Search PubMed⌕ Search

Biomedical subjects

M Lipkin

Publications and source records attributed to M Lipkin.

At least 73 records · Page 4Linked to original sources
PubMed1995

Inhibition of Western-diet induced hyperproliferation and hyperplasia in mouse colon by two sources of calcium.

A Western-style diet containing high-fat and phosphate, and low calcium and vitamin D was fed to mice for 20 weeks. Starting at week 8, subgroups of animals received the Western-style diet supplemented by two different calcium sources: tricalcium phosphate and calcium citrate malate. Hyperproliferation (increased [3H]thymidine-labelled cells/colonic crypt) and hyperplasia (increased total epithelial cells/crypt) developed in the sigmoid colon after 8 weeks of feeding the Western-style diet confirming previous results, and these were reversed at later periods by the addition of the two calcium sources to the Western-style diet. Findings indicate that the modified colonic epithelial cell hyperproliferation and hyperplasia which have been associated with subsequent development of colonic neoplasia, are induced in mice fed a Western-style diet, and the addition of calcium to the diet inhibited their development in the colonic mucosa.

Animals↗
PubMed1994

A targeted chain-termination mutation in the mouse Apc gene results in multiple intestinal tumors.

Germ-line mutations in the human adenomatous polyposis coli (APC) gene result in familial adenomatous polyposis, an autosomal dominant disorder characterized by the early onset of multiple adenomatous polyps in the large bowel with a high likelihood of developing colorectal carcinomas. To understand the role of APC in intestinal tumor formation, we have introduced a chain-termination mutation in the 15th exon of the mouse Apc gene and employed it to modify the endogenous gene by homologous recombination in embryonic stem cells. Mice which are heterozygous for the Apc gene modification progressively develop intestinal tumors in a manner that is similar to that observed in patients with familial adenomatous polyposis and in mice which carry a mutation called multiple intestinal neoplasia (Min). Our results indicate that the Apc gene modification is a critical event in the initiation of intestinal tumor formation and results in an autosomal dominant predisposition toward development of spontaneous colonic and intestinal tumors in mice.

Adenomatous Polyposis Coli↗
PubMed1994

General internal medicine.

Internists advanced toward a patient care model based on critical, qualitative, and quantitative assessment of clinical care processes and outcomes. The complete internist must consider social context as well as traditional risk factors in promoting the health of patients.

Internal Medicine↗
PubMed1994

Expression of plasminogen activator inhibitor type 1 (PAI-1) by HT-29di human large bowel carcinoma cells is modulated as a function of epithelial differentiation.

Highly differentiated epithelial populations (36% mucin-producing cells; sixfold increase in alkaline phosphatase activity; development of flat, substrate-adherent, entero-cytic foci) were induced upon in vitro exposure of HT-29di human colon carcinoma cells to sodium butyrate (NaB). 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] (10(-7) M) and the ionophore A23187 (0.5 microM) significantly augmented (two to threefold) NaB-induced HT-29di differentiation, whereas 1,25-(OH)2D3 or A23187 alone were not effective. Induction reflected specific changes in protein abundance, involving, most notably, a differentiation-associated increase in the expression and substrate-deposition of a 47-kDa protein with pI/mw two-dimensional map coordinates and immunochemical properties identical to that of plasminogen activator inhibitor type 1 (PAI-1), a major regulator of the pericellular proteolytic cascade. Culture of HT-29di cells in medium of either high (2.5 mM) or low (0.25 mM) Ca2+ concentration did not affect the incidence of 'spontaneous' differentiation, although NaB-induced goblet cell and enterocytic maturation was Ca(2+)-dependent. The inability of 1,25-(OH)2D3, A23187 or modulated Ca2+ levels alone (i.e., in the absence of NaB) to effect differentiation of HT-29di cells and the Ca(2+)-dependence of the NaB response indicate that NaB and Ca2+ act co-operatively to induce colonic epithelial maturation in vitro.

Alkaline Phosphatase↗
PubMed1994

Mammary ductal epithelial cell hyperproliferation and hyperplasia induced by a nutritional stress diet containing four components of a western-style diet.

We have studied effects of several nutrients on the proliferation of mammary ductal epithelial cells in C57BL/6J virgin female mice, using morphometry and [3H]dT in vivo labeling. A nutritional stress diet was given based on the AIN-76A semi-synthetic diet modified to contain four significant risk factors of a Western-style diet: high fat and phosphate and decreased calcium and vitamin D. The numbers of large, intermediate and terminal ducts and proliferating epithelial cells in mammary glands were assayed in control and stress diet groups. An increased number of mammary ducts and increased number of proliferating cells were found at the level of the small terminal ducts, a cancer-prone region in the mammary gland in the stress diet group compared to the control group after 20 weeks of diet administration. Thus, mammary terminal ductal hyperproliferation, expansion in the size of the proliferative epithelial cell compartment and excessive duplication of mammary ductal epithelial cells were found after this Western-style diet containing decreased dietary calcium and vitamin D. These changes are similar to those developing in colonic epithelium of mice maintained on the same diets and during chemically induced colonic carcinogenesis.

Animals↗
PubMed1994

Surrogate endpoint biomarker assays in phase II chemoprevention clinical trials.

Surrogate endpoint biomarker (SEB) assays carried out in rodent models have benefitted from large amounts of available colonic tissue, abundant well-aligned colonic crypts, and population groups with fairly uniform biological characteristics. In contrast, SEB assays in human colon studies have often been carried out on small groups of subjects, without the advantages inherent in rodent studies. Some factors that contribute to variations in human colon SEB assays include differences in genetic background, the extent and duration of previous colonic diseases, degree of previous chronic irritation to the colonic mucosa, the initial levels of nutrients ingested prior to the study, administration of large volumes of fluid prior to SEB measurement which induce hypermetabolic and then quiescent changes in the mucosa, failure to use strict morphologic criteria in counting colonic crypts, and availability of only a small number of crypts for analysis. Measurements of adenoma recurrence over short durations are limited by factors that include a large potential miss-rate of small adenomas, a window of observation with short duration which limits the stage of adenoma observed, and the consequent inability to measure mechanisms that a chemopreventive intervention is affecting in a different stage of adenoma development.

Animals↗
PubMed1994

Summary of recommendations for colonic biomarker studies of candidate chemopreventive compounds in phase II clinical trials.

New genetic, morphologic, proliferative and differentiation-associated biomarkers are available for study in Phase II chemoprevention clinical trials. These biomarkers have potential as surrogate intermediate endpoints for cancer incidence and eventual tumor inhibition. At this meeting, approaches to improve the standardization and quality control of biomarker assays were considered. Useful biomarkers should be amenable to quality control monitoring; sensitive, specific, and precise; sensitive to modulation by chemopreventive agents; and simple enough to be performed routinely in research or clinical laboratories. Human studies have more factors that contribute to biomarker assay variation than rodent studies. These include: (1) wider differences in genetic background of study subjects; (2) differing extent and duration of previous colonic diseases; (3) varying amounts of chronic irritation in the colonic mucosa of "normal" subjects induced by exposure to dietary and other factors; (4) differing initial levels of study nutrients ingested prior to the study; (5) administration of fluids prior to biomarker measurement which are followed by biopsies after hypermetabolic changes become quiescent; (6) failure to use strict morphologic criteria in counting fewer available human colonic crypts; (7) amplifying field variations in colonic mucosa by decreasing the number of colonic crypts counted; (8) colonoscopic miss-rate of adenomas; (9) a clinical trial window of observation of short duration which limits the stage of adenoma development that is measured; and (10) failure to measure the activity of a chemopreventive agent during the stage of adenoma development in which it is active. Some of these points are relevant to chemopreventive agents used in clinical trials involving other organs.(ABSTRACT TRUNCATED AT 250 WORDS)

Anticarcinogenic Agents↗
PubMed1993

Correlation of epithelial proliferation and squamous esophageal histology in 1185 biopsies from Linxian, China.

Epithelial proliferation is an active area of research in gastrointestinal cancer, but only a few studies have examined the relationship of esophageal epithelial proliferation and squamous histologic findings in populations with high rates of squamous esophageal cancer. In order to study this correlation, tritiated thymidine labeling was performed on 1185 esophageal biopsies from 745 residents of Linxian, China, a county with some of the highest esophageal-cancer rates in the world. Total labeling index (TLI = total labeled cells/total cells counted) was used to measure the amount of proliferation, and the proportion of labeled cells found in cell layers 4 to 10 (labeled cell fraction 4 plus, LF4+ = labeled cells in layers 4-10/total labeled cells) was used to measure the vertical distribution of proliferation. Of the biopsies, 979 were histologically normal, 51 showed acanthosis, 35 showed esophagitis, 116 showed squamous dysplasia, and 6 showed invasive squamous cancer. The mean values of both proliferation variables, stratified by histologic diagnosis, showed the following relationships: normal = acanthosis < esophagitis = dysplasia < cancer. The ranges of proliferation values overlapped extensively in all biopsy categories, so that measuring proliferation could not substitute for histologic diagnosis. It remains to be seen whether proliferation values, histologic diagnoses, or some combination of these methods is most predictive of subsequent esophageal cancer.

Adult↗
PubMed1993

Morphological and morphometric measurements in colorectal mucosa of subjects at increased risk for colonic neoplasia.

Measurements of intermediate biomarkers have recently increased, attempting to provide useful information about cancer risk. We report morphological findings in rectal mucosal biopsies from patients at low risk and at high risk for colorectal cancer. Rectal biopsies were analyzed from fourteen Seventh-Day Adventist (SDA) subjects at low risk and from twenty-seven members of families with hereditary nonpolyposis colonic cancer (HNPCC) at higher risk. The following measurements were made on rectal crypts: length of crypts, numbers of cells, diameter of the surface, middle and base of the crypts and infiltration of inflammatory cells into the lamina propria. Findings indicated morphological differences in normal-appearing rectal mucosa of individuals in the HNPCC group compared with SDA subjects (P < 0.05). They included shorter crypts with fewer epithelial cells and increased cellular infiltration in the mucosa of HNPCC subjects compared with SDA subjects, suggesting minimal inflammation, and an early stage of crypt atrophy in the rectal mucosa of subjects at higher risk for colonic neoplasia.

Colonic Neoplasms↗
PubMed1993

Abnormal rectal cell proliferation and p52/p35 protein expression in patients with ulcerative colitis.

We evaluated the presence of cell proliferation and antigenic abnormalities in rectal biopsies from 37 patients affected by ulcerative colitis and 15 controls. The study was carried out by thymidine labeling and immunochemistry, using antibodies against specific cytoskeletal-associated proteins (p52, p35, alpha-actinin). Among ulcerative colitis patients, 24 had an immunofluorescence pattern similar to that of controls, while 13 showed an abnormal distribution of one or more proteins (p52 alone or p52 and either p35 or alpha-actinin) within the rectal crypts. Patients showed a shift of the proliferative compartment towards the top of the rectal crypts compared with controls. This finding was more evident in patients with p52 or p35 abnormalities. Proliferative and antigenic defects were not related either to age or the duration of colitis. These phenotypic changes might be a biomarker of increased risk of colon cancer in ulcerative colitis.

Adult↗
PubMed1993

Effects of caloric restriction and dietary fat on epithelial cell proliferation in rat colon.

Epidemiological studies indicate that caloric intake and dietary fat content influence colonic carcinogenesis. In rodents, caloric restriction reduces, and some fats increase, carcinogen-induced colon cancer incidence. The present study was designed to investigate the effects of caloric restriction on colonic cell proliferation (CCP) in carcinogen-treated or control rats fed low- or high-fat diets. F344 rats were treated with azoxymethane (15 mg/kg x2) and then fed an isocaloric AIN 76A diet containing either 5 or 23% corn oil, ad libitum or calorie-restricted to 70 or 80% of the kilocalories consumed by ad libitum rats. Biopsies of the distal colon were taken at 10 and 20 weeks, and rats were sacrificed at 21 or 34 weeks on the experimental diets. Distal CCP was determined by microautoradiography after [3H]thymidine labeling in vitro or presacrifice administration in vivo. The labeling index and number of labeled cells per crypt column were significantly reduced by caloric restriction at all time points (10, 20, 21, 34 weeks). Caloric restriction reduced CCP in high fat- and low fat-fed rats and in azoxymethane-treated and control rats. High fat resulted in decreased CCP in the distal colon compared to low fat at 34 weeks but not earlier. The findings indicate that: (a) caloric restriction is effective in favorably modulating CCP, an intermediate biomarker of colon cancer risk; (b) a high fat ad libitum diet, which increased tumor yield, does not increase distal colon proliferation; (c) dietary fat intake alters proliferation in a manner differing from that induced by changing dietary caloric intake.

Animals↗
PubMed1993

Medical interviewing and interpersonal skills teaching in US medical schools. Progress, problems, and promise.

OBJECTIVE: To assess educational practices, problems, and needs in the teaching of medical interviewing and interpersonal skills. DESIGN: Questionnaires sent to curricular deans and introductory course leaders at all US medical schools in 1991. RESULTS: Of 130 programs, 114 deans (88%) and 92 course directors (71%) responded. Respondents indicated some advances since a similar survey in 1977: Virtually all medical schools now offer teaching in medical interviewing and interpersonal skills. More faculty from a greater variety of disciplines are involved in this teaching. Most programs feature observation and feedback of students' interviews with patients, and use a variety of effective teaching methods, including simulated patients and role-playing, both little used in 1977. The majority of schools address students' personal growth through discussion or support groups. However, there are problems. Most schools lack a faculty development process. About half of the introductory courses on medical interviewing take place within physical diagnosis courses, often, it appears, without systematic observation, feedback, and evaluation of student skills. Many programs do not explicitly incorporate certain educational principles into their course designs. As in 1977, there appears to be little coordination or sequencing of teaching interpersonal skills throughout the curriculum in most medical schools. Most deans identified significant barriers to improving teaching. CONCLUSIONS: While a number of educational advances have occurred there is still great variation in the quality and intensity of courses offered in US medical schools. However, the pace of progress bodes well for the future.

Curriculum↗
PubMed1993

Expansion of the epithelial cell proliferative compartment and frequency of adenomatous polyps in the colon correlate with the strength of family history of colorectal cancer.

Expansion of the proliferative compartment of epithelial cells in colonic crypts and colonic adenomas have been described as phenotypic precursors to colon cancer in individuals affected with hereditary or sporadic colon cancer. This study measured the size of the proliferative compartment in colonic crypts and the frequency of adenomas in asymptomatic members of families having sporadic colorectal cancer. The subjects were divided into 2 groups according to the frequency of colorectal cancer in their families. A shift of the compartment of proliferating epithelial cells toward the lumenal surface of colonic crypts was seen in the group of subjects with a stronger family history of colorectal cancer, with significant differences in the numbers of proliferative cells in the upper and the lower crypt compartments (P < 0.05) and in the fraction of proliferative cells at the highest compartment at the lumenal surface of the crypts (P < 0.05). Cell proliferation patterns in normal-appearing mucosa of the 2 groups revealed no difference in whole crypt [3H]thymidine labeling index. Colonoscopic examination of the 56 subjects revealed an overall prevalence of adenomas of 21%; when stratified by frequency of colorectal cancer in their families, 3 of 22 subjects (14%) with a weaker family history had adenomas, while 9 of 34 (26%) with a stronger family history had adenomas. Thus, parallel abnormalities of colonic epithelial cell proliferation and neoplasia were seen in individuals with a family history of colorectal cancer, both of which were more pronounced with increasing strength of family history. This observation provides further evidence of relationships among these factors in the etiology of "sporadic" colorectal cancer.

Adenoma↗