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Joshua R Korzenik

Publications and source records attributed to Joshua R Korzenik.

15 recordsLinked to original sources
PubMed2006

Dysregulation of Reg gene expression occurs early in gastrointestinal tumorigenesis and regulates anti-apoptotic genes.

Expression of anti-apoptotic genes is frequently elevated in tumors, where they increase resistance to chemotherapeutic agents and predict poor patient outcomes. However, key cellular factors regulating anti-apoptotic genes in tumors remain unknown. Increased expression of the regenerating (Reg) genes is commonly observed in gastrointestinal (GI) malignancies including colorectal cancer (CRC). We therefore examined Reg gene expression and associated changes in anti-apoptotic genes in an animal model of GI tumorigenesis. Using real time RT-PCR, we measured expression of Reg genes in human colorectal adenocarcinoma specimens, colon adenocarcinoma cell lines and adenomas from multiple intestinal neoplasia (min) mice heterozygous for a germ-line mutation of the adenomatous polyposis coli (APC) gene. Expression of Reg genes is increased in human colorectal adenocarcinomas and in the intestine of APCmin/+ mice at four weeks of age, a time preceding the spontaneous second mutation in the APC gene. Individual Reg genes exhibited regional expression profiles across the GI tract in mice. Adenomas from 14-week old mice had significant increases in at least one member of the Reg gene family, most commonly Reg IV and an associated increase in expression of the anti-apoptotic gene, Bcl-2. Addition of exogenous recombinant human Reg IV to human colon adenocarcinoma cells significantly increased Bcl-2 and Bcl-xL expression and induced resistance to ionizing radiation. These results show that dysregulation of Reg genes occur early in tumorigenesis. Furthermore, increased expression of Reg genes, specifically Reg IV contribute to adenoma formation and lead to increased resistance to apoptotic cell death in CRC.

Adenocarcinoma↗
PubMed2006

Risks and benefits of infliximab for the treatment of Crohn's disease.

BACKGROUND & AIMS: Infliximab is effective for the treatment of active Crohn's disease. However, rare but serious complications related to infliximab therapy including lymphoma, sepsis, and death have been reported. The purpose of this study was to analyze the risks and benefits of infliximab for the treatment of Crohn's disease with the goal of providing data to aid both physicians and patients in the process of making a decision about treatment. METHODS: A decision analytic model was constructed to determine the risks and benefits of infliximab when compared with standard therapy. The analysis simulated 2 cohorts of 100,000 patients each, with one arm receiving infliximab while the other remained on standard therapy. RESULTS: Model results showed that in 100,000 patients at 1 year, infliximab will lead to 12,216 more patients in remission, 4255 fewer surgeries, and 33 fewer deaths from flares of disease. This is at the cost of 201 more lymphomas and 249 more deaths related to complications from infliximab. Overall, the infliximab strategy resulted in more quality-adjusted life years (QALYs/patient) than the standard therapy strategy (.77 QALYs/patient vs .75 QALYs/patient). CONCLUSIONS: Despite an increased risk of lymphoma and death associated with use of infliximab, the substantial clinical improvement and fewer surgeries as a result of infliximab result in an increase in QALYs. In properly selected patients, the benefits of infliximab could outweigh its risks. These data should help guide decision making and the informed consent process when considering the use of infliximab for the treatment of Crohn's disease.

Adult↗
PubMed2006

Evolving knowledge and therapy of inflammatory bowel disease.

With recent advances in the understanding of its pathophysiology, inflammatory bowel disease has become a very active area for the development of novel therapeutic agents. New targets for biologics include cytokines involved in T-cell activation, with antibodies directed against IL-12 and interferon-gamma. Selective adhesion molecule blockade has produced promising, though mixed, results. Recombinant human granulocyte-macrophage colony-stimulating factor might be effective in active Crohn's disease, presumably through stimulation of intestinal innate immune responses. With increasing evidence for a crucial role for luminal flora in maintaining the health of the bowel, strategies to manipulate intestinal bacteria using probiotics and prebiotics are being actively investigated as well.

Animals↗
PubMed2006

Case closed? Diverticulitis: epidemiology and fiber.

A major advance in understanding diverticular disease occurred decades ago with the epidemiologic association between fiber intake and the development of diverticular disease. This association has been well documented with investigations into the emergence of diverticular disease in underdeveloped countries where the disease had been virtually unknown before the adoption of a westernized diet, low in fiber. The high frequency of right-sided diverticular disease in Asian countries diverges from what is seen in the West. The physiologic effects of insoluble fiber has been well examined as well, increasing bulk and decreasing transit time, with a deficiency contributing to the high pressures implicated in the physiology which leads to diverticular disease. However, at most, 10% to 25% of individuals with diverticular disease will develop diverticulitis. Risk factors for symptomatic diverticular have been increasingly described in recent years with obesity and red meat intake being of particular importance, in addition to age. However, the known factors poorly identify those at increased risk and the predisposing pathophysiology is incompletely understood as well. Insoluble fiber, but not soluble fiber, has been viewed as the principal component which has been deficient in western diets and is the culprit which leads to the establishment of diverticular disease and in turn, diverticulitis. Soluble fiber and its effect on the intestinal flora is proposed as having significant influence on the development of diverticulitis. This understanding, if demonstrated, would have important implications for the primary and secondary prevention of diverticulitis.

Age Factors↗
PubMed2006

Analysis of treatment effects on the microbial ecology of the human intestine.

A large number of studies have investigated gastrointestinal microbiota and changes in the gastrointestinal community. However, a concern in these studies is how best to assess changes in gastrointestinal community structure. This paper presents two different human trials where the fecal terminal restriction fragment length polymorphism data sets were analyzed to search for treatment effects. Principle components analysis and cluster analysis based on grouped data are compared with analysis of data by subject using distance coefficients. Comparison with baseline within an individual before grouping by treatment provided a clearer indication of treatment effects than did an evaluation of data grouped before analysis. In addition, a large within-subject sample size and multiple baseline samples are necessary to accurately analyze treatment effects.

Adult↗
PubMed2006

Growth factors as treatment options for intestinal inflammation.

On the basis of several studies that have been completed to date, some growth factors appear promising for the treatment of inflammatory bowel disease: keratinocyte-like growth factor-2 (KGF-2), epidermal growth factor (EGF) enemas used in combination with oral mesalamine, somatropin (human growth hormone), and sargramostim (recombinant human GM-CSF). The results of these studies are highlighted and suggest that new insights into the regulation of intestinal immunity may provide effective synergistic or single-agent treatment alternatives to immunosuppression for inflammatory bowel disease. These data focus on the reparative components of mucosal homeostasis.

Animals↗
PubMed2005

Sargramostim for active Crohn's disease.

BACKGROUND: Sargramostim, granulocyte-macrophage colony-stimulating factor, a hematopoietic growth factor, stimulates cells of the intestinal innate immune system. Preliminary studies suggest sargramostim may have activity in Crohn's disease. To evaluate this novel therapeutic approach, we conducted a randomized, placebo-controlled trial. METHODS: Using a 2:1 ratio, we randomly assigned 124 patients with moderate-to-severe active Crohn's disease to receive 6 mug of sargramostim per kilogram per day or placebo subcutaneously for 56 days. Antibiotics and aminosalicylates were allowed; immunosuppressants and glucocorticoids were prohibited. The primary end point was a clinical response, defined by a decrease from baseline of at least 70 points in the Crohn's Disease Activity Index (CDAI) at the end of treatment (day 57). Other end points included changes in disease severity and the health-related quality of life and adverse events. RESULTS: There was no significant difference in the rate of the primary end point of a clinical response defined by a decrease of at least 70 points in the CDAI score on day 57 between the sargramostim and placebo groups (54 percent vs. 44 percent, P=0.28). However, significantly more patients in the sargramostim group than in the placebo group reached the secondary end points of a clinical response defined by a decrease from baseline of at least 100 points in the CDAI score on day 57 (48 percent vs. 26 percent, P=0.01) and of remission, defined by a CDAI score of 150 points or less on day 57 (40 percent vs. 19 percent, P=0.01). The rates of either type of clinical response and of remission were significantly higher in the sargramostim group than in the placebo group on day 29 of treatment and 30 days after treatment. The sargramostim group also had significant improvements in the quality of life. Mild-to-moderate injection-site reactions and bone pain were more common in the sargramostim group, and three patients in this group had serious adverse events possibly or probably related to treatment. CONCLUSIONS: This study was negative for the primary end point, but findings for the secondary end points suggest that sargramostim therapy decreased disease severity and improved the quality of life in patients with active Crohn's disease.

Adult↗
PubMed2005

Past and current theories of etiology of IBD: toothpaste, worms, and refrigerators.

While tremendous advances have improved the understanding of inflammatory bowel disease, with regard to environmental risk factors as well as the biochemical nature of the inflammatory process, a determination of primary etiology remains elusive. Numerous theories have been proposed in the past century concerning the cause of Crohn's disease and ulcerative colitis with implications for specific therapies. On further study, most of these ideas and therapies have failed to be accurate in theory or therapeutic approach. Others remain untested or are the focus of current investigation and controversy. This paper reviews the dominant theories of primary etiology. These hypotheses include infectious causes such as Mycobacteria paratuberculosis and measles. Allergic and nutritionally related causes have been the focus of considerable research. Microparticles, which is part of the concept behind toothpaste as a cause, have been suggested more broadly to be the principal factor initiating Crohn's disease. Several of these concepts rely on the idea that there is an increased intestinal permeability that is the central defect leading to Crohn's disease. Rather than being an excessive T cell driven process, Crohn's has been suggested to be an innate immune deficiency, leading to the use of colony stimulating factors to augment the intestinal barrier function and innate immunity. A variety of changes in the gut flora, ranging from a basic dysbiosis to the absence of helminths, have been proposed as the root cause of inflammatory bowel disease.

Colitis, Ulcerative↗
PubMed2004

Infliximab maintenance therapy for fistulizing Crohn's disease.

BACKGROUND: Infliximab, a monoclonal antibody against tumor necrosis factor, is an effective maintenance therapy for patients with Crohn's disease without fistulas. It is not known whether infliximab is an effective maintenance therapy for patients with fistulas. METHODS: We performed a multicenter, double-blind, randomized, placebo-controlled trial to evaluate the efficacy of infliximab maintenance therapy in 306 adult patients with Crohn's disease and one or more draining abdominal or perianal fistulas of at least three months' duration. Patients received 5 mg of infliximab per kilogram of body weight intravenously on weeks 0, 2, and 6. A total of 195 patients who had a response at weeks 10 and 14 and 87 patients who had no response were then randomly assigned to receive placebo or 5 mg of infliximab per kilogram every eight weeks and to be followed to week 54. The primary analysis was the time to the loss of response among patients who had a response at week 14 and underwent randomization. RESULTS: The time to loss of response was significantly longer for patients who received infliximab maintenance therapy than for those who received placebo maintenance (more than 40 weeks vs. 14 weeks, P<0.001). At week 54, 19 percent of patients in the placebo maintenance group had a complete absence of draining fistulas, as compared with 36 percent of patients in the infliximab maintenance group (P=0.009). CONCLUSIONS: Patients with fistulizing Crohn's disease who have a response to induction therapy with infliximab have an increased likelihood of a sustained response over a 54-week period if infliximab treatment is continued every 8 weeks.

Adult↗
PubMed2004

Crohn's disease: future anti-tumor necrosis factor therapies beyond infliximab.

The dramatic benefit experienced by many Crohn's disease patients treated with the anti-tumor necrosis factor-alpha (TNF-alpha) antibody infliximab underscores the centrality of this cytokine in the pathogenesis of Crohn's disease and the potential use of the therapeutic strategy of blocking TNF-alpha in this disease. In the hopes of emulating and improving on the success of infliximab, numerous strategies are being devised and studied to inhibit the actions of TNF-alpha. This article focuses on those agents, other than infliximab, which target TNF-alpha to treat inflammatory bowel disease as their central mechanism of action.

Antibodies, Monoclonal↗
PubMed2002

Treatment of active Crohn's disease with recombinant human granulocyte-macrophage colony-stimulating factor.

Treatment for Crohn's disease is aimed at immunosuppression. Yet inherited disorders associated with defective innate immunity often lead to development of a Crohn's-like disease. We performed an open-label dose-escalation trial (4-8 microg/kg per day) to investigate the safety and possible benefit of granulocyte-macrophage colony-stimulating factor (GM-CSF) in the treatment of 15 patients with moderate to severe Crohn's disease. No patients had worsening of their disease. Adverse events were negligible and included minor injection site reactions and bone pain. Patients had a significant decrease in mean Crohn's disease activity index (CDAI) score during treatment (p<0.0001). After 8 weeks of treatment, mean CDAI had fallen by 190 points. Overall, 12 patients had a decrease in CDAI of more than 100 points, and eight achieved clinical remission. Retreatment was effective, and treatment was associated with increased quality-of-life measures. GM-CSF may offer an alternative to traditional immunosuppression in treatment of Crohn's disease.

Crohn Disease↗
PubMed2002

Association of glycogen storage disease 1b and Crohn disease: results of a North American survey.

UNLABELLED: Glycogen storage disease (GSD)-1b has been associated with neutropenia and abnormalities of neutrophil function. Many individuals with GSD-1b manifest chronic gastrointestinal inflammation. Our study was performed to precisely establish the type, frequency, and spectrum of gastrointestinal disease in patients with GSD-lb. We established a medical database of 36 individuals affected with GSD-1b, utilizing patients at our center, disease registries, and direct contacts with North American referral centers specializing in genetic disorders. Records were reviewed, focusing on documentation of gastrointestinal involvement. Gastrointestinal symptoms or manifestations were present in approximately 75% of the patients, including chronic abdominal pain and diarrhea, perianal fistula or abscess, and oral aphthous ulceration. Of patients identified, 28% had documented inflammatory bowel disease (IBD) and an additional 22% of patients had symptoms highly suggestive of IBD, but had not undergone comprehensive diagnostic evaluation. Gastrointestinal involvement was found to be indistinguishable from idiopathic Crohn disease (CD) by detailed review of clinical, radiologic, endoscopic and histopathologic findings. Many patients had significant improvement or resolution of gastrointestinal disease in response to G-CSF treatment. The expression of CD in patients with GSD-1b may be delayed or prevented by G-CSF treatment. CONCLUSION: a strong association exists between glycogen storage disease type 1b and inflammatory bowel disease. A high index of suspicion for Crohn disease should be applied in evaluating patients with glycogen storage disease type 1b and intestinal symptoms. These results provide further support for the hypothesis that some forms of inflammatory bowel disease may result from impaired mucosal innate immunity. Additional investigations into the intestinal disease in glycogen storage disease type 1b may be directly relevant to the etiology and treatment of idiopathic Crohn disease.

Adolescent↗
PubMed2002

Inflammatory bowel disease and environmental influences.

Some environmental factors have been established firmly as influences on the development of IBD, such as smoking and appendectomy. Other behaviors, such as oral contraceptive use and sugar intake, have been suggested as risk factors, but he data conflict sharply. The importance of other behaviors, such as breast-feeding, is even murkier with sharply divergent data. Some issues studied may not be factors in themselves but rather markers for other unidentified influences. The conflicting evidence in many of these studies may be clarified as specific genes are identified and the interplay between these environmental factors and genetic subtypes is investigated.

Appendectomy↗