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Biomedical subjects

Patrick Lynch

Publications and source records attributed to Patrick Lynch.

18 recordsLinked to original sources
PubMed2007

Spectroscopic characterization of novel polycyclic aromatic polymers.

A series of novel polyphenylenevinylene (PPV) derivative polymers were studied by absorption and photoluminescence spectroscopies. The effect of the sequential introduction of polycyclic aromatic ring substituents into the delocalized backbone was examined with relation to hypsochromatic and bathochromatic shifting. While the replacement of the phenyl units by naphthyl units results in a substantial hypsochromic shift of both the absorption and emission spectra, their subsequent substitution by anthryl units results in a bathochromic shift. The system is modeled according to, and is found to be consistent with, a previous study of donor-acceptor polyenes of varying length. The electronic structure of the backbone is found to be a balance between that of the high electron affinity polycyclic ring system and the contribution to conjugation across the linking vinyl unit. The model is adapted based on electron affinities of the constituent units, and a clear structure-property relationship for the absorption and emission properties of the system is elucidated. The Stokes shift is examined and is seen to be well-correlated with the vinyl contribution to the electron affinity total (EAtotal). The trends observed in the optical properties of the polymeric system are supported by Raman spectroscopy, whereby the spectral signature of the connecting vinyl bond is seen to soften in a fashion which is correlated with the modeled electron affinity parameters.

Absorption↗
PubMed2007

Association between Aurora-A kinase polymorphisms and age of onset of hereditary nonpolyposis colorectal cancer in a Caucasian population.

Aurora-A kinase is considered a potential cancer susceptibility gene that encodes a centrosome-associated, cell cycle-regulated serine/threonine kinase. We studied two single nucleotide polymorphisms (SNP) in the coding region of Aurora-A, 91T-to-A (F31I) and 169G-to-A (V57I). We studied the influence of these two polymorphisms on age of onset of hereditary nonpolyposis colorectal cancer (HNPCC). Genotyping of the Aurora-A polymorphisms was carried out on 125 Caucasian with mismatch repair (MMR) gene mutations with real-time pyrophosphate DNA sequencing. For the 91T-to-A polymorphism, we found that patients with HNPCC who were homozygous for the wild-type allele developed colorectal cancer (CRC) 7 years earlier than patients who were homozygous or heterozygous for the mutant allele. The169G-to-A polymorphism did not have a significant influence on risk for HNPCC. However, when we did haplotype analysis for these two polymorphisms, the 91A-169G haplotype was associated with protection from HNPCC at an earlier age.

Adolescent↗
PubMed2006

Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: a systematic review.

CONTEXT: About 2% of all colorectal cancer occurs in the context of the autosomal dominantly inherited Lynch syndrome, which is due to mutations in mismatch repair genes. Potential risk-reducing interventions are recommended for individuals known to have these mutations. OBJECTIVES: To review cancer risks and data on screening efficacy in the context of Lynch syndrome (hereditary nonpolyposis colorectal cancer) and to provide recommendations for clinical management for affected families, based on available evidence and expert opinion. DATA SOURCES AND STUDY SELECTION: A systematic literature search using PubMed and the Cochrane Database of Systematic Reviews, reference list review of retrieved articles, manual searches of relevant articles, and direct communication with other researchers in the field. Search terms included hereditary non-polyposis colon cancer, Lynch syndrome, microsatellite instability, mismatch repair genes, and terms related to the biology of Lynch syndrome. Only peer-reviewed, full-text, English-language articles concerning human subjects published between January 1, 1996, and February 2006 were included. The US Preventive Services Task Force's 2-tier system was adapted to describe the quality of evidence and to assign strength to the recommendations for each guideline. EVIDENCE SYNTHESIS: The evidence supports colonoscopic surveillance for individuals with Lynch syndrome, although the optimal age at initiation and frequency of examinations is unresolved. Colonoscopy is recommended every 1 to 2 years starting at ages 20 to 25 years (age 30 years for those with MSH6 mutations), or 10 years younger than the youngest age of the person diagnosed in the family. While fully acknowledging absence of demonstrated efficacy, the following are also recommended annually: endometrial sampling and transvaginal ultrasound of the uterus and ovaries (ages 30-35 years); urinalysis with cytology (ages 25-35 years); history, examination, review of systems, education and genetic counseling regarding Lynch syndrome (age 21 years). Regular colonoscopy was favored for at-risk persons without colorectal neoplasia. For individuals who will undergo surgical resection of a colon cancer, subtotal colectomy is favored. Evidence supports the efficacy of prophylactic hysterectomy and oophorectomy. CONCLUSIONS: The past 10 years have seen major advances in the understanding of Lynch syndrome. Current recommendations regarding cancer screening and prevention require careful consultation between clinicians, clinical cancer genetic services, and well-informed patients.

Adult↗
PubMed2006

ACE gene D/D genotype as a risk factor for chronic nephrotoxicity from calcineurin inhibitors in liver transplant recipients.

BACKGROUND: Chronic renal failure (CRF) is a major cause of morbidity and mortality after orthotopic liver transplantation (OLTX) and is predominantly caused by calcineurin inhibitors (CI)-induced nephrotoxicity. The activation of the renin angiotensin system (RAS) has been implicated in the pathogenesis of chronic nephrotoxicity from CI. METHODS: We retrospectively investigated the genes coding for components of the RAS (ACE gene, Angiotensin II receptor 1 gene, Angiotensinogen gene) in 233 liver transplant recipients receiving Cyclosporine (CsA) or Tacrolimus (Tac) as maintenance immunosuppressant. All patients with serum creatinine (sCr) <1.0 mg/dL (n=143) before orthotopic liver transplantation (OLTX) were included in the final analysis. Patients were than categorized into two groups based upon their most recent postliver transplant sCr level: Group 1 (n=83) with sCr <1.5 mg/dL (mean 1.1+/-0.2) and group 2 (n=60) with sCr > or =1.5 mg/dL (mean 2.5+/-1.3) RESULTS: ACE D/D genotype was found in 57% of patients with sCr > or =1.5 mg/dL compared to 20% of patients with sCr <1.5 mg/dL (P<0.0001) CONCLUSIONS: Our analysis strongly suggests that liver transplant patients with ACE gene D/D genotype are at a significant higher risk of developing CI-induced chronic nephrotoxicity.

Angiotensinogen↗
PubMed2006

Randomized controlled study of tenofovir and adefovir in chronic hepatitis B virus and HIV infection: ACTG A5127.

Chronic hepatitis B virus (HBV) infection is an important cause of morbidity and mortality in subjects coinfected with HIV. Tenofovir disoproxil fumarate (TDF) and adefovir dipivoxil (ADV) are licensed for the treatment of HIV-1 and HBV infection, respectively, but both have in vivo and in vitro activity against HBV. This study evaluated the anti-HBV activity of TDF compared to ADV in HIV/HBV-coinfected subjects. ACTG A5127 was a prospective randomized, double-blind, placebo-controlled trial of daily 10 mg of ADV versus 300 mg of TDF in subjects with HBV and HIV coinfection on stable ART, with serum HBV DNA >/= 100,000 copies/mL, and plasma HIV-1 RNA </= 10,000 copies/mL. This study closed early based on results of a prespecified interim review, as the primary noninferiority end point had been met without safety issues. Fifty-two subjects were randomized. At baseline, 73% of subjects had a plasma HIV-1 RNA < 50 copies/mL, 86% were HBeAg positive, 94% were 3TC resistant, median serum ALT was 52 IU/L, and 98% had compensated liver disease. The mean time-weighted average change in serum HBV DNA from baseline to week 48 (DAVG(48)) was -4.44 log(10) copies/mL for TDF and -3.21 log(10) copies/mL for ADV. There was no difference in toxicity between the 2 treatment arms, with 11 subjects (5 ADV and 6 TDF) experiencing elevations of serum ALT on treatment. In conclusion, over 48 weeks, treatment with either ADV or TDF resulted in clinically important suppression of serum HBV DNA. Both drugs are safe and efficacious for patients coinfected with HBV and HIV.

Adenine↗
PubMed2006

Celecoxib treatment alters the gene expression profile of normal colonic mucosa.

A clinical trial was recently conducted to evaluate the safety and efficacy of a selective inhibitor of cyclooxygenase-2 (celecoxib) in hereditary nonpolyposis colon cancer patients. In a randomized, placebo-controlled phase I/II multicenter trial, hereditary nonpolyposis colon cancer patients and gene carriers received either celecoxib at one of two doses or placebo. The goal was to evaluate the effects of these treatment arms on a number of endoscopic and tissue-based biomarker end points after 12 months of treatment. As part of this trial, we analyzed gene expression by cDNA array technology in normal descending (rectal) colonic mucosa of patients before and after treatment with celecoxib or placebo. We found that treatment of patients with celecoxib at recommended clinical doses (200 and 400 mg p.o. bid), in contrast to treatment with placebo, leads to changes in expression of >1,400 genes in the healthy colon, although in general, the magnitude of changes is <2-fold. Twenty-three of 25 pairs of colon biopsies taken before and after celecoxib treatment can be classified correctly by the pattern of gene expression in a leave-one-out cross-validation. Immune response, particularly T- and B-lymphocyte activation and early steps of inflammatory reaction, cell signaling and cell adhesion, response to stress, transforming growth factor-beta signaling, and regulation of apoptosis, are the main biological processes targeted by celecoxib as shown by overrepresentation analysis of the distribution of celecoxib-affected genes across Gene Ontology categories. Analysis of possible cumulative effects of celecoxib-induced changes in gene expression indicates that in healthy colon, celecoxib may suppress the immune response and early steps of inflammation, inhibit formation of focal contacts, and stimulate transforming growth factor-beta signaling.

Biomarkers↗
PubMed2005

The critical role of 15-lipoxygenase-1 in colorectal epithelial cell terminal differentiation and tumorigenesis.

Terminal differentiation is an important event for maintaining normal homeostasis in the colorectal epithelium, and the loss of apoptosis is an important mechanism underlying colorectal tumorigenesis. The very limited current data on the role of lipoxygenase (LOX) metabolism in tumorigenesis suggests that the oxidative metabolism of linoleic and arachidonic acid possibly shifts from producing antitumorigenic 15-LOX-1 and 15-LOX-2 products to producing protumorigenic 5-LOX and 12-LOX products. We examined whether this shift occurs in vitro in the human colon cancer cell line Caco-2 in association with the loss of terminal differentiation and apoptosis, or in vivo during the formation of colorectal adenomas in patients with familial adenomatous polyposis (FAP). Restoring terminal differentiation and apoptosis of Caco-2 cells increased the mRNA levels of 5-LOX, 15-LOX-2, and 15-LOX-1, but the only significant increases in protein expression and enzymatic activity were of 15-LOX-1. In FAP patients, 15-LOX-1 expression and activity were significantly down-regulated in adenomas (compared with paired nonneoplastic epithelial mucosa), whereas 5-LOX and 15-LOX-2 protein expressions and enzymatic activities were not. We conducted a validation study with immunohistochemical testing in a second group of FAP patients; 15-LOX-1 expression was down-regulated in colorectal adenomas (compared with nonneoplastic epithelial mucosa) in 87% (13 of 15) of this group. We confirmed the mechanistic relevance of these findings by demonstrating that ectopically restoring 15-LOX-1 expression reestablished apoptosis in Caco-2 cells. Therefore, 15-LOX-1 down-regulation rather than a shift in the balance of LOXs is likely the dominant alteration in LOX metabolism which contributes to colorectal tumorigenesis by repressing apoptosis.

Adenoma↗
PubMed2005

Staging intra-abdominal desmoid tumors in familial adenomatous polyposis: a search for a uniform approach to a troubling disease.

INTRODUCTION: Desmoid tumors are a clinical problem in 12 to 15 percent of patients with familial adenomatous polyposis. There is no predictably effective treatment for intra-abdominal desmoid tumors, which sometimes cause significant complications by their effects on the ureters or bowel. The relative rarity and the clinical heterogeneity of intra-abdominal desmoid tumors make randomized studies difficult to do. In this article a staging system is proposed to make multi-institutional studies easier. METHODS: Intra-abdominal desmoid tumors can be staged according to their size, clinical presentation and growth pattern. CONCLUSION: A way of staging intra-abdominal desmoid tumors is proposed to facilitate stratification by disease severity during collaborative studies of various treatments.

Abdominal Neoplasms↗
PubMed2005

Gynecologic cancer as a "sentinel cancer" for women with hereditary nonpolyposis colorectal cancer syndrome.

OBJECTIVE: Women with hereditary nonpolyposis colorectal cancer syndrome have a 40-60% lifetime risk for colon cancer, a 40-60% lifetime risk for endometrial cancer, and a 12% lifetime risk for ovarian cancer. A number of women with hereditary nonpolyposis colorectal cancer syndrome will have more than one cancer in their lifetime. The purpose of this study was to estimate whether women with hereditary nonpolyposis colorectal cancer syndrome who develop 2 primary cancers present with gynecologic or colon cancer as their "sentinel cancer." METHODS: Women whose families fulfilled Amsterdam criteria for hereditary nonpolyposis colorectal cancer syndrome and who developed 2 primary colorectal/gynecologic cancers in their lifetime were identified from 5 large hereditary nonpolyposis colorectal cancer syndrome registries. Information on age at cancer diagnoses and which cancer (colon cancer or endometrial cancer/ovarian cancer) developed first was obtained. RESULTS: A total of 117 women with dual primary cancers from 223 Amsterdam families were identified. In 16 women, colon cancer and endometrial cancer/ovarian cancer were diagnosed simultaneously. Of the remaining 101 women, 52 (51%) women had an endometrial or ovarian cancer diagnosed first. Forty-nine (49%) women had a colon cancer diagnosed first. For women who developed endometrial cancer/ovarian cancer first, mean age at diagnosis of endometrial cancer/ovarian cancer was 44. For women who developed colon cancer first, the mean age at diagnosis of colon cancer was 40. CONCLUSION: In this large series of women with hereditary nonpolyposis colorectal cancer syndrome who developed 2 primary colorectal/gynecologic cancers, endometrial cancer/ovarian cancer was the "sentinel cancer," preceding the development of colon cancer, in half of the cases. Therefore, gynecologists and gynecologic oncologists play a pivotal role in the identification of women with hereditary nonpolyposis colorectal cancer syndrome.

Adult↗
PubMed2005

Elevated plasma concentrations of protease inhibitors and nonnucleoside reverse transcriptase inhibitors in patients coinfected with human immunodeficiency virus and hepatitis B or C: case series and literature review.

STUDY OBJECTIVE: To evaluate antiretroviral pharmacokinetics in patients who are coinfected with human immunodeficiency virus (HIV) and hepatitis B and/or C virus. Specifically, we sought to determine whether coinfection results in higher than expected concentrations of protease inhibitors and nonnucleoside reverse transcriptase inhibitors (NNRTIs). DESIGN: Case series. SETTING: Human immunodeficiency virus clinic. PATIENTS: Twenty-six patients infected with HIV and hepatitis B and/or C virus. MEASUREMENTS AND MAIN RESULTS: Patients' plasma trough concentrations (Cmeasured) of protease inhibitors and NNRTIs were compared with population average trough concentrations reported in the literature (Cpredicted). Trough concentrations were obtained irrespective of the patients' liver function. A concentration ratio of Cmeasured: Cpredicted was determined for each patient. The mean concentration ratio of the 26 patients was 1.43 (95% confidence interval 1.08-1.78). For the six patients taking nelfinavir, the ratio of nelfinavir's active metabolite (M8): parent drug was calculated. The median M8:nelfinavir ratio for these six patients was 69% lower than what has been reported in a general HIV population. CONCLUSION: These preliminary findings suggest that trough concentrations of protease inhibitors and NNRTIs may be elevated in patients with HIV infection who are coinfected with hepatitis B and/or C, compared with a general population of patients with HIV infection. Until further investigation defines the relationship between coinfection, metabolic dysfunction, and increased antiretroviral exposure, therapeutic drug monitoring may be helpful to identify coinfected patients at risk for antiretroviral toxicity secondary to elevated plasma drug concentrations.

Chromatography, High Pressure Liquid↗
PubMed2004

Computed tomographic colonography (virtual colonoscopy): a multicenter comparison with standard colonoscopy for detection of colorectal neoplasia.

CONTEXT: Conventional colonoscopy is the best available method for detection of colorectal cancer; however, it is invasive and not without risk. Computed tomographic colonography (CTC), also known as virtual colonoscopy, has been reported to be reasonably accurate in the diagnosis of colorectal neoplasia in studies performed at expert centers. OBJECTIVE: To assess the accuracy of CTC in a large number of participants across multiple centers. DESIGN, SETTING, AND PARTICIPANTS: A nonrandomized, evaluator-blinded, noninferiority study design of 615 participants aged 50 years or older who were referred for routine, clinically indicated colonoscopy in 9 major hospital centers between April 17, 2000, and October 3, 2001. The CTC was performed by using multislice scanners immediately before standard colonoscopy; findings at colonoscopy were reported before and after segmental unblinding to the CTC results. MAIN OUTCOME MEASURES: The sensitivity and specificity of CTC and conventional colonoscopy in detecting participants with lesions sized at least 6 mm. Secondary outcomes included detection of all lesions, detection of advanced lesions, possible technical confounders, participant preferences, and evidence for increasing accuracy with experience. RESULTS: A total of 827 lesions were detected in 308 of 600 participants who underwent both procedures; 104 participants had lesions sized at least 6 mm. The sensitivity of CTC for detecting participants with 1 or more lesions sized at least 6 mm was 39.0% (95% confidence interval [CI], 29.6%-48.4%) and for lesions sized at least 10 mm, it was 55.0% (95% CI, 39.9%-70.0%). These results were significantly lower than those for conventional colonoscopy, with sensitivities of 99.0% (95% CI, 97.1%->99.9%) and 100%, respectively. A total of 496 participants were without any lesion sized at least 6 mm. The specificity of CTC and conventional colonoscopy for detecting participants without any lesion sized at least 6 mm was 90.5% (95% CI, 87.9%-93.1%) and 100%, respectively, and without lesions sized at least 10 mm, 96.0% (95% CI, 94.3%-97.6%) and 100%, respectively. Computed tomographic colonography missed 2 of 8 cancers. The accuracy of CTC varied considerably between centers and did not improve as the study progressed. Participants expressed no clear preference for either technique. CONCLUSIONS: Computed tomographic colonography by these methods is not yet ready for widespread clinical application. Techniques and training need to be improved.

Colonography, Computed Tomographic↗
PubMed2004

Who takes the most revenge? Individual differences in negative reciprocity norm endorsement.

The authors report that beliefs favoring the reciprocation of unfavorable treatment form a unitary factor that is distinct from beliefs favoring the reciprocation of favorable treatment. Individual differences in endorsement of this negative reciprocity norm were related to (a) beliefs that people are generally malevolent; (b) inclination toward anger in everyday life; (c) anger, disagreement, and ridicule directed toward a new acquaintance who treated participants unfavorably; and (d) reduced anxiety, positive emotional engagement, and encouragement of a new acquaintance who treated participants favorably. These findings suggest that individual differences in endorsement of the negative norm of reciprocity influence the extent of vengeance.

Adult↗
PubMed2003

Panic in the emergency room.

OBJECTIVE: This paper examines the relation between coronary artery disease (CAD) and panic disorder (PD), discusses the implications of this relation to the general medical system, and suggests future assessment and intervention strategies for emergency departments. METHOD: We reviewed the literature on CAD and PD using Medline and PsycINFO. RESULTS: PD is more expensive to our nonpsychiatric, general medical system than any other psychiatric condition. The main reason for PD patients' continued use of general medicine for their psychological symptoms is that their PD remains undiagnosed. In the emergency room (ER), PD patients with chest pain have their PD go undiagnosed about 98% of the time. By having ERs implement specific assessment and intervention strategies for patients presenting with chest pain, the savings to the general medical system could be substantial. CONCLUSIONS: By improving recognition of PD in the ER, there is the potential to generate large savings in general medical care. With the availability of empirically supported or effective psychological and pharmacologic treatments for PD, appropriately diagnosing and subsequently treating patients with PD may prevent them from experiencing many years of disability and higher rates of fatal coronary events.

Chest Pain↗
PubMed2003

Distinguishing right from left colon by the pattern of gene expression.

Distinct epidemiological and clinicopathological characteristics of colorectal carcinomas (CRCs) based on their anatomical location suggest different risk factors and pathways of transformation associated with proximal and distal colon carcinogenesis. These differences may reflect distinct biological characteristics of proximal and distal colonic mucosa, acquired in embryonic or postnatal development, that determine a differential response to uniformly distributed environmental factors. Alternatively, the differences in the epidemiology of proximal and distal CRCs could result from the presence of different procarcinogenic factors in the ascending versus descending colon, acting on cells with either similar or distinct biological characteristics. We applied cDNA microarray technology to explore the possibility that mucosal epithelium from adult proximal and distal colon can be distinguished by their pattern of gene expression. In addition, gene expression was studied in fetal (17-24 weeks gestation) proximal and distal colon. More than 1000 genes were expressed differentially in adult ascending versus descending colon, with 165 genes showing >2-fold and 49 genes showing >3-fold differences in expression. With almost complete concordance, biopsies of adult colonic epithelium can be correctly classified as proximal or distal by gene expression profile. Only 87 genes were expressed differently in ascending and descending fetal colon, indicating that, although anatomically relevant differences are already established in embryonic colon, additional changes in gene expression occur in postnatal development.

Adult↗
PubMed2002

Effects of sex and racial/ethnic group on the pattern of gastric cancer localization.

BACKGROUND: In Western countries, the overall incidence of gastric cancer is declining, while the incidence of proximal gastric cancer is rising. We evaluated the effect of sex, racial/ethnic group, and age on the localization of gastric cancer. METHODS: The records of all gastric cancer patients who registered at The University of Texas M. D. Anderson Cancer Center from January 1, 1985, to May 31, 1998, were reviewed. Tissue diagnosis and established tumor location were required. RESULTS: The case records of 1242 eligible patients, consisting of 821 non-Hispanic white, 230 Hispanic, 125 African American, 63 Asian, and 3 Native American patients, were analyzed. Among the 459 women, racial/ethnic group did not have a significant impact on gastric cancer localization (P = 0.57). However, among the 783 men, proximal cancers were significantly more frequent in the non-Hispanic white patients (57% vs 38% Hispanic, 41% African American, 17% Asian; P < 0.0001). Symptoms at diagnosis significantly varied for proximal vs non-proximal cancers. CONCLUSION: Proximal gastric cancer localization was more frequent among non-Hispanic white men, while non-Hispanic white women had a localization pattern similar to those of other racial/ethnic groups. Proximal gastric cancer represents a distinct subtype of gastric cancer that may have different biology, risk factors, and clinical behavior.

Adenocarcinoma↗
PubMed2002

Lupus membranous glomerulonephritis mimicking hepatitis C-associated nephropathy.

About 20% to 40% of hepatitis C virus (HCV)-infected patients have antinuclear antibody (ANA) seropositivity. Despite the high prevalence of ANA seropositivity in HCV infection, only a few cases of systemic lupus erythematosus (SLE) coinciding with HCV infection have been reported. This discrepancy may be the result of underdiagnosing SLE in patients with chronic HCV infection. The possible underdiagnosis of SLE in HCV-infected patients may be of great concern because interferon-based therapy should be avoided in patients with autoimmune diseases. We report a case of a patient with chronic HCV infection who presented with nephrotic syndrome. She had no previous history of SLE. A kidney biopsy specimen revealed characteristic lesions of lupus membranous nephritis. Further serologic studies confirmed the diagnosis of SLE in this patient. Lupus nephropathy should be ruled out in patients with chronic HCV infection who present with kidney disease and moderate-to-high titers of ANA seropositivity because (1) the association between lupus nephritis and HCV infection may not be coincidental and (2) the diagnosis of lupus nephritis has important therapeutic implications in HCV-infected patients.

Adult↗