Mouse Model of Mutated in Colorectal Cancer Gene Deletion Reveals Novel Pathways in Inflammation and Cancer

© 2019 The Authors Background & Aims: The early events by which inflammation promotes cancer are still not fully defined. The MCC gene is silenced by promoter methylation in colitis-associated and sporadic colon tumors, but its functional significance in precancerous lesions or polyps is not known. Here, we aimed to determine the impact of Mcc deletion on the cellular pathways and carcinogenesis associated with inflammation in the mouse proximal colon. Methods: We generated knockout mice with deletion of Mcc in the colonic/intestinal epithelial cells (MccΔIEC) or in the whole body (MccΔ/Δ). Drug-induced lesions were analyzed by transcriptome profiling (at 10 weeks) and histopathology (at 20 weeks). Cell-cycle phases and DNA damage proteins were analyzed by flow cytometry and Western blot of hydrogen peroxide–treated mouse embryo fibroblasts. Results: Transcriptome profiling of the lesions showed a strong response to colon barrier destruction, such as up-regulation of key inflammation and cancer-associated genes as well as 28 interferon γ–induced guanosine triphosphatase genes, including the homologs of Crohn's disease susceptibility gene IRGM. These features were shared by both Mcc-expressing and Mcc-deficient mice and many of the altered gene expression pathways were similar to the mesenchymal colorectal cancer subtype known as consensus molecular subtype 4 (CMS4). However, Mcc deletion was required for increased carcinogenesis in the lesions, with adenocarcinoma in 59% of MccΔIEC compared with 19% of Mcc-expressing mice (P =.002). This was not accompanied by hyperactivation of β-catenin, but Mcc deletion caused down-regulation of DNA repair genes and a disruption of DNA damage signaling. Conclusions: Loss of Mcc may promote cancer through a failure to repair inflammation-induced DNA damage. We provide a comprehensive transcriptome data set of early colorectal lesions and evidence for the in vivo significance of MCC silencing in colorectal cancer

In vitro leishmanicidal, antibacterial and antitumour potential of anhydrocochlioquinone A obtained from the fungus Cochliobolus sp

The bioassay-guided fractionation of the ethyl acetate extract of the fungus Cochliobolus sp. highlighted leishmanicidal activity and allowed for anhydrocochlioquinone A (ANDC-A) isolation. MS, 1D and 2D NMR spectra of this compound were in agreement with those published in the literature. ANDC-A exhibited leishmanicidal activity with EC50value of 22.4 \uc2\ub5g/mL (44 \uce\ubcM) and, when submitted to the microdilution assay against Gram-positive and Gram-negative bacteria, showed a minimal inhibitory concentration against Staphylococcus aureus ATCC 25295 of 128 \uce\ubcg/mL (248.7 \uce\ubcM). It was also active against five human cancer cell lines, showing IC50values from 5.4 to 20.3 \uce\ubcM. ANDC-A demonstrated a differential selectivity for HL-60 (SI 5.5) and THP-1 (SI 4.3) cell lines in comparison with Vero cells and was more selective than cisplatin and doxorubicin against MCF-7 cell line in comparison with human peripheral blood mononuclear cells. ANDC-A was able to eradicate clonogenic tumour cells at concentrations of 20 and 50 \uce\ubcM and induced apoptosis in all tumour cell lines at 20 \uce\ubcM. These results suggest that ANDC-A might be used as a biochemical tool in the study of tumour cells biochemistry as well as an anticancer agent with durable effects on tumours

Availability of substance abuse treatment services in Spanish: A GIS analysis of Latino communities in Los Angeles County, California

<p>Abstract</p> <p>Background</p> <p>The percentage of Latino clients entering outpatient substance abuse treatment (OSAT) in the United States has increased significantly in the past 10 years. Evidence suggests that a lack of services in Spanish is a significant barrier to treatment access among Latinos.</p> <p>Methods</p> <p>Using a geographic information system (GIS) approach, data from the U.S. Census Bureau and the National Survey of Substance Abuse Treatment Services (N-SSATS) were analyzed to determine the geographic distance between OSAT facilities with services in Spanish and Latino communities throughout Los Angeles County, CA. Data from N-SSATS were also analyzed using logistic regression models to examine organizational characteristics and their association with offering services in Spanish. Our GIS methods are tested in their ability to provide baseline measures to inform future analysis comparing changes in demography and service infrastructure.</p> <p>Results</p> <p>GIS analysis revealed cold spots representing high-density Latino communities with extensive travel distance to facilities offering services in Spanish. The average linear distance between Latino communities and facilities offering Spanish-language services ranged from 2 to 6 miles, while the location of the cold spots pointed to a need for services in Spanish in a particular subregion of the county. Further, secondary data analysis revealed that, on average, being privately owned (<it>OR </it>= .23, 95% CI = 0.06-0.90) was associated with a lower likelihood of providing services in Spanish compared to public facilities. Additionally, a facility with a state license (<it>OR </it>= 2.08, 95% CI = 1.12-3.88) or a higher number of Medicaid recipients (<it>OR </it>= 2.98, 95% CI = 1.76-5.05) was twice as likely to offer services in Spanish.</p> <p>Conclusion</p> <p>Despite the significant presence of Latinos in L.A. County in 2000, low capacity was found in discrete Latino communities in terms of offering OSAT services in Spanish. Funding and regulation play a significant role in facilities' capacity to offer these services. Future studies should build from our multi-method approach to compare changes in population demography and system infrastructure and inform health care policy that seeks to improve providers' capacity to provide linguistically competent care.</p

State recognition for ‘contested languages’: a comparative study of Sardinian and Asturian, 1992–2010

While the idea of a named language as a separate and discrete identity is a political and social construct, in the cases of Sardinian and Asturian doubts over their respective ‘languageness’ have real material consequences, particularly in relation to language policy decisions at the state level. The Asturian example highlights how its lack of official status means that it is either ignored or subjected to repeated challenges to its status as a language variety deserving of recognition and support, reflecting how ‘official language’ in the Spanish context is often understood in practice as synonymous with the theoretically broader category of ‘language’. In contrast, the recent state recognition of Sardinian speakers as a linguistic minority in Italy (Law 482/1999) illustrates how legal recognition served to overcome existing obstacles to the implementation of regional language policy measures. At the same time, the limited subsequent effects of this Law, particularly in the sphere of education, are a reminder of the shortcomings of top-down policies which fail to engage with the local language practices and attitudes of the communities of speakers recognized. The contrastive focus of this article thus acknowledges the continued material consequences of top-down language classification, while highlighting its inadequacies as a language policy mechanism which reinforces artificial distinctions between speech varieties and speakers deserving of recognition

Mother-to-child transmission of human immunodeficiency virus in aten years period

<p>Abstract</p> <p>Objectives</p> <p>to evaluate mother-to-child transmission (MTCT) rates and related factors in HIV-infected pregnant women from a tertiary hospital between 2000 and 2009.</p> <p>Subjects and method</p> <p>cohort of 452 HIV-infected pregnant women and their newborns. Data was collected from recorded files and undiagnosed children were enrolled for investigation. Statistical analysis: qui-square test, Fisher exact test, Student <it>t </it>test, Mann-Whitney test, ANOVA, risk ratio and confidence intervals.</p> <p>Results</p> <p>MTCT occurred in 3.74%. The study population displayed a mean age of 27 years; 86.5% were found to have acquired HIV through sexual contact; 55% were aware of the diagnosis prior to the pregnancy; 62% were not using HAART. Mean CD4 cell-count was 474 cells/ml and 70.3% had undetectable viral loads in the third trimester. HAART included nevirapine in 35% of cases and protease inhibitors in 55%; Zidovudine monotherapy was used in 7.3%. Mean gestational age at delivery was 37.2 weeks and in 92% by caesarian section; 97.2% received intravenous zidovudine. Use of AZT to newborn occurred in 100% of them. Factors identified as associated to MTCT were: low CD4 cell counts, elevated viral loads, maternal AIDS, shorter periods receiving HAART, other conditions (anemia, IUGR (intra uterine growth restriction), oligohydramnium), coinfecctions (CMV and toxoplasmosis) and the occurrence of labor. Use of HAART for longer periods, caesarian and oral zidovudine for the newborns were associated with a decreased risk. Poor adhesion to treatment was present in 13 of the 15 cases of transmission; in 7, coinfecctions were diagnosed (CMV and toxoplasmosis).</p> <p>Conclusion</p> <p>Use of HAART and caesarian delivery are protective factors for mother-to-child transmission of HIV. Maternal coinfecctions and other conditions were risk factors for MTCT.</p