt University Nashville TN USA. TASK Cape Town Western Cape Cape Town South Africa. Vietnam National Tuberculosis Program-University of California San Francisco Research Collaboration Unit Hanoi Vietnam. National Lung Hospital Hanoi Vietnam. Lung Institute and Division of Pulmonology Department of Medicine University of Cape Town Cape Town South Africa. Department of Bioengineering and Therapeutic Sciences University of California San Francisco San Francisco CA USA. rada.savic@ucsf.edu. UCSF Center for Tuberculosis University of California San Francisco San Francisco CA USA. rada.savic@ucsf.edu.

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Plecanatide-mediated activation of guanylate cyclase-C suppresses inflammation-induced colorectal carcinogenesis in Apc+/Min-FCCC mice

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World Journal of Gastrointestinal Pharmacology and Therapeutics 2017年第1期8卷 47-59页

作者： Wen-Chi L Chang Shet Masih Anusha Thadi Viren Patwa Apoorva Joshi Harry S Cooper Vaseem A Palejwala Margie L Clapper Kunwar Shailubhai Cancer Prevention and Control Program Fox Chase Cancer Center Baruch S.Blumberg Institute Department of Pathology Fox Chase Cancer Center R and D Center Synergy Pharmaceuticals Inc.

AIM To evaluate the effect of orally administered plecanatide on colorectal dysplasia in Apc^(+/Min-FCCC) mice with dextran sodium sulfate(DSS)-induced inflammation. METHODS Inflammation driven colorectal carcinogenes... 详细信息

AIM To evaluate the effect of orally administered plecanatide on colorectal dysplasia in Apc^(+/Min-FCCC) mice with dextran sodium sulfate(DSS)-induced inflammation. METHODS Inflammation driven colorectal carcinogenesis was induced in Apc^(+/Min-FCCC) mice by administering DSS in their drinking water. Mice were fed a diet supplemented with plecanatide(0-20 ppm) and its effect on the multiplicity of histopathologically confirmed polypoid,flat and indeterminate dysplasia was evaluated. Plecanatide-mediated activation of guanylate cyclase-C(GC-C) signaling was assessed in colon tissues by measuring cyclic guanosine monophosphate(cG MP) by ELISA, protein kinase G-II and vasodilator stimulated phosphoprotein by immunoblotting. Ki-67, c-myc and cyclin D1 were used as markers of proliferation. Cellular levels and localization of b-catenin in colon tissues were assessed by immunoblotting and immunohistochemistry, respectively. Uroguanylin(UG) and GC-C transcript levels were measured by quantitative reverse transcription polymerase chain reaction(RT-PCR). A mouse cytokine array panel was used to detect cytokines in the supernatant of colon explant cultures. RESULTS Oral treatment of Apc^(+/Min-FCCC) mice with plecanatide produced a statistically significant reduction in the formation of inflammation-driven polypoid, flat and indeterminate dysplasias. This anti-carcinogenic activity of plecanatide was accompanied by activation of cG MP/GC-C signaling mediated inhibition of Wnt/b-catenin signaling and reduced proliferation. Plecanatide also decreased secretion of pro-inflammatory cytokines(IL-6, IL-1 TNF), chemokines(MIP-1, IP-10) and growth factors(GCSF and GMCSF) from colon explants derived from mice with acute DSS-induced inflammation. The effect of plecanatidemediated inhibition of inflammation/dysplasia on endogenous expression of UG and GC-C transcripts was measured in intestinal tissues. Although GC-C expression was not altered appreciably, a statistically significant i

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