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M Lipkin

Publications and source records attributed to M Lipkin.

At least 37 records · Page 2Linked to original sources
PubMed1999

Tumorigenesis in Mlh1 and Mlh1/Apc1638N mutant mice.

An3 1 KAL I MutL homologue 1 (MLH1) is a member of the family of proteins required for DNA mismatch repair. Germ-line mutations in MLH1 lead to the cancer susceptibility syndrome hereditary nonpolyposis colorectal cancer (HNPCC). We generated mice carrying a null mutation in the Mlh1 gene. We showed that mice heterozygous and homozygous for the Mlh1 gene are predisposed to developing tumors of the gastrointestinal (GI) tract, lymphomas, and a number of other tumor types. We also examined the role of adenomatous polyposis coli gene (Apc) gene mutations in the GI tumors of Mlh1 mutant mice by different methods and showed that the GI tumors in Mlh1 mice express little or no adenomatous polyposis coli protein. When an Apc gene mutation was bred into the Mlh1 mutant mice, the GI tumor incidence increased 40-100-fold. The wild-type Apc allele in these tumors was found to contain mutations. Together, these results show that we have developed two mouse models for human HNPCC and that the mechanisms of tumor development in the GI tract of these mice involve loss of Apc gene function in a manner very similar to that seen in the GI tumors of HNPCC.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Influence of dietary calcium and vitamin D on diet-induced epithelial cell hyperproliferation in mice.

BACKGROUND: Previous epidemiologic and laboratory studies, including some from our own laboratory, have suggested that a high-fat diet increases risk of cancer development in the pancreas, prostate, colon, and breast and that carcinogenesis in some of these organs may be influenced by alterations in dietary calcium and vitamin D. In this study, we sought to investigate the effect of added dietary calcium or vitamin D on the development of epithelial cell hyperproliferation induced by a Western-style diet in the exocrine pancreas, prostate, and mammary gland of mice. METHODS: Four-week-old C57BL/6J mice were given either a control diet (American Institute of Nutrition [AIN]-76A), a Western-style diet (containing reduced calcium and vitamin D and the fat level of the average human Western diet), or a putative chemopreventive diet (a Western-style diet with the addition of dietary calcium and vitamin D). Nine weeks after dietary intervention, osmotic pumps were implanted in the mice to provide 3 days of bromodeoxyuridine (BrdU) infusion. All P values are two-sided. RESULTS: Mice on the Western-style diet had statistically significant increases in BrdU-labeling indices of epithelial cells in the interlobular (P = .015) and intralobular (P = .012) ducts and centroacinar cells (P = .001) of the pancreatic duct system, the dorsal lobe of the prostate (P = .045), and the terminal ducts of the mammary gland (P = .032), compared with mice in the respective control diet groups. Adding dietary calcium and vitamin D markedly suppressed the Western-style diet-induced hyperproliferation of epithelial cells in those tissues (P = .001-.033). CONCLUSIONS: This study confirms previous findings that a Western-style diet produces hyperproliferation of epithelial cells in several organs and that the changes can be prevented by increasing dietary calcium and vitamin D alone.

Animals↗
PubMed1999

Psychiatry and primary care: two cultures divided by a common cause.

Traditional problems between primary care physicians and psychiatrists have persisted, including inability to understand each other, disrespect, mutual distrust, and competition. Unfortunately, although these two medical specialties, which both use a whole-person approach to the patient, should be pulling together, they are often pulling apart.

Culture↗
PubMed1999

Vitamin D, calcium and prevention of breast cancer: a review.

Several recent epidemiologic and experimental studies have suggested that decreased calcium and vitamin D intake and high dietary fat are associated with mammary gland carcinogenesis. Complete reduction or elimination of human exposure to environmental factors such as high-fat diets is inherently difficult to implement. Recent studies have begun to evaluate a possible role for increased dietary calcium and vitamin D in reducing the risk of colonic and mammary cancers, even in the presence of a high-fat diet. Studies from our laboratory recently found that decreased dietary calcium and vitamin D in a high-fat diet induced adverse changes in the mammary gland and several other organs, which were reversed by increasing dietary calcium and vitamin D; the findings further suggest a possible role for increased dietary calcium and vitamin D in the chemoprevention of these cancers.

Breast Neoplasms↗
PubMed1999

Preclinical mouse models for cancer chemoprevention studies.

To aid in identifying the ability of chemopreventive agents to inhibit tumor development, new preclinical in vivo rodent models have recently been developed. Some of the models contain targeted mutations capable of increasing the incidence and progression of neoplastic lesions, whereas in other models dietary nutrients induce preneoplastic lesions in normal mice. These new preclinical models are assisting the analysis of genetic and environmental factors leading to neoplasia, and clinical studies to evaluate the chemopreventive efficacy of specific nutrients and pharmacological agents.

Animals↗
PubMed1999

Preclinical and early human studies of calcium and colon cancer prevention.

Colorectal cancer continues to be a major cause of tumor mortality in the United States and other countries; despite attempts to improve the screening of high-risk populations, the incidence of this disease is still very high. Therefore, chemoprevention continues to be an important goal for the primary prevention of colorectal cancer. Among recent chemopreventive approaches, the administration of calcium and vitamin D continue to be evaluated in both preclinical and clinical studies. Many experimental findings described below have indicated associations between high calcium and vitamin D intake and decreased risk for colorectal cancer.

Animals↗
PubMed1999

Dietary factors in human colorectal cancer.

Colorectal cancer is a significant cause of mortality in Western societies. The progression of the disease from normal colonic epithelium to the acquisition of the malignant phenotype is accompanied by numerous genetic and epigenetic alterations. Compelling experimental and epidemiological evidence indicates that diet and nutrition are key factors in the modulation of colorectal cancer. A salient case in point is the recent observation that a dietary regimen based on a Western-style diet provokes in the rodent colon the appearance of preneoplastic lesions in the absence of any genotoxic insult. This review mainly describes dietary factors that inhibit the development and progression of colorectal cancer. Much is unknown about the precise mechanisms of action of chemically disparate nutrients and how they interfere with the development and progression of this disease. Current knowledge about this important issue is summarized. We believe that continuing scrutiny and precise assessment of the benefits (and potential risks) of nutrients in the treatment and prevention of colorectal cancer will prove significant to controlling this devastating disease.

Animals↗
PubMed1998

Dietary modulation of carcinoma development in a mouse model for human familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) is caused by a dominant mutation in the adenomatous polyposis coli (APC) gene. Individuals with FAP progressively develop adenomas and carcinomas of the colon and rectum. We developed a mouse model for this disorder by genetically modifying the Apc gene. The resulting mice Apc1638 progressively develop neoplasms in the colon and remainder of the gastrointestinal tract. In this study when Apc1638 mice were fed a Western-style diet, they developed an increased incidence of the end point of carcinomas and number of invasive tumors. The findings therefore demonstrated dietary modulation of carcinoma incidence in mice with a targeted mutation providing a model for the study of gene-environment interactions in cancer.

Adenoma↗
PubMed1998

Piroxicam--dietary interactions in a long-term tolerance study in mice.

Piroxicam is a commonly prescribed nonsteroidal anti-inflammatory drug. In this study, piroxicam was fed at 60 ppm to mice in a semipurified AIN-76A (low-fat) control diet and in a Western-style diet (i.e., a modified AIN-76A diet with increased fat and reduced calcium and vitamin D, developed as a mimic of the human "Western" diet in the United States). Piroxicam in the AIN-76A diet produced only small adverse effects. However, 21-28 weeks of feeding piroxicam in the Western-style diet was lethal to mice. This suggest potent magnification of piroxicam toxicity in a high-fat-containing Western-style diet. This surprising finding suggests careful consideration of diet composition when potent agents such as nonsteroidal anti-inflammatory drugs are tested in animal studies and in clinical trials by humans who ingest the high-fat diets of Western countries.

Animals↗
PubMed1998

Teaching senior oncologists communication skills: results from phase I of a comprehensive longitudinal program in the United Kingdom.

PURPOSE: To determine the communication difficulties experienced by clinicians in cancer medicine and to develop, implement, and evaluate communication skills training courses. METHODS: One hundred seventy-eight senior clinicians attended 1 1/2- or 3-day residential courses designed to enhance skills development, knowledge acquisition, and personal awareness. Course content included structured feedback, video review of interviews, interactive group demonstrations, and discussion in groups of four led by trained facilitators. The main outcomes were self-rated confidence in key aspects of communication, attitudinal shift toward more patient-centered interviewing, perceived changes in personal practice, and initiation of teaching programs for junior staff. RESULTS: Less than 35% of the participants had received any previous communications training. Time, experience, and seniority had not improved skills; before the course, oncologists expressed difficulty with 998 different communication issues. Primary problems concerned giving complex information, obtaining informed consent, and handling ethnic and cultural differences. Confidence ratings for key communication areas were significantly improved postcourse (P < .01). Three months postcourse, 95% of the physicians reported significant changes in their practice of medicine. Seventy-five percent had started new teaching initiatives in communication for junior clinicians. Clinicians showed positive shifts in attitude toward patients' psychosocial needs (P=.0002) and were more patient centered (P=.03). The courses were highly rated and 97% would "definitely" recommend them to colleagues. CONCLUSION: Oncologists are hampered by inadequate communication skills training and will give up time to correct this. Subjective improvements reported immediately postcourse were maintained at 3 months. Resources for educational initiatives are needed to help both patients and their physicians.

Communication↗
PubMed1997

Mutation in the mismatch repair gene Msh6 causes cancer susceptibility.

Mice carrying a null mutation in the mismatch repair gene Msh6 were generated by gene targeting. Cells that were homozygous for the mutation did not produce any detectable MSH6 protein, and extracts prepared from these cells were defective for repair of single nucleotide mismatches. Repair of 1, 2, and 4 nucleotide insertion/deletion mismatches was unaffected. Mice that were homozygous for the mutation had a reduced life span. The mice developed a spectrum of tumors, the most predominant of which were gastrointestinal tumors and B- as well as T-cell lymphomas. The tumors did not show any microsatellite instability. We conclude that MSH6 mutations, like those in some other members of the family of mismatch repair genes, lead to cancer susceptibility, and germline mutations in this gene may be associated with a cancer predisposition syndrome that does not show microsatellite instability.

Adenomatous Polyposis Coli Protein↗
PubMed1997

A mouse model of human familial adenomatous polyposis.

In an effort to generate a good mouse model for human colorectal cancer, we generated mice which carry a mutation in the adenomatous polyposis coli (Apc) gene. Mice which are heterozygous for the mutation, designated Apc1638, develop colonic polyps and tumors of the small intestine. Neoplasms were found in 96% of animals studied, and they included adenomas, adenocarcinomas, and polypoid hyperplasias. The mice developed an average of 3.3 tumors, with the highest number in duodenum, followed by jejunum, stomach, ileum, and colon. Focal areas of dysplasias were observed in the colonic mucosa in 50% of mice which were 10 months old or older. These results suggest that mice carrying the Apc1638 mutation can serve as a good model to study the initiation, progression, and inhibition of gastrointestinal tumors.

Adenomatous Polyposis Coli↗
PubMed1997

Cancer prevention.

Explore the source record for details and available documents.

Anticarcinogenic Agents↗
PubMed1997

Induced hyperproliferation in epithelial cells of mouse prostate by a Western-style diet.

In this study the effects of a Western-style diet on epithelial cell proliferation in the prostate and bladder of C57BL/6J mice were investigated. The Western-style diet contained increased fat and low calcium and vitamin D, compared with AIN-76A control diet, at levels simulating human Western diets based on nutrient density. After feeding the Western-style and AIN-76A diets for 5 and 16 weeks, mice were infused with bromodeoxyuridine (BrdU) for 72 h using s.c. implanted osmotic pumps. Findings revealed that in bladder epithelium BrdU labeling indices were not significantly different (P > 0.05) between mice on the control and Western-style diets at both time periods. However, significant increases in BrdU labeling indices occurred in epithelial cells of the anterior (P = 0.024) and dorsal (P = 0.049) lobes, but not in the ventral lobe (P = 0.21), of the mouse prostate after feeding the Western-style diet for 16 weeks, compared with mice on the control diet. These findings demonstrate Western-style diet induction of epithelial cell hyperproliferation in anterior and dorsal lobes of the mouse prostate. The findings further suggest that these nutrients may have a role in human prostatic carcinogenesis, since the anterior and dorsal lobes of the mouse prostate are homologous with the human prostate in embryological origin and histological structure and carcinomas induced in rodent models have similar characteristics to those found in human prostatic cancer.

Animals↗
PubMed1997

New rodent models for studies of chemopreventive agents.

Some recent studies of the effects of chemopreventive agents have begun to use new rodent models to improve the analysis of stages of colonic preneoplasia, and how chemopreventive agents modify progressive abnormal cell development. In one of the models of inherited predisposition to colon cancer, mice carrying a truncated Apc allele with a nonsense mutation in exon 15 have been generated by gene targeting and embryonic stem cell technology (Apc1638 mice). These mice develop multiple gastrointestinal lesions, including adenomas and carcinomas, focal areas of high-grade dysplasia (FAD), and polypoid hyperplasias with FADS. The incidence of inherited colonic neoplasms has now been modulated by a chemopreventive regimen. Colonic lesions significantly increased in Apc1638 mice on a Western-style diet, which has higher fat content and lower calcium and vitamin D compared to the same mice on AIN-76A diet. In another rodent model, Min mice were treated with sulindac, which markedly reduced the incidence of intestinal tumors. A third new rodent model containing a targeted mutation in the gene Mcc (mutated in colorectal cancer) recently became available for chemoprevention studies. These mice develop multiple types of neoplasms including adenocarcinomas, focal areas of gastrointestinal dysplasia, papillomas of the forestomach, and tumors in other organs including lung, liver, and lymphoid tissue. Feeding a Western-style diet to the Mcc mutant mice also resulted in significantly increased gastrointestinal lesions. These nutrient modifications also have been given to normal mice, demonstrating without any chemical carcinogen that a Western-style diet induced colonic tumorigenesis. Western-style diets also have now induced modulation of cell proliferation in other organs including mammary gland, pancreas, and prostate. These findings help develop new preclinical rodent models to aid the analysis of genetic and environmental factors leading to neoplasia, as well as new methods for evaluating the chemopreventive efficacy of specific nutrients and pharmacological agents.

Animals↗
PubMed1996

Epithelial cell hyperproliferation induced in the exocrine pancreas of mice by a western-style diet.

BACKGROUND: Pancreatic cancer is a common cause of mortality in the United States, with an estimated 27,800 people dying of the disease in this country in 1996. Epidemiologic studies have suggested that Western diets containing high fat, high protein, and low calcium contents are associated with increased incidence of pancreatic cancer. PURPOSE: We investigated whether a Western-style diet containing increased fat content and decreased calcium and vitamin D contents would induce epithelial cell hyperproliferation (excess cell duplication) or hyperplasia (excess cell accumulation) in the pancreas, as was previously demonstrated in the colon and mammary gland. METHODS: C57BL/6J mice at 4 weeks of age were randomly assigned to one of two groups of 14 mice each. One group received the control diet ad libitum, and the other group was given the Western-style diet ad libitum. After 6, 9, and 15 weeks on the diet, four or five mice per group were infused with 5-bromo-2'-deoxyuridine (BrdU) for 72 hours by use of subcutaneously implanted Alzet osmotic pumps. The mice were then killed, and the pancreas of each mouse was removed. In the exocrine pancreas with ductal secretion, the duct system (including interlobular and intralobular ducts and centroacinar [i.e., centroductular] cells) and acini were measured both histopathologically and immunohistochemically (BrdU) and were analyzed without knowledge of the source of the specimens. Two-way analysis of variance was carried out. All P values were generated from two-sided tests for statistical significance. RESULTS: The number of pancreatic ducts (interlobular, intralobular, and centro-acinar-cancer-prone regions in certain rodent models and in humans) and acini per mouse in the Western-style diet group was similar to that in the control diet group during the entire feeding period (P = .76, .32, .93, and .42, respectively). Statistically significant higher BrdU-labeling indices of the ductal interlobular and intralobular epithelial cells were seen in mice fed the Western-style diet than in mice fed the control diet during the entire observation period (P = .014 and .016, respectively). There was no statistically significant difference (P = .098) between both diet groups in the BrdU-labeling indices of the centroacinar epithelial cells. CONCLUSIONS: A Western-style diet induced pancreatic epithelial cell hyperproliferation in mice, further suggesting that increased fat content and decreased calcium and vitamin D contribute to the development of pancreatic neoplasms.

Animals↗