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Sex disparity in colonic adenomagenesis involves promotion by male hormones, not protection by female hormones
It recently has been recognized that men develop colonic adenomas and carcinomas at an earlier age and at a higher rate than women. In the Apc ᴾⁱʳᶜ/⁺ (Pirc) rat model of early colonic cancer, this sex susceptibility was recapitulated, with male Pirc rats developing twice as many adenomas as females. Analysis of large datasets revealed that the Apc ᴹⁱⁿ/⁺ mouse also shows enhanced male susceptibility to adenomagenesis, but only in the colon. In addition, WT mice treated with injections of the carcinogen azoxymethane (AOM) showed increased numbers of colonic adenomas in males. The mechanism underlying these observations was investigated by manipulation of hormonal status. The preponderance of colonic adenomas in the Pirc rat model allowed a statistically significant investigation in vivo of the mechanism of sex hormone action on the development of colonic adenomas. Females depleted of endogenous hormones by ovariectomy did not exhibit a change in prevalence of adenomas, nor was any effect observed with replacement of one or a combination of female hormones. In contrast, depletion of male hormones by orchidectomy (castration) markedly protected the Pirc rat from adenoma development, whereas supplementation with testosterone reversed that effect. These observations were recapitulated in the AOM mouse model. Androgen receptor was undetectable in the colon or adenomas, making it likely that testosterone acts indirectly on the tumor lineage. Our findings suggest that indirect tumor-promoting effects of testosterone likely explain the disparity between the sexes in the development of colonic adenomas.
Significance The age-adjusted incidence of colonic adenomas and colorectal cancer is higher in men than in women. In a careful analysis of two established animal models, we found that castration reduced, and testosterone supplementation restored, the number of adenomas in the male rat and mouse colon, whereas ovariectomy and replacement of female hormones had no measureable effect on colonic adenomagenesis. In Min mice, in which most of the tumors arise in the small intestine, this testosterone-dependent sexual dimorphism in mice was specific to the colon. Our results support a paradigm shift: Testosterone promotes early adenomagenesis through an indirect mechanism, explaining the enhanced susceptibility of males to colonic adenomagenesis in the human, rat, and mouse.
Journal Article
Integration of genomics, metagenomics, and metabolomics to identify interplay between susceptibility alleles and microbiota in adenoma initiation
Colorectal cancer (CRC) is a multifactorial disease resulting from both genetic predisposition and environmental factors including the gut microbiota (GM), but deciphering the influence of genetic variants, environmental variables, and interactions with the GM is exceedingly difficult. We previously observed significant differences in intestinal adenoma multiplicity between C57BL/6 J-Apc
(B6-Min/J) from The Jackson Laboratory (JAX), and original founder strain C57BL/6JD-Apc
(B6-Min/D) from the University of Wisconsin.
To resolve genetic and environmental interactions and determine their contributions we utilized two genetically inbred, independently isolated Apc
mouse colonies that have been separated for over 20 generations. Whole genome sequencing was used to identify genetic variants unique to the two substrains. To determine the influence of genetic variants and the impact of differences in the GM on phenotypic variability, we used complex microbiota targeted rederivation to generate two Apc mutant mouse colonies harboring complex GMs from two different sources (GMJAX originally from JAX or GMHSD originally from Envigo), creating four Apc
groups. Untargeted metabolomics were used to characterize shifts in the fecal metabolite profile based on genetic variation and differences in the GM.
WGS revealed several thousand high quality variants unique to the two substrains. No homozygous variants were present in coding regions, with the vast majority of variants residing in noncoding regions. Host genetic divergence between Min/J and Min/D and the complex GM additively determined differential adenoma susceptibility. Untargeted metabolomics revealed that both genetic lineage and the GM collectively determined the fecal metabolite profile, and that each differentially regulates bile acid (BA) metabolism. Metabolomics pathway analysis facilitated identification of a functionally relevant private noncoding variant associated with the bile acid transporter Fatty acid binding protein 6 (Fabp6). Expression studies demonstrated differential expression of Fabp6 between Min/J and Min/D, and the variant correlates with adenoma multiplicity in backcrossed mice.
We found that both genetic variation and differences in microbiota influences the quantitiative adenoma phenotype in Apc
mice. These findings demonstrate how the use of metabolomics datasets can aid as a functional genomic tool, and furthermore illustrate the power of a multi-omics approach to dissect complex disease susceptibility of noncoding variants.
Journal Article
الطب النفسي الجسدي : مقدمة في الطب النفسي التواصلي
تضمنت محتويات الكتاب الموضوعات التالية : الفصل الأول: عملية الاستشارة. الفصل الثاني : تقييم قدرة المرضى على اتخاذ القرار. الفصل الثالث : مواجهة المريض الصعب. الفصل الرابع : علم الأدوية النفسية لدى المعتلين طبيا. الفصل الخامس : تقييم مخاطر الانتحار. الفصل السادس : تقييم المريض العنيف وعلاجه. الفصل السابع : تقييم اضطراب الهذيان وعلاجه. الفصل الثامن : التدبير العلاجي للاضطراب الجسدية الشكل. الفصل التاسع : التدبير العلاجي للاضطراب المفتعل والتمارض. الفصل العاشر : الهياج لدى مرضى الخرف. الفصل الحادي عشر: الاكتئاب وأمراض القلب. الفصل الثاني عشر : علاج اكتئاب ما بعد السكتة. الفصل الثالث عشر : المظاهر النفسية لمرضى الباركنسون. الفصل الرابع عشر : علاج الاكتئاب لدى مرضى إصابة الدماغ الرضحية. الفصل الخامس عشر : التدبير العلاجي للجوانب النفسية للاضطرابات الصرعية. الفصل السادس عشر : الكدر والاكتئاب في رعاية مرضى السرطان. الفصل السابع عشر : الاكتئاب لدى مرضى التهاب الكبد (C). الفصل الثامن عشر : الجوانب النفسية لمتلازمة العوز المناعي المكتسب (الإيدز). الفصل العشرون : علاج المتلازمات النفسية بسبب أمراض الغدد الصماء والأمراض الاستقلابية. الفصل الحادي والعشرون : التدبير العلاجي للأثار الانسحابية للامتناع عن الكحول وأمور أخرى متعلقة بالامتناع عن مواد أخرى. الفصل الثاني والعشرون: التدبير العلاجي للاكتئاب في فترة الحمل. الفصل الثالث والعشرون : الجوانب النفسية لعمليات زرع الأعضاء. الفصل الرابع والعشرون : التقييم النفسي قبل جراحات السمنة. الفصل الخامس والعشرون : الرعاية النفسية في مرحلة نهاية العمر : رعاية المحتضرين والطب الملطف. الفصل السادس والعشرون : ضعف المعنويات في المحيط الطبي. الفصل السابع والعشرون : العلاج النفسي للمرضى الطبيين المنومين في المستشفيات. الفصل الثامن والعشرون : ردود فعل الأطفال، وعواقب المرض والإقامة بالمستشفى عليهم، وانتقال الرعاية الطبية لهم من أماكن الأطفال الى أماكن البالغين.
Book
The utility of Apc-mutant rats in modeling human colon cancer
Prior to the advent of genetic engineering in the mouse, the rat was the model of choice for investigating the etiology of cancer. Now, recent advances in the manipulation of the rat genome, combined with a growing recognition of the physiological differences between mice and rats, have reignited interest in the rat as a model of human cancer. Two recently developed rat models, the polyposis in the rat colon (Pirc) and Kyoto Apc Delta (KAD) strains, each carry mutations in the intestinal-cancer-associated adenomatous polyposis coli (Apc) gene. In contrast to mouse models carrying Apc mutations, in which cancers develop mainly in the small intestine rather than in the colon and there is no gender bias, these rat models exhibit colonic predisposition and gender-specific susceptibility, as seen in human colon cancer. The rat also provides other experimental resources as a model organism that are not provided by the mouse: the structure of its chromosomes facilitates the analysis of genomic events, the size of its colon permits longitudinal analysis of tumor growth, and the size of biological samples from the animal facilitates multiplexed molecular analyses of the tumor and its host. Thus, the underlying biology and experimental resources of these rat models provide important avenues for investigation. We anticipate that advances in disease modeling in the rat will synergize with resources that are being developed in the mouse to provide a deeper understanding of human colon cancer.
Journal Article
Validating the knowledge represented by a self-organizing map with an expert-derived knowledge structure
Professionals are reluctant to make use of machine learning results for tasks like curriculum development if they do not understand how the results were generated and what they mean. Visualizations of peer reviewed medical literature can summarize enormous amounts of information but are difficult to interpret. This article reports the validation of the meaning of a self-organizing map derived from the Medline/PubMed index of peer reviewed medical literature by its capacity to coherently summarize the references of a core psychiatric textbook.
Reference lists from ten editions of Kaplan and Sadock's Comprehensive Textbook of Psychiatry were projected onto a self-organizing map trained on Medical Subject Headings annotating the complete set of peer reviewed medical research articles indexed in the Medline/PubMed database (MedSOM). K-means clustering was applied to references from every edition to examine the ability of the self-organizing map to coherently summarize the knowledge contained within the textbook.
MedSOM coherently clustered references into six psychiatric knowledge domains across ten editions (1967-2017). Clustering occurred at the abstract level of broad psychiatric practice including General/adult psychiatry, Child psychiatry, and Administrative psychiatry.
The uptake of visualizations of published medical literature by medical experts for purposes like curriculum development depends upon validation of the meaning of the visualizations. The current research demonstrates that a self-organizing map (MedSOM) can validate the stability and coherence of the references used to support the knowledge claims of a standard psychiatric textbook, linking the products of machine learning to a widely accepted standard of knowledge.
Journal Article
Evaluation of a Tumor-Targeting, Near-Infrared Fluorescent Peptide for Early Detection and Endoscopic Resection of Polyps in a Rat Model of Colorectal Cancer
The goal of these studies was to use a tumor-targeting, near-infrared (NIR) fluorescent peptide to evaluate early detection and to guide surgical removal of polyps in a genetically engineered rat model of spontaneous colorectal cancer. This peptide, LS301, was conjugated to Cy7.5 and applied topically to the colon of adenoma-bearing Pirc rats. Ten minutes after administration, rats underwent targeted NIR laser colonoscopy. Rats were also evaluated by white light colonoscopy and narrow-band imaging, for comparison to the NIR technique. Unlike white light and narrow-band colonoscopy, NIR imaging detected unexpected flat lesions in young Pirc rats. NIR imaging was also used to assess resection margins after electrocauterization of polyps. Tumor margins remained negative at 5 weeks postsurgery, demonstrating successful polypectomy. The present studies show that NIR-targeted colonoscopy is an attractive strategy to improve screening for and resection of colorectal neoplasia.
Journal Article
target-selected Apc-mutant rat kindred enhances the modeling of familial human colon cancer
Progress toward the understanding and management of human colon cancer can be significantly advanced if appropriate experimental platforms become available. We have investigated whether a rat model carrying a knockout allele in the gatekeeper gene Adenomatous polyposis coli (Apc) recapitulates familial colon cancer of the human more closely than existing murine models. We have established a mutagen-induced nonsense allele of the rat Apc gene on an inbred F344/NTac (F344) genetic background. Carriers of this mutant allele develop multiple neoplasms with a distribution between the colon and small intestine that closely simulates that found in human familial adenomatous polyposis patients. To distinguish this phenotype from the predominantly small intestinal phenotype found in most Apc-mutant mouse strains, this strain has been designated the polyposis in the rat colon (Pirc) kindred. The Pirc rat kindred provides several unique and favorable features for the study of colon cancer. Tumor-bearing Pirc rats can live at least 17 months, carrying a significant colonic tumor burden. These tumors can be imaged both by micro computed tomography scanning and by classical endoscopy, enabling longitudinal studies of tumor genotype and phenotype as a function of response to chemopreventive and therapeutic regimes. The metacentric character of the rat karyotype, like that of the human and unlike the acrocentric mouse, has enabled us to demonstrate that the loss of the wild-type Apc allele in tumors does not involve chromosome loss. We believe that the Pirc rat kindred can address many of the current gaps in the modeling of human colon cancer.
Journal Article
Fischer-344 Tp53-knockout rats exhibit a high rate of bone and brain neoplasia with frequent metastasis
Somatic mutations in the Tp53 tumor suppressor gene are the most commonly seen genetic alterations in cancer, and germline mutations in Tp53 predispose individuals to a variety of early-onset cancers. Development of appropriate translational animal models that carry mutations in Tp53 and recapitulate human disease are important for drug discovery, biomarker development and disease modeling. Current Tp53 mouse and rat models have significant phenotypic and genetic limitations, and often do not recapitulate certain aspects of human disease. We used a marker-assisted speed congenic approach to transfer a well-characterized Tp53-mutant allele from an outbred rat to the genetically inbred Fischer-344 (F344) rat to create the F344-Tp53
/Rrrc (F344-Tp53) strain. On the F344 genetic background, the tumor spectrum shifted, with the primary tumor types being osteosarcomas and meningeal sarcomas, compared to the hepatic hemangiosarcoma and lymphoma identified in the original outbred stock model. The Fischer model is more consistent with the early onset of bone and central nervous system sarcomas found in humans with germline Tp53 mutations. The frequency of osteosarcomas in F344-Tp53 homozygous and heterozygous animals was 57% and 36%, respectively. Tumors were highly representative of human disease radiographically and histologically, with tumors found primarily on long bones with frequent pulmonary metastases. Importantly, the rapid onset of osteosarcomas in this promising new model fills a current void in animal models that recapitulate human pediatric osteosarcomas and could facilitate studies to identify therapeutic targets.
Journal Article