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Steven Itzkowitz

Publications and source records attributed to Steven Itzkowitz.

15 recordsLinked to original sources
PubMed2006

Trefoil factor family-1 mutations enhance gastric cancer cell invasion through distinct signaling pathways.

BACKGROUND & AIMS: Trefoil factor family-1 (TFF1) is a key gastric tumor-suppressor gene. TFF1 knockout mice develop multiple gastric adenomas and carcinomas, and human gastric cancers typically lack TFF1 expression. Recently, TFF1 mutations have been found in human gastric cancer. The purpose of this study was to determine the functionality of these mutants. METHODS: Recombinant wild-type TFF1 and the gastric cancer-associated TFF1 mutants (A10D and E13K) were produced and tested for their effect on gastric cancer cell proliferation, apoptosis, and invasion. Molecular modeling was used to guide the choice of mutants and to evaluate structure-function relationships. RESULTS: Molecular modeling suggested that A10D and E13K altered the surface charge of the loop 1 region of TFF1 without disturbing protein stability. Recombinant wild-type TFF1 significantly inhibited cell growth; A10D and E13K lost this tumor-suppressive property along with the ability to block etoposide-induced apoptosis. Although wild-type TFF1 promoted cell invasion, A10D and E13K were even more pro-invasive. Invasion induced by both mutants was blocked by inhibiting PI3-kinase or phospholipase-C, but inhibiting Rho-associated kinase (ROCK) blocked only E13K-induced invasion. CONCLUSIONS: The loss of tumor-suppressor activity and gain of invasiveness from single point mutations constitute evidence for a functional role of TFF1 mutations in gastric cancer. These site-directed mutagenesis experiments provide the tools for continued probing of signal transduction mechanisms and structural elements responsible for TFF1 functions.

Apoptosis↗
PubMed2005

Trefoil factor family-3 is associated with aggressive behavior of colon cancer cells.

BACKGROUND AND AIM: Trefoil factor family 3 (TFF3) is expressed by intestinal epithelial cells and it mainly functions to protect the mucosa from injury. Expression of TFF3 has been correlated with a poor prognosis in patients with cancer, but little is known about whether TFF3 directly contributes to the malignant behavior of cancer cells. The present study was conducted to determine whether TFF3 expression contributes to the malignant behavior of cancer cells in vitro and in vivo. METHODS: Two subclones of a metastatic rat colorectal cancer cell line, demonstrated previously to manifest aggressive (LN cells) and non-aggressive (LP cells) growth in vivo, were analyzed for expression of TFF3 and tested in assays of cancer cell migration, invasion, and apoptosis in vitro, and mortality in vivo. RESULTS: The aggressive LN cell line endogenously expressed TFF3 and supported the transcription of a TFF3 promoter-driven reporter construct, whereas the non-aggressive LP cell line did not express TFF3. LN cells demonstrated enhanced migration, invasion, and less apoptosis compared to LP cells. Transfecting TFF3 into LP cells enhanced their ability to migrate, invade, block apoptosis, and behave more aggressively in vivo, thereby resembling the phenotype of LN cells. CONCLUSIONS: In rat colon cancer cells, both endogenous and constitutive expression of TFF3 correlates with an aggressive phenotype. These data provide direct evidence that TFF3 contributes to the malignant behavior of cancer cells.

Animals↗
PubMed2005

Chemoprevention of colorectal neoplasia in ulcerative colitis: the effect of 6-mercaptopurine.

BACKGROUND & AIMS: Evidence suggests that mesalamine-based anti-inflammatory medicines may prevent colorectal cancer (CRC) in ulcerative colitis (UC). If mesalamine exerts its chemopreventive effect by its anti-inflammatory activity, then other medications that reduce colitis activity also should possess chemopreventive properties. Our aim was to determine the effect of the immunomodulators 6-mercaptopurine (6MP) and azathioprine (AZA) in preventing the development of dysplasia or CRC in UC. METHODS: Patients with UC who underwent a surveillance colonoscopy in 1996-1997 were identified from a gastrointestinal pathology database. A proportional hazards analysis assessing 6MP/AZA use as a time-changing covariate was performed to evaluate the effect of 6MP/AZA on: (1) progression to any neoplasia (low-grade dysplasia, high-grade dysplasia, or CRC), and (2) progression to advanced neoplasia (high-grade dysplasia or CRC). RESULTS: A total of 315 subjects met inclusion criteria and were followed for an average of 8 years from their first surveillance examination. There were no significant differences in rates of progression to advanced neoplasia or to any neoplasia between 6MP/AZA users and never-users by log-rank testing. The proportional hazards analysis resulted in hazard ratios of 1.06 (95% confidence interval, .59-1.93) and 1.30 (95% confidence interval, .45-3.75) when considering the effect of exposure to 6MP/AZA on progression to any or to advanced neoplasia, respectively. The results were unaffected by known potential confounders. CONCLUSIONS: In UC patients with no initial history of dysplasia, 6MP/AZA use appears to have little or no effect on the rate of neoplastic transformation in the colon. Importantly, the use of 6MP/AZA did not increase malignant transformation in UC.

Adult↗
PubMed2005

Short-chain fatty acid induces intestinal mucosal injury in newborn rats and down-regulates intestinal trefoil factor gene expression in vivo and in vitro.

BACKGROUND: Luminal administration of short-chain fatty acids (SCFAs) induces dose-dependent intestinal mucosal injury in newborn rats. However, the mechanism underlying the injurious effects of SCFAs on intestinal mucosa in neonates is unclear. Intestinal trefoil factor (ITF) is a factor important for the maintenance and repair of the intestinal mucosal barrier. Regulation of ITF gene expression by SCFAs may be involved as one of the mechanisms. OBJECTIVES: To examine the effect of butyrate-induced colonic injury on ITF gene expression in vivo and to determine the molecular mechanisms underlying the butyrate regulation of ITF gene expression in vitro. METHODS: Whole-section colonic tissues from 9- to 10-day-old Sprague-Dawley rats that have received butyric acid at two different concentrations (150 mmol/L and 300 mmol/L) and for different time periods were processed for total RNA extraction and Northern blot analysis. Littermates that received normal saline or lactic acid at 300 mmol/L served as controls. The effect of butyrate on ITF gene expression was also examined in vitro with human colonic epithelial LS 174T cells. To further define ITF gene regulation by butyrate, transient transfection assays were performed on a 930 bp human ITF promoter-luciferase reporter gene plasmid in LS174T cells with or without the presence of butyrate. RESULTS: Concurrent with mucosal injury, butyric acid inhibited ITF gene expression in colonic tissues of newborn rats as well as in intestinal epithelial cells in a dose- and time-dependent manner. Furthermore, butyrate reduced ITF promoter report gene activity in transfected LS174T cell, suggesting that butyric acid regulation of ITF gene is by way of a specific ITF promoter. CONCLUSIONS: Butyric acid induced-intestinal mucosal injury in newborn rats is associated with down-regulation of ITF gene expression. The changes in ITF gene expression in vivo may play a role in the pathogenesis of SCFA-induced intestinal mucosal injury.

Animals↗
PubMed2005

Barriers to colorectal cancer screening: inadequate knowledge by physicians.

BACKGROUND: The rate of colorectal cancer (CRC) screening remains relatively low. One potential barrier to higher rates is the lack of physician knowledge regarding CRC screening. The purpose of this study was to assess physicians' knowledge of (a) American Cancer Society (ACS) CRC screening guidelines for average-risk and high-risk patients, and (b) general colorectal cancer facts which support these guidelines. METHODS: We administered a questionnaire to internal medicine residents, internal medicine attendings and medical students who provide care to patients in a low-income, predominantly minority community, to compare their levels of knowledge regarding CRC screening. Mean knowledge scores were calculated based on the number of correct responses. RESULTS: Knowledge of ACS guidelines for average-risk patients was low, although it did increase directly with level of training: medical students obtained a mean score of 32%, residents 49%, and attendings 56% (p<0.001). Knowledge scores for high-risk patients were even lower, with fewer than half of the respondents offering correct answers. Mean knowledge scores of general CRC screening facts increased with level of training: medical students scored 31%, residents 38% and attendings 42% (p<0.001). CLINICAL IMPLICATIONS: Knowledge of CRC screening guidelines for both average- and high-risk patients was suboptimal among the medical students, residents and attendings studied. Lack of knowledge about CRC is one barrier to screening that may contribute to underutilization of screening for minority populations. Further educational efforts should be targeted to these health care professionals.

Adult↗
PubMed2005

Predictors of endoscopy in minority women.

BACKGROUND: Colorectal cancer (CRC) is the second leading cause of cancer related deaths in the United States. Underrepresented minorities suffer disproportionately from CRC largely because of disparities in CRC screening rates, particularly by endoscopic methods. This study evaluates the association between socioeconomic, medical and psychosocial factors and the use of endoscopy in low-income minority women. METHODS: The participants were recruited from community health fairs, tenant association meetings, senior centers and local medical clinics. A survey instrument was administered to the minority women. RESULTS: Eighty-one women age >50 were included in this analysis (44 African Americans and 37 Hispanics). The two ethnic groups were demographically similar. The factors associated with having had endoscopy were language spoken (English versus Spanish), physician recommendation, cancer cons and decisional balance (difference between cancer cons and cancer pros). When endoscopy was modeled as a function of decisional balance and language spoken, only decisional balance was a significant predictor of endoscopy. CONCLUSIONS: Physician recommendation and decisional balance have a tremendous influence on whether minority women undergo endoscopy. These data suggest that if physicians increase their communication with patients regarding the benefits of screening and address patients concerns, adherence with endoscopic CRC screening can be improved in minority women.

Black or African American↗
PubMed2003

Progression of flat low-grade dysplasia to advanced neoplasia in patients with ulcerative colitis.

BACKGROUND & AIMS: Long-standing ulcerative colitis has long been recognized as a risk factor for colorectal cancer, but there is still no universal consensus on the optimal management of ulcerative colitis patients with low-grade dysplasia in flat mucosa. Some authorities favor prompt colectomy, whereas others recommend continued surveillance. The purpose of our study was to determine the frequency with which flat low-grade dysplasia in ulcerative colitis progresses to advanced neoplasia (high-grade dysplasia or colorectal cancer) and whether specific variables could predict such progression. METHODS: We reviewed the medical histories, colonoscopic findings, and surgical and pathology reports of 46 patients with ulcerative colitis diagnosed with flat low-grade dysplasia on a surveillance colonoscopy. The rates of neoplastic progression, as well as the frequency of advanced neoplasia, were tabulated. We correlated progression with several clinical and colonoscopic variables: the number of biopsy samples positive for flat low-grade dysplasia, the duration and anatomic extent of disease, patient age, and medication use. RESULTS: Among these 46 patients, there were 7 cases of colorectal cancer, 5 of which were stage II or higher. Unexpected advanced neoplasia occurred in 4 of 17 (23.5%) patients who underwent colectomy for flat low-grade dysplasia. On an actuarial basis, the rate of neoplastic progression was 53% at 5 years. No clinical features predicted progression to advanced neoplasia. Cancers, including 2 at advanced stages, developed despite frequent follow-up surveillance examinations. CONCLUSIONS: A finding of flat low-grade dysplasia during ulcerative colitis surveillance is a strong predictor of progression to advanced neoplasia. Early colectomy should be recommended for such patients.

Actuarial Analysis↗
PubMed2002

Awareness of genetic testing for colorectal cancer predisposition among specialists in gastroenterology.

OBJECTIVES: Adult gastroenterologists practicing in New York State were surveyed to determine their practice with regard to identifying family histories consistent with inherited forms of colorectal cancer, and to assess their awareness of cancer genetic counseling and molecular genetic testing for familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). METHODS: A closed-ended questionnaire was mailed to 815 gastroenterologists identified through the membership Directory of the American Gastroenterological Association (1998). Two mailings resulted in a response rate of 35%. RESULTS: In all, 99% of the gastroenterologists obtained a family history from their patients, and 95% were aware of cancer genetic counseling. However, only 51% would routinely refer patients for genetic counseling before providing cancer predisposition testing. In addition, only 52% were aware of the availability of genetic tests for FAP and 34% for HNPCC. Presented with a family history consistent with HNPCC, 79% could identify the syndrome, 26% recommended genetic counseling for the consultand, and 16% advised appropriate screening, according to current recommendations. CONCLUSIONS: The majority of gastroenterologists do obtain a family history on their patients. However, there is a need for physician education regarding the recognition of pedigrees consistent with inherited colorectal cancer, the genetic counseling process, and the availability of mutation testing for FAP and HNPCC.

Adenomatous Polyposis Coli↗
PubMed2002

Intestinal trefoil factor: a marker of poor prognosis in gastric carcinoma.

PURPOSE: Intestinal trefoil factor (ITF) is a marker of intestinal differentiation that may also play a role in cancer cell biology by inhibiting cell adhesion, promoting cell invasion, and blocking apoptosis. Gastric adenocarcinomas can arise through a process of intestinalization, but no study has yet comprehensively examined the expression of ITF in gastric cancer or correlated ITF expression with clinical outcome in any cancer type. EXPERIMENTAL DESIGN: Patients (209) with primary gastric adenocarcinoma were evaluated for ITF expression by immunohistochemistry. Results of immunostaining were correlated with clinicopathological variables and overall survival. RESULTS: In normal gastric mucosa, ITF expression was absent, whereas areas of intestinal metaplasia revealed strong ITF expression by goblet cells. A portion of gastric cancers (55%) demonstrated ITF expression. Women were more likely than men to express ITF in gastric cancers. However, in men, the expression of ITF correlated with aggressive phenotype of tumors (advanced stage, infiltrative growth pattern, and positive lymph nodes). Multivariate analysis revealed that expression of ITF was associated with a poor prognosis, independent of tumor stage. CONCLUSIONS: This is the first study to correlate ITF expression with clinicopathological features or outcome in any cancer type. ITF expression in gastric cancer exhibited a curious gender-associated relationship, being more frequently expressed in tumors of women, but associated with more aggressive pathological features in men. The poor prognosis of patients with ITF-positive gastric cancers further implicates ITF in cancer cell biology.

Adenocarcinoma↗
PubMedDate not supplied

Colon carcinogenesis in inflammatory bowel disease: applying molecular genetics to clinical practice.

Although both sporadic colorectal cancer (CRC) and colitis-associated CRC arise from dysplastic precursor lesions and share several molecular alterations, the nature of the dysplasia and the frequency and timing of several of the key molecular changes differ enough to consider colitis-associated CRC a rather unique entity. To date, cancer surveillance in both ulcerative colitis and Crohn's colitis rests upon the detection of dysplasia. However, because there are considerable limitations to the detection and interpretation of dysplasia, there is a need for other molecular markers to complement the histologic analysis of dysplasia. Because patients with inflammatory bowel disease (IBD) undergo repeated, periodic surveillance colonoscopies, it affords an opportunity to study marker expression over time. Of the few markers that have been studied chronologically, aneuploidy, p53, and mucin-associated sialyl-Tn antigen expression each hold promise as markers of CRC risk in IBD. It will be important to study whether these markers, or other panels of gene or protein expression, can identify patients at highest risk for developing CRC in future clinical studies.

Biomarkers, Tumor↗
PubMedDate not supplied

Teaching clinical management skills for genetic testing of hereditary nonpolyposis colorectal cancer using a Web-based tutorial.

PURPOSE: To pilot and evaluate an interactive Web-based continuing medical education tutorial on clinical management of hereditary nonpolyposis colon cancer (HNPCC) and genetic testing. METHODS: Gastroenterology fellows and genetic counseling trainees were asked to read standard written materials before taking the tutorial. A pretest/post-test assessment was used to measure change in subjects' clinical management skills. RESULTS: Subjects made the correct management decision 63.9% of the time before the tutorial and 81.1% of the time after the tutorial (P < 0.001). CONCLUSIONS: Supplementing written materials with an interactive program may assist medical professionals in integrating their knowledge of HNPCC and genetic testing into clinical practice.

Adult↗
PubMedDate not supplied

Indeterminate colitis.

Explore the source record for details and available documents.

Antibodies, Antineutrophil Cytoplasmic↗
PubMedDate not supplied

The diagnosis and treatment of pouchitis in inflammatory bowel disease.

The ileal pouch anal anastomosis (IPAA) procedure has become the preferred surgical option for most patients with ulcerative colitis who require surgical removal of the colorectum. The vast majority of patients with this new anatomy will either not develop pouchitis or develop a few discrete episodes of acute pouchitis. However approximately one fourth of patients will develop recurrent pouchitis, with 5% being categorized as chronic pouchitis requiring maintenance therapy or, on rare occasion, pouch excision. Factors that are associated with an increased risk of pouchitis include primary sclerosing cholangitis, extraintestinal manifestations, and nonsmokers. Controversy surrounds other risk factors such as extent of colitis, backwash ileitis, preoperative pANCA levels, and carrying a specific allele for IL-1 receptor antagonist. The etiology of pouchitis is unknown, but theories range from genetic susceptibility, bacterial overgrowth, ischemia, and fecal stasis, to a recurrence of ulcerative colitis in the pouch, a missed diagnosis of Crohn's disease, or possibly a novel third form of inflammatory bowel disease. Some patients with symptoms of pouchitis will not have inflammation of the pouch, but rather, irritable pouch syndrome. Thus, endoscopic investigation with biopsy is important for declaring whether a patient has pouchitis. Indeed, the more commonly used scores, such as the pouch disease activity index, incorporate both endoscopic and histologic criteria. Not surprisingly, treatment options for patients with pouchitis resemble that of regular inflammatory bowel disease, although there have only been a few controlled trials. Antibiotics are the mainstay of therapy, with metronidazole and ciprofloxacin demonstrating benefit in controlled trials. Probiotics are effective for maintaining remission of pouchitis. Mesalamine, corticosteroids, and immunomodulators have been used with some success. Occasionally, patients with well-documented ulcerative colitis as the indication for IPAA will develop what appears to be Crohn's disease of the pouch, on the basis of granulomatous inflammation, pre-pouch ileitis, or fistulae. The treatment is similar to Crohn's disease, including the use of infliximab. Dysplasia within the pouch mucosa itself is quite rare. Reports of dysplasia occurring in patients with IPAA are usually due to neoplastic change within the residual cuff of rectal or transition zone mucosa just below the pouch, rather than in the ileal mucosa of the pouch. With further elucidation of the genetic basis for inflammatory bowel disease, we should be able to more accurately classify patients with ulcerative colitis and Crohn's disease genotypically. Hopefully, this will also bring more clarity to the heterogeneous population of patients with pouchitis and allow for more focused therapeutic strategies.

Anti-Infective Agents↗