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John Hart

Publications and source records attributed to John Hart.

At least 19 recordsLinked to original sources
PubMed2006

A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC.

The proteins encoded by the classical HLA class I and class II genes in the major histocompatibility complex (MHC) are highly polymorphic and are essential in self versus non-self immune recognition. HLA variation is a crucial determinant of transplant rejection and susceptibility to a large number of infectious and autoimmune diseases. Yet identification of causal variants is problematic owing to linkage disequilibrium that extends across multiple HLA and non-HLA genes in the MHC. We therefore set out to characterize the linkage disequilibrium patterns between the highly polymorphic HLA genes and background variation by typing the classical HLA genes and >7,500 common SNPs and deletion-insertion polymorphisms across four population samples. The analysis provides informative tag SNPs that capture much of the common variation in the MHC region and that could be used in disease association studies, and it provides new insight into the evolutionary dynamics and ancestral origins of the HLA loci and their haplotypes.

Genetic Predisposition to Disease↗
PubMed2006

Neural correlates of the object-recall process in semantic memory.

The recall of an object from features is a specific operation in semantic memory in which the thalamus and pre-supplementary motor area (pre-SMA) are integrally involved. Other higher-order semantic cortices are also likely to be involved. We used the object-recall-from-features paradigm, with more sensitive scanning techniques and larger sample size, to replicate and extend our previous results. Eighteen right-handed healthy participants performed an object-recall task and an association semantic task, while undergoing functional magnetic resonance imaging. During object-recall, subjects determined whether words pairs describing object features combined to recall an object; during the association task they decided if two words were related. Of brain areas specifically involved in object recall, in addition to the thalamus and pre-SMA, other regions included the left dorsolateral prefrontal cortex, inferior parietal lobule, and middle temporal gyrus, and bilateral rostral anterior cingulate and inferior frontal gyri. These regions are involved in semantic processing, verbal working memory and response-conflict detection and monitoring. The thalamus likely helps to coordinate activity of these different brain areas. Understanding the circuit that normally mediates this process is relevant for schizophrenia, where many regions in this circuit are functionally abnormal and semantic memory is impaired.

Adult↗
PubMed2006

Epidermal growth factor receptor signaling is up-regulated in human colonic aberrant crypt foci.

Aberrant crypt foci (ACF) are collections of abnormal colonic crypts with heterogeneous molecular and pathologic characteristics. Large and dysplastic ACF are putative precursors of colon cancer with neoplastic risk related to increased proliferation. In this study, we examined the role of epidermal growth factor receptor (EGFR) signaling in regulating ACF proliferation. Using magnification chromoendoscopy, we collected large ACF with endoscopic features of dysplasia and separately biopsied adjacent mucosa. Transcript levels were measured by real-time PCR, proteins were assessed by Western blotting, and levels were expressed as fold changes of adjacent mucosa. K-ras and B-Raf mutations were assessed by PCR and Ras activation by the ratio Ras-GTP / (Ras-GTP + Ras-GDP). At the RNA level, 38% of ACF were hyperproliferative, with proliferating cell nuclear antigen (PCNA) mRNA >/=2-fold of adjacent mucosa. Hyperproliferative ACF had significantly increased mRNA levels of EGFR (6.0 +/- 1.7-fold), transforming growth factor-alpha (14.4 +/- 5.0-fold), heparin-binding EGF-like growth factor (4.5 +/- 1.4-fold), cyclin D1 (4.6 +/- 0.7-fold), and cyclooxygenase-2 (COX-2; 9.3 +/- 4.2-fold; P < 0.05). At the protein level, 46% of ACF were hyperproliferative (PCNA, 3.2 +/- 1.2-fold). In hyperproliferative ACF, 44% possessed significant increases in four EGFR signaling components: EGFR (9.5 +/- 1.3-fold), phosphoactive ErbB2 (2.6 +/- 0.4-fold), phosphoactive extracellular signal-regulated kinase (3.7 +/- 1.1-fold), and cyclin D1 (3.4 +/- 0.8-fold; P < 0.05). Ras was activated in 46% of ACF (3.2 +/- 0.4-fold; P < 0.05), but K-ras mutations were present in only 7% of ACF. In contrast to COX-2 mRNA, the protein was not increased in hyperproliferative ACF. In summary, we have shown that ACF with up-regulated PCNA possess increased EGFR signaling components that likely contribute to the enhanced proliferative state of dysplastic-appearing ACF.

Cell Growth Processes↗
PubMed2006

Liver biopsy interpretation for causes of late liver allograft dysfunction.

Evaluation of needle biopsies and extensive clinicopathological correlation play an important role in the determination of liver allograft dysfunction occurring more than 1 year after transplantation. Interpretation of these biopsies can be quite difficult because of the high incidence of recurrent diseases that show histopathological, clinical, and serological features that overlap with each other and with rejection. Also, more than one insult can contribute to allograft injury. In an attempt to enable centers to compare and pool results, improve therapy, and better understand pathophysiological disease mechanisms, the Banff Working Group on Liver Allograft Pathology herein proposes a set of consensus criteria for the most common and problematic causes of late liver allograft dysfunction, including late-onset acute and chronic rejection, recurrent and new-onset viral and autoimmune hepatitis, biliary strictures, and recurrent primary biliary cirrhosis and primary sclerosing cholangitis. A discussion of differential diagnosis is also presented.

Biopsy, Needle↗
PubMed2006

Association of E-cadherin, matrix metalloproteinases, and tissue inhibitors of metalloproteinases with the progression and metastasis of hepatocellular carcinoma.

Molecular markers can provide additional information to traditional histomorphological evaluation for the assessment of tumor progression and predicting the likelihood of invasion and metastasis in various types of malignancies. We studied the association of E-cadherin, matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinase with the progression and metastasis of hepatocellular carcinoma. Tissue microarray including six normal livers, 14 cirrhotic livers, 39 macroregenerative nodules, 16 dysplastic nodules, 22 grade I hepatocellular carcinomas, 43 grade II hepatocellular carcinomas, seven grade III hepatocellular carcinomas, and 10 metastatic hepatocellular carcinomas were stained immunohistochemically with antibodies against MMPs -1, -2, -3, -7, -9, tissue inhibitors of metalloproteinase-1, -2, -3, and E-cadherin. The intensities of staining were scored manually by two pathologists and verified by the Chromavision Automated Cellular Imaging System. Compared with normal liver, cirrhotic liver had significantly lower E-cadherin and tissue inhibitors of metalloproteinase-1 but higher MMP-1 and -7, which suggest a more favorable environment for tumor invasion and metastasis. Grade I and grade II hepatocellular carcinomas demonstrated high E-cadherin and decreased MMP-3 and -9, which may explain the rarity of extrahepatic metastasis in low-grade hepatocellular carcinomas despite the high circulatory volume of the liver. The histological progression from dysplastic nodule to well-differentiated hepatocellular carcinoma and to less differentiated tumors was associated with a gradual decrease in tissue expression of E-cadherin, tissue inhibitors of metalloproteinase-2 and -3. Metastatic hepatocellular carcinomas showed significantly lower level of tissue inhibitors of metalloproteinase-1, -2, -3 but higher level of MMP-7. These data suggest that tissue expression of E-cadherin, certain MMPs, and tissue inhibitors of metalloproteinases could be useful markers to predict the progression and metastasis of hepatocellular carcinoma.

Adolescent↗
PubMed2006

The impact of pathologist experience on liver transplant biopsy interpretation.

We studied the impact of pathologist experience on liver transplant biopsy interpretation for cases designated 'nonspecific' by pathologists at a nontransplant center. Among 102 consecutive liver transplant biopsies from 92 patients performed at the Foothills Medical Center, 30 liver biopsies from 23 patients were designated 'nonspecific' by the local pathologist. These biopsy slides were independently reviewed by an expert in liver transplant pathology at a major US transplant center. The expert pathologist was given only the information on the original requisition. In seven biopsies from five patients, there was full agreement between the external expert and the local pathologist. In 10 biopsies from six patients, the expert concurred with the initial assessment but emphasized critical negatives such as 'no evidence of rejection or recurrent hepatitis'. A discrepant diagnosis was found in 13 biopsies from 12 patients. In five biopsies from four patients, the revised diagnoses were inaccurate due to insufficient or misleading clinical information on the requisition. In eight biopsies from eight patients, the revised diagnoses were proven to be correct by clinicopathologic correlation. Our study shows that pathology expertise helped to clarify the diagnosis in about 27% of cases, which justifies the cost of obtaining a second opinion in difficult biopsies. Misinterpretation by the expert pathologist in up to 17% of biopsies highlights the importance of direct communication between hepatologist and pathologist in order to achieve a correct diagnosis. Familiarity with those cases with relatively uncommon histology, a diligent search for subtle morphologic changes, and use of standard terminology could improve the quality of liver transplant biopsy interpretation in a nontransplant center.

Adult↗
PubMed2006

A patient with abdominal pain and markedly elevated transaminase levels after cholecystectomy.

BACKGROUND: A 33-year-old white female with a history of cholecystectomy presented to the emergency department with intermittent severe abdominal pain radiating from the left upper quadrant to the right upper quadrant, associated with nausea and emesis. Three weeks previously the patient had presented to the emergency department with similar pain in the abdomen. Laboratory investigations had revealed elevated bilirubin, transaminase, and alkaline phosphatase levels. At that time, pain and liver chemistry test results improved and the patient was discharged on hospital day 3. She denied a history of alcohol use, new medications, or the ingestion of other toxins. INVESTIGATIONS: History and physical examination, liver chemistry tests, viral hepatitis serology tests, autoimmune serology tests, abdominal ultrasound, liver biopsy, and an endoscopic retrograde cholangiopancreatogram. DIAGNOSIS: Choledocholithiasis. MANAGEMENT: Endoscopic retrograde cholangiopancreatogram with sphincterotomy, removal of an 8 mm distal common bile duct stone, and pancreatic stent placement.

Abdominal Pain↗
PubMed2006

Glycogen pseudoground glass change in hepatocytes.

Ground glass cytoplasmic change in hepatocytes is typically associated with chronic hepatitis B infection. We report 12 cases of glycogen pseudoground glass change that closely mimics hepatitis B inclusions. Nine individuals were immunosuppressed secondary to liver or kidney transplant (N=3), bone marrow transplant (N=2), HIV infection (N=2), kidney dialysis (N=1), or chronic inflammatory bowel disease (N=1). Medication history was available in 10 individuals and all were on multiple medications (range 2 to 33). Histologically, the pseudoground glass change was identical to the ground glass change seen in chronic hepatitis B infection, with distinct, circumscribed, gray-glassy inclusions surrounded by a rim of cytoplasm. The background livers showed mild or no inflammation and mild or no fibrosis. All cases were negative for chronic hepatitis B infection. The pseudoground glass change was PAS positive and diastase sensitive. Electron microscopy of the inclusions showed glycogen in 3/3 cases. No evidence for viral particles or significant endoplasmic reticulum proliferation was seen. Three cases had follow-up biopsies (1, 1, and 36 mo), and the pseudoground glass was persistent in 2 cases and showed partial resolution in 1 case (1 mo biopsy interval). We conclude that glycogen pseudoground glass change is typically seen in immunosuppressed individuals on numerous medications. The changes are generally seen in the background of mild chronic hepatitis with mild or no fibrosis. Glycogen pseudoground glass change can resolve, but may also persist for years.

Adult↗
PubMed2006

The Semantic Object Retrieval Test (SORT) in normal aging and Alzheimer disease.

OBJECTIVE: To characterize performance on a test of semantic object retrieval (Semantic Object Retrieval Test-SORT) in healthy, elderly subjects and patients with Alzheimer disease (AD). BACKGROUND: Although the initial presentation of patients with AD often reflects impairment in delayed recall for verbally encoded memory, common complaints of patients with early AD are actually related to semantic memory impairment. DESIGN: Thirty-eight AD patients and 121 healthy aging controls enrolled in an Alzheimer's Disease Center received a battery of standard neuropsychologic tests including the SORT. RESULTS: Compared with normal controls, AD patients had SORT memory impairments with significantly more false positive memory errors, fewer correctly produced names, and more substitutions in the name production aspect of the test. SORT had robust test-retest reliability in normals. CONCLUSIONS: The SORT task provides a direct, specific assessment of semantic memory, and has now been administered to 121 healthy, aging controls for normative ranges of performance, and to AD patients. The task detected semantic memory deficits in approximately half of patients with mild-moderate AD, which is comparable to other studies assessing semantic deficits in AD with less specific measures.

Aged↗
PubMed2006

Chemoprevention of colon carcinogenesis by polyethylene glycol: suppression of epithelial proliferation via modulation of SNAIL/beta-catenin signaling.

Polyethylene glycol (PEG) is one of the most potent chemopreventive agents against colorectal cancer; however, the mechanisms remain largely unexplored. In this study, we assessed the ability of PEG to target cyclin D1-beta-catenin-mediated hyperproliferation in the azoxymethane-treated rat model and the human colorectal cancer cell line, HT-29. Azoxymethane-treated rats were randomized to AIN-76A diet alone or supplemented with 5% PEG-8000. After 30 weeks, animals were euthanized and biopsies of aberrant crypt foci and uninvolved crypts were subjected to immunohistochemical and immunoblot analyses. PEG markedly suppressed both early and late markers of azoxymethane-induced colon carcinogenesis (fractal dimension by 80%, aberrant crypt foci by 64%, and tumors by 74%). In both azoxymethane-treated rats and HT-29 cells treated with 5% PEG-3350 for 24 hours, PEG decreased proliferation (45% and 52%, respectively) and cyclin D1 (78% and 56%, respectively). Because beta-catenin is the major regulator of cyclin D1 in colorectal cancer, we used the T-cell factor (Tcf)-TOPFLASH reporter assay to show that PEG markedly inhibited beta-catenin transcriptional activity. PEG did not alter total beta-catenin expression but rather its nuclear localization, leading us to assess E-cadherin expression (a major determinant of beta-catenin subcellular localization), which was increased by 73% and 71% in the azoxymethane-rat and HT-29 cells, respectively. We therefore investigated the effect of PEG treatment on levels of the negative regulator of E-cadherin, SNAIL, and observed a 50% and 75% decrease, respectively. In conclusion, we show, for the first time, a molecular mechanism through which PEG imparts its antiproliferative and hence profound chemopreventive effect.

Animals↗
PubMed2006

Neuroanatomic organization of sound memory in humans.

The neural interface between sensory perception and memory is a central issue in neuroscience, particularly initial memory organization following perceptual analyses. We used functional magnetic resonance imaging to identify anatomic regions extracting initial auditory semantic memory information related to environmental sounds. Two distinct anatomic foci were detected in the right superior temporal gyrus when subjects identified sounds representing either animals or threatening items. Threatening animal stimuli elicited signal changes in both foci, suggesting a distributed neural representation. Our results demonstrate both category- and feature-specific responses to nonverbal sounds in early stages of extracting semantic memory information from these sounds. This organization allows for these category-feature detection nodes to extract early, semantic memory information for efficient processing of transient sound stimuli. Neural regions selective for threatening sounds are similar to those of nonhuman primates, demonstrating semantic memory organization for basic biological/survival primitives are present across species.

Acoustic Stimulation↗
PubMed2005

Evidence of resilience: neuroimaging in former prisoners of war.

In this study, single voxel proton magnetic resonance spectroscopic imaging ((1)H-MRS) and volumetric analysis of hippocampal magnetic resonance imaging (MRI) images were used to determine if any differences in hippocampal biochemistry or volume were present between former prisoners of war (POWs) with and without posttraumatic stress disorder (PTSD) and control subjects matched for age and education. This study did not find lower hippocampal concentrations of N-acetylaspartate (NAA), smaller hippocampal volumes, or more impaired memory function in older veterans with PTSD compared with a group matched for traumatic experience or a nontraumatized control group.

Aged↗
PubMed2005

Abnormal object recall and anterior cingulate overactivation correlate with formal thought disorder in schizophrenia.

BACKGROUND: The neural basis of formal thought disorder (FTD) is unknown. An influential theory is that FTD results from impaired semantic memory processing. We explored the neural correlates of semantic memory retrieval in schizophrenia using an imaging task assessing semantic object recall. METHOD: Sixteen healthy control subjects and sixteen schizophrenia patients whose FTD symptoms were measured with the Thought Disorder Index completed a verbal object-recall task during functional magnetic resonance imaging. Participants viewed two words describing object features that either evoked (object recall) or did not evoke a semantic concept. RESULTS: Schizophrenia patients tended to overrecall objects for feature pairs that did not describe the same object. Functionally, rostral anterior cingulate cortex (ACC) activation in patients positively correlated with FTD severity during both correct recalled and overrecalled trials. Compared with control subjects, during object recalling, patients overactivated bilateral ACC, temporooccipital junctions, temporal poles and parahippocampi, right inferior frontal gyrus, and dorsolateral prefrontal cortex, but underactivated inferior parietal lobules. CONCLUSIONS: Our results support impaired semantic memory retrieval as underlying FTD pathophysiology. Schizophrenia patients showed abnormal activations of brain areas involved in semantic memory, verbal working memory, and initiation and suppression of conflicting responses, which were associated with semantic overrecall and FTD.

Adult↗
PubMed2005

Down-regulation of the tumor suppressor gene C-terminal Src kinase: an early event during premalignant colonic epithelial hyperproliferation.

Hyperproliferation of the premalignant epithelium is critical for colonic carcinogenesis; however the mechanisms remain largely unexplored. We report herein that prior to occurrence of neoplastic lesions in the azoxymethane-rat model of colon carcinogenesis; the tumor suppressor gene C-terminal Src kinase (Csk) was down-regulated with a concomitant increase in Src activity. Furthermore, pharmacological or genetic (RNA interference) inhibition of Csk resulted in increased proliferation in colon cancer cell lines through the mitogen-activated protein kinase dependent pathway. Thus, we demonstrate, for the first time, that Csk suppression is an important early event in colorectal cancer pathogenesis.

Animals↗
PubMed2005

Progression of Barrett's metaplasia to adenocarcinoma is associated with the suppression of the transcriptional programs of epidermal differentiation.

We did expressional profiling on 24 paired samples of normal esophageal epithelium, Barrett's metaplasia, and esophageal adenocarcinomas. Matching tissue samples representing the three different histologic types were obtained from each patient undergoing esophagectomy for adenocarcinoma. Our analysis compared the molecular changes accompanying the transformation of normal squamous epithelium with Barrett's esophagus and adenocarcinoma in individual patients rather than in a random cohort. We tested the hypothesis that expressional profiling may reveal gene sets that can be used as molecular markers of progression from normal esophageal epithelium to Barrett's esophagus and adenocarcinoma. Expressional profiling was done using U133A GeneChip (Affymetrix), which represent approximately two thirds of the human genome. The final selection of 214 genes permitted the discrimination of differential gene expression of normal esophageal squamous epithelium, Barrett's esophagus, and adenocarcinoma using two-dimensional hierarchical clustering of selected genes. These data indicate that transformation of Barrett's esophagus to adenocarcinoma is associated with suppression of the genes involved in epidermal differentiation, including genes in 1q21 loci and corresponding to the epidermal differentiation complex. Correlation analysis of genes concordantly expressed in Barrett's esophagus and adenocarcinoma revealed 21 genes that represent potential genetic markers of disease progression and pharmacologic targets for treatment intervention. PCR analysis of genes selected based on DNA array experiments revealed that estimation of the ratios of GATA6 to SPRR3 allows discrimination among normal esophageal epithelium, Barrett's dysplasia, and adenocarcinoma.

Adenocarcinoma↗
PubMed2005

The nonsteroidal anti-inflammatory drug, nabumetone, differentially inhibits beta-catenin signaling in the MIN mouse and azoxymethane-treated rat models of colon carcinogenesis.

The mechanisms through which beta-catenin signaling is inhibited during colorectal cancer chemoprevention by nonsteroidal anti-inflammatory agents is incompletely understood. We report that nabumetone decreased uninvolved intestinal mucosal beta-catenin levels in the MIN mouse with a concomitant increase in glycogen synthase kinase (GSK)-3beta levels, an enzyme that targets beta-catenin for destruction. However, in the azoxymethane-treated rat, where beta-catenin is frequently rendered GSK-3beta-insensitive, nabumetone failed to alter beta-catenin levels but did decrease beta-catenin nuclear localization and transcriptional activity as gauged by cyclin D1. In conclusion, we demonstrate that the differential mechanisms for beta-catenin suppression may be determined, at least partly, by GSK-3beta.

Animals↗
PubMed2005

Microsatellite analysis of sporadic flat and depressed lesions of the colon.

Prior studies of molecular and genetic derangements in flat and depressed lesions of the colon have revealed lower frequencies in a number of markers commonly present in exophytic lesions. These and other differences suggest that flat lesions are driven by alternative pathways. We reviewed a database of patients who had undergone endoscopic mucosal resection (EMR) for flat and depressed lesions at the University of Chicago from January 2001 to April 2003. Formalin-fixed and paraffin-embedded colonic samples were retrieved from the tissue bank, and five standardized mononucleotide and dinucleotide microsatellite regions were analyzed for instability (MSI) using fluorescently labeled forward primers in nonmultiplex reactions. Sixteen patients were identified with flat or depressed lesions who had adequate tissue specimens available for MSI analysis. Of these specimens, eight were tubular adenomas, three were tubulovillous adenomas, and five were carcinomas in situ. Four of the lesions were microsatellite unstable, each at a single locus, and one lesion showed probable instability at a second locus. Eleven lesions were microsatellite stable. Aberrations in DNA repair mechanisms do not appear to significantly contribute to the molecular derangements underlying sporadic flat or depressed colonic lesions. The molecular bases that underlie the aggressive behavior of sporadic flat and depressed lesions remain to be determined, and further investigation is warranted.

Adenoma, Villous↗