Biomedical subjects

John Hart

Publications and source records attributed to John Hart.

At least 55 records · Page 3Linked to original sources

PubMed2003

Ursodeoxycholic acid inhibits Ras mutations, wild-type Ras activation, and cyclooxygenase-2 expression in colon cancer.

K-ras mutations occur frequently in colon cancer and contribute to autonomous growth. In the azoxymethane (AOM) model of colon cancer, in addition to K-ras mutations, we have shown that wild-type (WT) Ras can be activated by upstream pathways, including, e.g., signaling by ErbB receptors. Tumors with mutant or activated WT Ras had increased cyclooxygenase-2 (Cox-2) expression. We have also shown that ursodeoxycholic acid (UDCA) prevented AOM-induced colon cancer and suppressed Cox-2 induction. In this study, we examined the role of Ras in Cox-2 inhibition by UDCA. Rats were fed AIN-76A chow alone, or supplemented with 0.4% UDCA, and received 20 mg/kg AOM i.p. weekly x 2 weeks. At 40 weeks, rats were sacrificed, and tumors were harvested. K-ras mutations were assessed by primer-mediated RFLP, allele-specific oligonucleotide hybridization, and direct DNA sequencing. Ras was immunoprecipitated and defined as activated if [Ras - GTP/(Ras - GTP + Ras - GDP)] was >3 SD above normal colonocytes. Cox-2 mRNA was determined by reverse transcription-PCR, and protein expression was assessed by Western blotting and immunostaining. In the AOM alone group, Ras was activated by mutations in 8 of 30 (27%) tumors, and WT Ras was activated in 7 of 30 (23%) tumors. UDCA significantly suppressed the incidence of tumors with mutant Ras (1 of 31, 3.2%; P < 0.05) and totally abolished the development of tumors with activated WT Ras (0 of 10; P < 0.05). In the AOM alone group, Cox-2 was up-regulated >50-fold in tumors with normal Ras activity and further enhanced in tumors with mutant or signaling-activated Ras. UDCA significantly inhibited Cox-2 protein and mRNA levels in tumors with normal Ras activity. In summary, we have shown for the first time that UDCA suppressed the development of tumors with Ras mutations and blocked activation of WT Ras. Furthermore, UDCA inhibited Cox-2 induction by Ras-dependent and -independent mechanisms.

Animals↗

PubMed2003

cDNA microarray analysis of macroregenerative and dysplastic nodules in end-stage hepatitis C virus-induced cirrhosis.

Hepatocellular carcinoma is a common malignancy causing significant morbidity and mortality worldwide. In this study we use expression microarray technology to identify novel genes that consistently displayed altered expression levels in the earliest identifiable precursors to hepatocellular carcinoma, dysplastic and macroregenerative nodules. The gene expression profiles from nine patients with end-stage hepatitis C cirrhosis that contained a combined 11 dysplastic or macroregenerative nodules were compared to the patient's matched cirrhotic liver tissue. A total of 53 genes were consistently dysregulated in the patient liver specimens. Six of seven genes were validated by quantitative real-time reverse transcriptase-polymerase chain reaction, or by immunohistochemical studies performed on an independent set of lesions. The novel genes, including caveolin-1, semaphorin E, and FMS-like tyrosine kinase 3 ligand, have putative roles in carcinogenesis but have not been reported in hepatocellular carcinogenesis. Microarray expression analysis of dysplastic and macroregenerative liver nodules provide insight into the earliest changes in hepatocellular carcinogenesis.

Base Sequence↗

PubMed2003

Surgical treatment of gastrointestinal stromal tumors in the imatinib (STI-571) era.

BACKGROUND: Gastrointestinal stromal tumors (GIST) are rare mesenchymal tumors that are characterized by constitutive overexpression of the tyrosine kinase receptor KIT (CD117). Imatinib mesylate is a selective inhibitor of tyrosine kinase-mediated activity. This study reports a single-institution experience of surgical resection and the use of imatinib in the treatment of GIST. METHODS: A retrospective review from 1995 to 2002 identified 57 patients (M:F, 29:28; median age, 61 years) with GIST who were treated at the University of Chicago. Twenty-eight patients underwent exploratory surgery with curative intent; 29 patients were referred for treatment of metastatic disease after surgery at outside institutions. Twenty-nine patients were treated with oral imatinib for either metastatic disease (n=26 patients) or in the adjuvant setting after complete resection (n=3 patients). RESULTS: Resections were performed in 53 patients, and metastatic disease was identified in 17 patients at the time of exploratory surgery. Immunohistochemical staining for CD117 was positive in 96% of patients. A size larger than 5 cm, a mitotic rate larger than 1/10 high-power field, and tumor necrosis predicted recurrence in patients after resection. The median follow-up period was 18 months (range, 4-81 months). Twenty-three patients (40%) are alive without disease; 22 patients (39%) are alive with disease; 7 patients died, and 5 patients are lost to follow-up. Among the 26 patients with metastatic disease who were treated with imatinib, 5 deaths have occurred, and disease stabilization or tumor regression was observed initially in 22 patients, with a median duration of response of 19 months. CONCLUSIONS: Complete surgical extirpation remains the only curative treatment of GIST. Imatinib-targeted therapy of metastatic disease yields encouraging clinical responses. The true efficacy of imatinib in this setting, as induction therapy or as an adjuvant treatment in patients with GIST, is unknown pending the completion of ongoing prospective trials.

Antineoplastic Agents↗

PubMed2003

Distinct prefrontal cortex activity associated with item memory and source memory for visual shapes.

In contrast to item memory, which refers to recognition or recall of previously presented information, source memory refers to memory for the context of previously presented information. The relatively few functional MRI (fMRI) source memory studies conducted to date have provided evidence that item memory and source memory are associated with differential activity in right and left prefrontal cortex, respectively. To both confirm this distinction in prefrontal cortex and to determine whether other differences in the neural substrates associated with these cognitive functions exist, an event-related fMRI study was conducted. In this study, item memory and source memory encoding phases were identical; participants viewed a series of abstract visual shapes presented on the left or right side of the screen and were instructed to remember each shape and its spatial location. During the item memory retrieval phase, shapes from the encoding phase were intermixed with new shapes and participants made an old-new judgment. During the source memory retrieval phase, all shapes were from the encoding phase and participants made a left-right judgment. An event-related analysis of item memory and source memory revealed a right and left prefrontal cortex distinction. Moreover, only item memory was associated with activity in the medial temporal lobes. These results confirm and extend previous findings that item memory and source memory are associated with distinct neural substrates.

Adult↗

PubMed2003

Neural hybrid model of semantic object memory: implications from event-related timing using fMRI.

Previous studies by our group have demonstrated fMRI signal changes and synchronized gamma rhythm EEG oscillations between thalamus and cortical regions as subjects recall objects from visually presented features. Here, we extend this work by estimating the time course of fMRI signal changes in the cortical and subcortical regions found to exhibit evidence for task-related activation. Our results indicate that there are separate loci of signal changes in the thalamus (dorsomedial and pulvinar) that exhibit notable differences in times of onset, peak and return to baseline of signal changes. The signal changes in the pulvinar demonstrate the slowest transients of all the cortical and subcortical regions we examined. Evaluation of cortical regions demonstrated salient differences as well, with the signal changes in Brodmann area 6 (BA6) rising, peaking, and returning to baseline earlier than those detected in other regions. We conclude that BA6 mediates early designation or refinement of search criteria, and that the pulvinar may be involved in the binding of feature stimuli for an integrated object memory.

Adult↗

PubMed2003

Role of 4-1BB in allograft rejection mediated by CD8+ T cells.

Blockade of traditional costimulatory molecules fails to inhibit rejection in many models where CD8+ T cells are sufficient to mediate rejection. This observation demonstrates that in many settings CD8+ T cells are not dependent upon CD28 or CD154 signals to mediate rejection. 4-1BB (CD137) has been shown to be an important regulatory molecule for CD8+ T cells in a variety of nontransplant models. Here we show that blocking the 4-1BB pathway significantly inhibited rejection of intestinal allografts by CD8+ but not CD4+ T cells. This effect was associated with significantly decreased expression of the genes encoding TNFalpha and secondary lymphoid chemokine (SLC) within the spleens of recipient mice. Disruption of the 4-1BB pathway also impaired the priming of alloantigen-specific CD8+ T cells and the accumulation of recipient dendritic cells within the spleen. These data directly demonstrate an important role for 4-1BB in allograft rejection; particularly rejection mediated by CD8+ T cells. Our data suggest that in addition to providing a direct costimulatory signal to T cells, the 4-1BB pathway may regulate other important steps in the immune response such as the migration of T cells and dendritic cells.

Animals↗

PubMed2003

Long-term survival of intestinal allografts induced by costimulation blockade, busulfan and donor bone marrow infusion.

Tolerance-inducing strategies that infuse donor bone marrow cells in conjunction with costimulation blockade have not been applied to intestinal transplantation. Intestines from BALB/c mice were transplanted into C57BL/6 recipients treated with anti-CD40L mAb, CTLA4-Ig, donor bone marrow, and busulfan. The majority of mice transplanted after completion of this regimen developed hematopoietic macrochimerism, although the degree of chimerism varied widely between recipients, and experienced long-term allograft survival. T cells from these mice demonstrated donor-specific hyporesponsiveness in vitro. However, T cells from chimeric mice proliferated to donor alloantigen in vivo. Furthermore, chimeric mice bearing intestinal allografts were capable of rejecting subsequently placed donor-strain skin grafts. These data suggest that although long-term allograft survival occurs in the absence of acute or chronic rejection, recipient mice are not completely unresponsive to donor alloantigens. When intestinal transplantation was performed at the time of initial bone marrow infusion (initiation of the chimerism protocol), most recipients failed to develop chimerism and promptly rejected the intestinal allograft. Although this is the most effective protocol that we have tested using this stringent model of transplantation, our observations suggest that modifications will be necessary before it can be reliably applied to the transplantation of highly immunogeneic organs like the intestine.

Abatacept↗

PubMed2003

The effect of immunosuppressive regimens on the recurrence of primary biliary cirrhosis after liver transplantation.

Recurrence of primary biliary cirrhosis (PBC) has been described in liver transplant recipients. Type of immunosuppression has been reported to influence the frequency of recurrence. The aim of this study is to evaluate the occurrence and pattern of recurrent PBC in our liver transplant recipients and determine any association of immunosuppressive agents with its recurrence. Patients who underwent orthotopic liver transplantation (OLT) for PBC were identified from the University of Chicago Liver Transplant Database. Recurrent PBC was diagnosed based on specific pathological criteria. Of 46 patients who underwent OLT for PBC between 1984 and 2000, a total of 7 patients (15%) were diagnosed with recurrent PBC at a median of 78 months (range, 27 to 120 months) after OLT. Forty-three percent of patients were administered cyclosporine, whereas 57% were administered tacrolimus before disease recurrence. Rates of recurrence were not different between patients maintained on cyclosporine therapy (16%) compared with those maintained on tacrolimus therapy (18%; P = 1.0). There also was no difference in frequency of rejection episodes or duration of corticosteroid therapy between those who did and did not have recurrent PBC. In conclusion, recurrent PBC developed in a small number of patients 2 years or longer after OLT. In our population, there was no difference in recurrence rates between those administered cyclosporine or tacrolimus for immunosuppression.

Adult↗

PubMed2003

Hepatic manifestations of Jeune syndrome (asphyxiating thoracic dystrophy).

Asphyxiating thoracic dystrophy, or Jeune syndrome, is an autosomal recessive skeletal dysplasia with multiorgan involvement. Most patients develop progressive respiratory insufficiency related to the abnormally small thorax and renal insufficiency. Other clinical manifestations include cystic lesions of the pancreas and retinal abnormalities. Hepatic abnormalities have been described both clinically and at autopsy, but the pathogenesis of the liver disease is not clear. A patient with Jeune syndrome developed complications because of progressive portal hypertension necessitating transplantation. We present a discussion of the gross and histopathologic findings in the explanted liver, along with a review of the pathology of liver disease in Jeune syndrome.

Asphyxia↗

PubMed2003

Histopathological features of L-asparaginase-induced liver disease.

We studied the histopathological changes of liver in four patients who developed hepatomegaly and abnormal liver chemistry tests 2 to 20 days following administration of L-asparaginase as a part of a combination chemotherapy regimen for treatment of acute lymphoblastic leukemia. The severity of the liver disease due to L-asparaginase was unpredictable. One patient developed acute fulminant hepatic failure and required liver transplantation. The most consistent pathological change, observed in all four cases, was diffuse steatosis. Other changes included patchy hepatocyte necrosis, mixed inflammatory cell infiltrates in the portal tracts, and variable degrees of hepatocellular, or canalicular cholestasis, or a combination of these.

Aged↗

PubMed2003

Analysis of protein expression and gene mutation of c-kit in colorectal neuroendocrine carcinomas.

Primary neuroendocrine carcinomas of the colon are rare but highly aggressive malignancies. The recent observations that c-kit protooncogene, a tyrosine kinase, is overexpressed in a subset of small cell lung cancer and that selective kinase inhibitors block the in vitro growth of small cell lung cancer cell lines prompted us to investigate the expression and mutation status of the c-kit gene in colorectal neuroendocrine carcinomas. Sixty-six cases of primary colorectal neuroendocrine carcinoma were collected from 13 institutions, including 36 small cell carcinomas and 30 moderately differentiated neuroendocrine carcinomas. Immunohistochemical studies using a polyclonal antibody against c-kit protein (CD117) demonstrated a strong and diffuse cytoplasmic staining in 15 cases (23%), which were relatively equally distributed in the small cell and moderately differentiated subgroups. As controls, 25 conventional colorectal adenocarcinomas, 26 colorectal adenomas and 19 colorectal carcinoid tumors were all negative, whereas 15 gastrointestinal stromal tumors were all positive, for kit expression. In contrast to gastrointestinal stromal tumors, kit-overexpressing neuroendocrine carcinomas showed no mutations in the juxtamembrane domain (exon 11) of the c-kit gene as determined by mutational analysis. Kaplan-Meier analysis with the log-rank test revealed that the patients with kit-positive tumors did not differ significantly in survival from those with kit-negative tumors (P = 0.77). These results indicate that c-kit overexpression observed in a subset of colorectal neuroendocrine carcinomas may not be mediated via activating mutations, and does not appear to be an initiating event during tumorigenesis because of lack of c-kit expression in other types of colorectal epithelial neoplasms. More importantly, our observations may have potential therapeutic implications since specific tyrosine kinase inhibitors have shown promise in the management of patients with kit-expressing malignancies.

Adult↗

PubMed2003

Rosai-Dorfman disease presenting in the gastrointestinal tract.

Rosai-Dorfman disease (RDD) rarely presents a diagnostic challenge. However, unusual sites of presentation can cause confusion. We present a case of RDD of the colon in a symptomatic 51-year-old woman. The gastrointestinal tract is the organ system least commonly affected by RDD, with only 11 cases reported. Most cases have been found incidentally or at autopsy. The widespread use of endoscopic procedures makes it more likely that this entity will be encountered. Most patients with gastrointestinal tract involvement have evidence of widespread extranodal disease and have a protracted clinical course.

Adult↗

PubMed2002

Elevated protein expression of cyclin D1 and Fra-1 but decreased expression of c-Myc in human colorectal adenocarcinomas overexpressing beta-catenin.

Mutations of the adenomatous polyposis coli tumor suppressor gene, or its downstream target beta-catenin, have been implicated in the initiation of most sporadic human colorectal epithelial neoplasms. These mutations, in turn, lead to aberrant nuclear accumulation of beta-catenin and subsequent activation of the beta-catenin/Tcf transcription factor complex. In vitro studies utilizing cultured human colon cancer cell lines have identified c-myc, cyclin D1 and fra-1 as target genes of beta-catenin/Tcf signaling. In our study, 12 cases of human colorectal adenocarcinomas were examined by Western immunoblotting analysis and immunohistochemical staining to specifically investigate whether the protein expression of these target genes was indeed altered in vivo by beta-catenin dysregulation. The results show that the protein level of beta-catenin was significantly increased in all 12 tumors (3.4 +/- 1.0-fold increase compared to the control normal mucosa by Western immunoblotting, p < 0.05), and this increase was associated with positive nuclear staining by immunohistochemistry in 10 cases. Increased levels of expression of cyclin D1 and Fra-1 proteins were also demonstrated in every tumor (9.0 +/- 2.7 and 3.3 +/- 0.9-fold increases compared to normal mucosa, respectively). Surprisingly, the protein level of c-Myc was significantly decreased in all tumors examined by 49 +/- 19% (p < 0.05), but the c-myc mRNA level was increased in 8 of 12 tumors when compared to that in normal mucosa by RT-PCR. Immunohistochemical staining performed on these carcinomas and additional 27 colorectal carcinomas further demonstrated that the protein expression level of c-Myc and beta-catenin nuclear localization were not correlated. Moreover, 15 of 20 colorectal adenomas exhibited positive nuclear beta-catenin immunostaining, among which 11 also exhibited increased c-Myc protein expression. These data thus support the notion that upregulation of cyclin D1 and Fra-1 in human colorectal adenocarcinomas is driven by abnormally expressed beta-catenin. However, the regulation of c-myc expression in colorectal tumors appears to be more complex. While dysregulated beta-catenin may cause a transcriptional upregulation of the c-myc gene, the c-Myc protein expression appears to be further regulated by a posttranscriptional mechanism(s) during the process of neoplastic progression.

Adenocarcinoma↗

PubMed2002

Interactions between thalamic and cortical rhythms during semantic memory recall in human.

Human scalp electroencephalographic rhythms, indicative of cortical population synchrony, have long been posited to reflect cognitive processing. Although numerous studies employing simultaneous thalamic and cortical electrode recording in nonhuman animals have explored the role of the thalamus in the modulation of cortical rhythms, direct evidence for thalamocortical modulation in human has not, to our knowledge, been obtained. We simultaneously recorded from thalamic and scalp electrodes in one human during performance of a cognitive task and found a spatially widespread, phase-locked, low-frequency rhythm (7-8 Hz) power decrease at thalamus and scalp during semantic memory recall. This low-frequency rhythm power decrease was followed by a spatially specific, phase-locked, fast-rhythm (21-34 Hz) power increase at thalamus and occipital scalp. Such a pattern of thalamocortical activity reflects a plausible neural mechanism underlying semantic memory recall that may underlie other cognitive processes as well.

Brain Mapping↗

PubMed2002

A prospective study of motor recovery following multiple subpial transections.

A prospective study of motor recovery was undertaken in a patient scheduled to undergo multiple subpial transections (MST) of right sensorimotor cortex. Pre-transection, functional MRI (fMRI) and cortical stimulation mapping confirmed left hand motor control within right primary motor cortex. Immediately post-transection, behavioral testing demonstrated preserved strength bilaterally but decreased dexterity in the left hand. Seven weeks post-transection, dexterity returned to normal and left hand finger tapping corresponded with multiple bilateral foci of fMRI activation. At 16 weeks, fMRI activation returned to pre-transection levels. These data indicate that cortical injury due to MST resulted in the temporary recruitment of distant cortical sites which presumably subserved normal motor function during recovery.

Adult↗

PubMed2002

Large-scale cortical displacement of a human retinotopic map.

The aim of the current study was to determine the retinotopic organization of a patient with congenital cortical dysgenesis and normal visual function. Using functional magnetic resonance imaging (fMRI), detailed retinotopic maps corresponding to the four visual field quadrants were projected onto cortical surfaces. Similar to control subjects, the upper right visual field mapped onto ventral left hemisphere and was retinotopically organized. The lower right visual field's cortical representation was also retinotopically organized, yet was displaced many centimeters anteriomedially. Moreover, the entire left visual field was represented in non-retinotopically organized islands in both hemispheres. These results indicate retinotopic maps can shift in both location and topography illustrating cortical reorganization presumably due to either cortical dysgenesis or functional displacement. NeuroReport

Adult↗

PubMed2002

Object activation from features in the semantic system.

The human brain is thought to elicit an object representation via co-activation of neural regions that encode various object features. The cortical regions and mechanisms involved in this process have never been elucidated for the semantic system. We used functional magnetic resonance imaging (fMRI) to evaluate regions activated during a task designed to elicit object activation within the semantic system (e.g., presenting the words "desert" and "humps" with the task to determine if they combine to form an object, in this case a "camel"). There were signal changes in the thalamus for word pairs that activated an object, but not for pairs that (a) failed to activate an object, (b) were simply semantically associated, or (c) were members of the same category. These results suggest that the thalamus has a critical role in coordinating the cortical activity required for activating an object concept in the semantic system.

Adult↗

PubMed2002

Object activation in semantic memory from visual multimodal feature input.

The human brain's representation of objects has been proposed to exist as a network of coactivated neural regions present in multiple cognitive systems. However, it is not known if there is a region specific to the process of activating an integrated object representation in semantic memory from multimodal feature stimuli (e.g., picture-word). A previous study using word-word feature pairs as stimulus input showed that the left thalamus is integrally involved in object activation (Kraut, Kremen, Segal, et al., this issue). In the present study, participants were presented picture-word pairs that are features of objects, with the task being to decide if together they "activated" an object not explicitly presented (e.g., picture of a candle and the word "icing" activate the internal representation of a "cake"). For picture-word pairs that combine to elicit an object, signal change was detected in the ventral temporo-occipital regions, pre-SMA, left primary somatomotor cortex, both caudate nuclei, and the dorsal thalami bilaterally. These findings suggest that the left thalamus is engaged for either picture or word stimuli, but the right thalamus appears to be involved when picture stimuli are also presented with words in semantic object activation tasks. The somatomotor signal changes are likely secondary to activation of the semantic object representations from multimodal visual stimuli.

Adult↗