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Biomedical subjects

John McLaughlin

Publications and source records attributed to John McLaughlin.

At least 19 recordsLinked to original sources
PubMed2026

Germline ATRIP variants and the risk of ovarian cancer.

PURPOSE: We have previously reported that inherited variants in ATRIP confer a 3-fold risk of developing breast cancer. Here, we investigated potential association between this novel breast cancer susceptibility gene and the risk of ovarian cancer. METHODS: We genotyped the ATRIP c.1152_1155del p.(Gly385Ter) Polish founder variant on germline DNA from 3404 Polish women with ovarian cancer and 9285 healthy controls. Additionally, we sequenced all coding exons of ATRIP among 1322 unselected ovarian cancer patients and 930 cancer-free women from Ontario, Canada. RESULTS: The heterozygous ATRIP c.1152_1155del p.(Gly385Ter) variant was identified in 8 of 3404 ovarian cancer cases and 11 of 9285 controls in the Polish population (OR = 1.98, 95% CI = 0.79-4.94, P = .19). In the Ontario cohort, 4 ovarian cancer cases harbored ATRIP loss-of-function (LoF) variants, versus none observed among controls (OR = 5.6, P = .14). In a combined analysis of both cohorts, adjusted for age, self-reported ethnicity, and study, ATRIP LoF variants were significantly associated with ovarian cancer risk (OR = 2.51, 95% CI = 1.108-5.699, P = .037). CONCLUSION: ATRIP plays a critical role in DNA damage response and genomic stability. Our findings support its candidacy as a novel ovarian cancer susceptibility gene.

Humans↗
PubMed2006

Do probiotics have a therapeutic role in gastroenterology?

Several hundred species of bacteria inhabit the gut, and affect its cell biology, morphology and homeostasis. Many bacteria are however potential pathogens, especially if the integrity of the epithelial barrier is physically or functionally breached. Conversely, the interaction between host and commensal microbes can confer important health benefits. This has led to commercial and public interest in "probiotics", live microbes principally taken as food supplements. Might probiotics also be used in disease therapy? Experimental evidence that probiotics modulate gut physiology, particularly barrier integrity and immunological function, underpins exciting new gastroenterological research. We discuss below the scientific basis for probiotic effects and present a critical perspective for their use in relation to gastrointestinal disease.

Gastrointestinal Diseases↗
PubMed2006

R-253 disrupts microtubule networks in multiple tumor cell lines.

PURPOSE: The design and development of synthetic small molecules to disrupt microtubule dynamics is an attractive therapeutic strategy for anticancer drug discovery research. Loss of clinical efficacy of many useful drugs due to drug resistance in tumor cells seems to be a major hurdle in this endeavor. Thus, a search for new chemical entities that bind tubulin, but neither are a substrate of efflux pump, P-glycoprotein 170/MDR1, nor cause undesired side effects, would potentially increase the therapeutic index in certain cancer treatments. EXPERIMENTAL DESIGN: A high-content cell-based screen of a compound library led to the identification of a new class of compounds belonging to a thienopyrimidine series, which exhibited significant antitumor activities. On structure-activity relationship analysis, R-253 [N-cyclopropyl-2-(6-(3,5-dimethylphenyl)thieno[3,2-d]pyrimidin-4-yl)hydrazine carbothioamide] emerged as a potent antiproliferative agent (average EC(50), 20 nmol/L) when examined in a spectrum of tumor cell lines. RESULTS: R-253 is structurally unique and destabilizes microtubules both in vivo and in vitro. Standard fluorescence-activated cell sorting and Western analyses revealed that the effect of R-253 on cell growth was associated with cell cycle arrest in mitosis, increased select G(2)-M checkpoint proteins, and apoptosis. On-target activity of R-253 on microtubules was further substantiated by immunofluorescence studies and selected counter assays. R-253 competed with fluorescent-labeled colchicine for binding to tubulin, indicating that its binding site on tubulin could be similar to that of colchicine. R-253 neither is a substrate of P-glycoprotein 170/MDR1 nor is cytotoxic to nondividing human hepatocytes. CONCLUSION: Both biochemical and cellular mechanistic studies indicate that R-253 could become a promising new tubulin-binding drug candidate for treating various malignancies.

Adenocarcinoma↗
PubMed2006

Gene therapy in the nervous system with superoxide dismutase.

Neuronal death following necrotic insults involves the generation of reactive oxygen species (ROS). We investigated the effects of antioxidant gene therapy on ROS accumulation after exposure to either sodium cyanide, kainic acid or oxygen glucose deprivation (OGD). Specifically, we generated herpes simplex virus-1 amplicon vector expressing the gene for the antioxidant enzyme CuZnSOD. Overexpression of this gene in primary hippocampal cultures resulted in increased enzymatic activity of the corresponding protein. CuZnSOD significantly protected hippocampal neurons against sodium cyanide insult and the subsequent lipid peroxidation. However, it did not protect against OGD- or kainic-acid-induced toxicity. Moreover, CuZnSOD significantly worsened the toxicity, hydrogen peroxide accumulation and lipid peroxidation induced by kainic acid. As a possible explanation for this surprising worsening, CuZnSOD overexpression increased glutathione peroxidase activity in the presence of sodium cyanide but had no effect on catalase or glutathione peroxidase activity in the presence of kainic acid. Thus, cells were unlikely to be able to detoxify the excess hydrogen peroxide produced as a result of the CuZnSOD overexpression. These studies can be viewed as a cautionary note concerning gene therapy intervention against necrotic insults.

Animals↗
PubMed2006

The rationale, efficacy and safety evidence for tegaserod in the treatment of irritable bowel syndrome.

A growing body of evidence implicates abnormal serotonergic regulation of gastrointestinal function in the pathogenesis of the irritable bowel syndrome (IBS). Drugs targeting this system are therefore attractive concepts. The partial 5-HT4 receptor agonist tegaserod might be predicted to have positive therapeutic effects on a constipated and uncomfortable gut. However, IBS runs a chronic, benign course and carries no associated mortality, so it is imperative that the safety profile of new pharmacological agents made available to physicians is exemplary. The authors review the evidence for 5-HT in the aetiology of IBS and its symptoms, and the data available concerning the partial 5-HT4 receptor agonist tegaserod, in terms of rationale, efficacy and safety.

Biological Availability↗
PubMed2005

Multiple roles for the receptor tyrosine kinase axl in tumor formation.

A focus of contemporary cancer therapeutic development is the targeting of both the transformed cell and the supporting cellular microenvironment. Cell migration is a fundamental cellular behavior required for the complex interplay between multiple cell types necessary for tumor development. We therefore developed a novel retroviral-based screening technology in primary human endothelial cells to discover genes that control cell migration. We identified the receptor tyrosine kinase Axl as a novel regulator of endothelial cell haptotactic migration towards the matrix factor vitronectin. Using small interfering RNA-mediated silencing and overexpression of wild-type or mutated receptor proteins, we show that Axl is a key regulator of multiple angiogenic behaviors including endothelial cell migration, proliferation, and tube formation in vitro. Moreover, using sustained, retrovirally delivered short hairpin RNA (shRNA) Axl knockdown, we show that Axl is necessary for in vivo angiogenesis in a mouse model. Furthermore, we show that Axl is also required for human breast carcinoma cells to form a tumor in vivo. These findings indicate that Axl regulates processes vital for both neovascularization and tumorigenesis. Disruption of Axl signaling using a small-molecule inhibitor will hence simultaneously affect both the tumor and stromal cell compartments and thus represents a unique approach for cancer therapeutic development.

Animals↗
PubMed2005

Colorectal screening is associated with reduced colorectal cancer risk: a case-control study within the population-based Ontario Familial Colorectal Cancer Registry.

OBJECTIVE: This is the first study to evaluate the association between colonic screening and colorectal cancer risk among Canadians. METHODS: A case-control study was conducted. Cases were diagnosed with cancer of the colorectum, between 1997 and 2000, aged 20 to 74 years, identified through the population-based Ontario Cancer Registry and recruited by the Ontario Familial Colorectal Cancer Registry. Controls were a sex- and age-matched random sample of the population of Ontario. 971 cases and 1944 controls completed questionnaires (including colorectal screening history and many risk factors). Multivariate logistic regression analysis was used to obtain adjusted odds ratios (OR) estimates. RESULTS: Having had a fecal occult blood screen was associated with reduced colorectal cancer risk (OR=0.76; 95% confidence interval (CI): 0.59, 0.97). Having had a screening sigmoidoscopy was associated with a halving of colorectal cancer risk (OR = 0.52; 95% CI: 0.34, 0.80). Having had a screening colonoscopy did not significantly reduce colorectal cancer risk (OR = 0.69; 95% CI: 0.44, 1.07); however, having had either screening endoscopy was associated with a significant reduction in colorectal cancer risk (OR = 0.62; 95% CI: 0.44, 0.87). Findings differed slightly by anatomic sub-site (proximal and distal colorectum). CONCLUSIONS: We report a reduction in colorectal cancer risk among persons who underwent colorectal cancer screening; in particular, sigmoidoscopy. Findings are of great importance for the prevention of colorectal cancer.

Adult↗
PubMed2005

Association between colonic screening, subject characteristics, and stage of colorectal cancer.

OBJECTIVES: Colorectal cancer remains a significant cause of mortality and morbidity in North America. Colorectal cancer survival is highly dependent on stage at diagnosis, therefore it is important to identify factors related to stage. This study evaluated the association between subject factors (e.g., colonic screening, family history) and stage of colorectal cancer at diagnosis. METHODS: Population-based colorectal cancer cases recruited by the Ontario Familial Colon Cancer Registry between 1997 and 1999 were staged according to the tumor-nodal-metastasis (TNM) staging system and classified as early (TNM I/II) or late (TNM III/IV) stage. Epidemiologic information and stage was available for 768 cases. Multivariate logistic regression was used to obtain odds ratios (OR) estimates. RESULTS: Having had screening endoscopy reduced the risk of late stage diagnosis (OR = 0.46, 95% CI 0.22-0.98). Being older (>45 yr) was associated with a reduced risk of late stage cancer (OR = 0.36, 95% CI 0.18-0.74), as was having a first degree relative with colorectal cancer (OR =0.66, 95% CI 0.46-0.95). Rural residence (OR = 1.48, 95% CI 1.01-2.17) and non-white ethnicity (OR = 3.34, 95% CI 1.20-9.36) were associated with an increased risk of late stage cancer. CONCLUSIONS: Several factors are independently associated with late stage colorectal cancer. Colorectal cancer screening awareness and education programs need to consider targeting persons most likely to present with late stage colorectal cancer.

Adult↗
PubMed2004

A clinicobiological model predicting survival in medulloblastoma.

PURPOSE: The purpose of this study was to determine the relative contributions of biological and clinical predictors of survival in patients with medulloblastoma (MB). EXPERIMENTAL DESIGN: Clinical presentation and survival information were obtained for 119 patients who had undergone surgery for MB at the Hospital for Sick Children (Toronto, Ontario, Canada) between 1985 and 2001. A tissue microarray was constructed from the tumor samples. The arrays were assayed for immunohistochemical expression of MYC, p53, platelet-derived growth factor receptor-alpha, ErbB2, MIB-1, and TrkC and for apoptosis (terminal deoxynucleotidyl transferase-mediated nick end labeling). Both univariable and multivariable analyses were conducted to characterize the association between survival and both clinical and biological markers. For the strongest predictors of survival, a weighted predictive score was calculated based on their hazard ratios (HRs). The sum of these scores was then used to give an overall prediction of survival using a nomogram. RESULTS: The four strongest predictors of survival in the final multivariable model were the presence of metastatic disease at presentation (HR, 2.02; P=0.01) and p53 (HR, 2.29; P=0.02), TrkC (HR, 0.65; P=0.14), and ErbB2 (HR, 1.51; P=0.21) immunopositivity. A linear prognostic index was derived, with coefficients equal to the logarithm of these HRs. The 5-year survival rate for patients at the 10th, 50th, and 90th percentiles of the score distribution was 80.0%, 71.0%, and 35.7%, respectively, with radiation therapy and 70.5%, 58.5%, and 20.0%, respectively, without radiation therapy. CONCLUSIONS: In this study, we demonstrate an approach to combining both clinical and biological markers to quantify risk in MB patients. This provides further prognostic information than can be obtained when either clinical factors or biological markers are studied separately and establishes a framework for comparing prognostic markers in future clinical studies.

Adolescent↗
PubMed2004

Ochratoxin A increases permeability through tight junctions by removal of specific claudin isoforms.

On interaction with the intestine, the mycotoxin ochratoxin A is know to cause rapid inflammation, diarrhea, and increased bacterial translocation. All these effects are consistent with a decrease in epithelial barrier function. However, this has not been shown directly. We determined that ochratoxin A is able to reduce the barrier properties of the model intestinal cell line Caco-2. Over 24 h, ochratoxin A reduces the transepithelial electrical resistance of Caco-2 monolayers growing on Transwell filters by approximately 40%. At the same time, the permeability of the monolayer is increased with respect to 4- and 10-kDa FITC dextrans, but not to 20- or 40-kDa dextrans. Immunoblotting and immunofluorescence reveal that the decrease in barrier properties is concomitant with disappearance of claudins 3 and 4, but not claudin 1 from Caco-2 cell membranes. These results suggest that ochratoxin A is able to modulate the barrier function of Caco-2 cells by removal of specific claudin isoforms.

Caco-2 Cells↗
PubMed2004

Cholecystokinin pathways modulate sensations induced by gastric distension in humans.

Ingested fat releases CCK, causes gastric relaxation, delays gastric emptying, and limits meal size; however, the mechanistic link among these actions has not been established. Fatty acid release of CCK is chain-length sensitive; dodecanoic acid (C12) induces greater CCK release than decanoic acid (C10). The effect of C12 or C10 on tolerance to subsequent intragastric infusion of liquid was determined in healthy subjects, with and without the CCK(1) receptor antagonist dexloxiglumide. Gastric wall relaxation after either fatty acid was assessed by graded volume distension and by barostat; gastric emptying was measured by gastric aspiration and by a [(13)C]octanoic acid breath technique. C12 released more CCK (mean plasma CCK after vehicle, 4.7 +/- 0.8 pM; C10, 4.8 +/- 0.3 pM; C12, 8 +/- 1.2 pM; P < 0.05 C12 vs. C10 or vehicle) and reduced the volume of water (and of 5 and 25% glucose solutions) delivered at maximum tolerance compared with C10 or vehicle (volume of water tolerated after vehicle, 1,535 +/- 164 ml; C10, 1,335 +/- 160 ml; C12, 842 +/- 103 ml; P < 0.05 C12 vs. C10 or vehicle); this effect was abolished by dexloxiglumide. Intragastric volumes were always similar at the limit of tolerance, and, whereas gastric relaxation occurred to similar degrees after the fatty acids, its duration was longer after C12, which also induced a longer delay in half-gastric emptying [t(1/2)(min) after vehicle, 53 +/- 2; C10, 67 +/- 3; C12, 88 +/- 7; P < 0.05 C12 vs. C10 or vehicle]. In conclusion, ingestion of a CCK-releasing fatty acid reduces the tolerated volume of liquid delivered into the stomach, primarily via a CCK(1) receptor-mediated delay in gastric emptying.

Adult↗
PubMed2004

How do primary care physicians manage children with possible developmental delays? A national survey with an experimental design.

OBJECTIVE: Although early detection and treatment of developmental delays can improve outcome, little is known about factors that influence how primary care physicians manage young children with probable developmental delays. The objective of this study was to describe physician referral practices for children with developmental delays and to test whether the probability of referral is increased by 1) the expression of parental concern; 2) female gender in a child with language delay; 3) disruptive, as opposed to avoidant behaviors; and 4) physician characteristics, including female gender or being a pediatrician. METHODS: A cross-sectional survey was mailed to a national random sample of 800 pediatricians and 800 family practice physicians in primary care practice, using an experimental randomized block design. Recipients randomly received alternative variants of clinical vignettes, which differed only in regard to the variable specific to each of the first 3 hypotheses. Physicians answered questions about the likelihood of referral on a 5-point scale for listed referral options. Hypotheses were tested using multivariable logistic regression modeling. A total of 55% of pediatricians and 43% of family practice physicians returned the survey, for an overall response rate of 49%. RESULTS: A girl with language delay was 60% more likely to be referred to audiology than a boy (odds ratio: 1.6; 95% confidence interval: 1.1-2.3), and respondents who were female or pediatricians were more likely to refer patients. The expression of parental concern did not increase the probability of referral to diagnostic and treatment services, and avoidant rather than disruptive patient behaviors were associated with an increased probability of referral. CONCLUSIONS: Patient gender and type of behavioral presentation seem to influence referrals to diagnostic and treatment services for young children with probable developmental delays described in clinical vignettes. These findings can guide targeted educational interventions to increase rates of detection and referral for young children with developmental delays.

Child, Preschool↗
PubMed2003

How do primary care physicians identify young children with developmental delays? A national survey.

Little is known about the current practices of primary care physicians regarding developmental surveillance and screening during pediatric preventive care visits. We conducted a mailed survey of a random national sample of pediatricians and family physicians to describe their practices and identify factors that predict use of developmental screening tools, an efficacious way of identifying children with developmental delays. Most physicians reviewed developmental milestones and prompted parents for developmental concerns at preventive care visits. Approximately half of the physicians used a formal developmental screening instrument. Female physician gender predicted higher rates of use of screening tools for family physicians, but not for pediatricians. Most physicians seemed committed to the early diagnosis of developmental delays. Substantial variability in surveillance and screening practices, barriers of time and reimbursement, and under-reliance on parent-completed questionnaires underscore areas for improvement.

Adult↗
PubMed2003

Chemical composition of some components of the arrestment pheromone of the black-legged tick, Ixodes scapularis (Acari: Ixodidae) and their use in tick control.

Chemical analysis (high-performance liquid chromatography) and bioassay demonstrated the presence of compounds that seem to be components of the Ixodes scapularis arrestment pheromone. Only two purines, guanine and xanthine, were found in acidified saline extracts made from cast skins after molting of fed nymphs, fed larvae, and fecal/excretory exudates deposited by unfed adults on substrates in their environment. The ratio of guanine to xanthine was 10.6:1 in an extract from the nymphal skins versus 0.95:1 in an extract from the larval skins. Guanine, xanthine, and traces of a third purine, tentatively identified as 8-azaguanine, were found in extracts made from filter paper strips or washings from glass vials contaminated with tick feces and excreta left by unfed adults. 8-azaguanine may be a product of microbial degradation of the other purines rather than a natural product from the ticks. Low concentrations of ammonia also were detected in saline extracts of excreta from feeding ticks. Hematin also was found in NH4OH extracts of the black fecal/excretory exudates deposited by the unfed ticks. Hematin was tentatively identified by comparison of spectra with that of the authentic standard. Bioassays demonstrated a strong positive arrestment response to cast skins found to contain a mixture of guanine and xanthine and to black fecal/excretory exudates containing guanine, xanthine, the putative 8-azaguanine, and hematin. A Noldus video tracking system using a CCD video camera and Ethovision Pro tracking software showed statistically significant increases in the frequency of visits to the treated zone versus the control. Ticks were significantly more likely to assemble in response to the tick exudates within as little as 3 h compared with the controls. Previous bioassay studies also showed strong positive responses to guanine, xanthine, other purines, and hematin. Comparisons with the arrestment pheromones of other tick species are described. The inclusion of the pheromone components in a permethrin-impregnated oily matrix, Last Call, increased the lethal activity of the product to 95% compared with only 65% in the formulation with permethrin alone. More detailed knowledge of I. scapularis arrestment pheromone may be useful for improving the efficacy of this tick-killing technology even further.

Adenine↗