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At least 55 records · Page 3Linked to original sources
PubMed1983

Glucagonomas. Ultrastructure and immunocytochemistry.

Pancreatic tumors harboring glucagon immunoreactive cells were found in four patients with diabetes mellitus. Alpha-cell (glucagon) granules were present in three tumors; pancreatic polypeptide (PP) immunoreactive cells were detected in two. In two patients the tumors were malignant and one of these had the glucagonoma syndrome; the other was a member of a family with MEN-type I syndrome. These cases illustrate three clinical subtypes of glucagonoma.

Adenoma, Islet Cell↗
PubMed1997

Candida infection following severe trauma exacerbates Th2 cytokines and increases mortality.

Following trauma, there is an increase of Th2 cytokines (IL-4, IL-6, and IL-10) and a decrease in Th1 cytokines (IFN-gamma and IL-2) that may account for impaired cellular immunity. However, the functional significance of a dominant Th2 pattern to the host remains unclear. The aim of this study was to evaluate whether Candida albicans (CA) sepsis in the setting of a Th2 response to trauma leads to increased mortality and to examine the mediators involved. Female BALB/c mice were randomized (12 per group) to receive no injury (C); trauma, consisting of a combined femur fracture and 40% total blood loss (T); no injury plus CA infection (C+CA); and CA infection 1 week following trauma (T+CA). Survival was then followed for 3 weeks. In a separate study, mice were treated as above (5 per group) and sacrificed. Harvested splenocytes were evaluated for concanavalin A-stimulated cytokine production and liver and kidney homogenates were plated to evaluate CA growth per organ and examined histologically. Candida infection at 1 week following trauma resulted in significantly increased mortality compared to infected controls. Furthermore, the Th2 dominant cytokine pattern was significantly augmented in the presence of CA infection in both C+CA and T+CA groups. Additional analysis showed significant growth of CA in liver and kidney homogenates from T+CA compared to C+CA mice. These results suggest that injured and infected mice demonstrate augmentation of Th2 dominant responses above that of injury or infection alone, as well as a decreased ability to clear Candida which may partially explain the increase in mortality observed. Therapies designed to neutralize Th2 cytokines or augment Th1 cytokines may prove beneficial in the setting of sepsis following trauma.

Acute Disease↗
PubMed2001

NS-398 treatment after trauma modifies NF-kappaB activation and improves survival.

Prostaglandin E(2) (PGE(2)) production after trauma contributes to immune alterations that increase susceptibility to infections. We hypothesize that blocking PGE(2) with NS-398, a selective COX-2 inhibitor, will modulate this response and improve outcome. This study evaluated the effect of NS-398 given over 7 days on proinflammatory cytokines, intracellular signaling, and survival after a septic challenge. Balb/C mice (n = 8/group) were given 10 mg/kg NS-398 intraperitoneally over 7 days, starting after anesthesia or trauma (femur fracture + 40% hemorrhage). Four groups, anesthesia + vehicle (C), anesthesia + NS-398 (CN), trauma + vehicle (T), or trauma + NS-398 (TN), were studied. On Day 7 after trauma, mice were sacrificed, serum was collected, and splenic macrophages were evaluated for PGE(2), LTB(4), IL-6, TNF-alpha, and NO production. Additionally, macrophage COX-2 mRNA, IkappaB-alpha, and NF-kappaB were evaluated. In a separate study, mice (n = 10-11/group) were traumatized and given NS-398 over 7 days, and then cecal ligation and puncture (CLP) were performed. Mice were then followed for survival over 10 days (via log-rank test). NS-398 treatment of injured mice decreased PGE(2) production compared to T (3.9 +/- 0.3 vs 3.1 +/- 0.4 pg/microg protein), and significantly decreased IL-6, NO, and TNF-alpha production. NS-398 treatment also attenuated COX-2 mRNA levels and NF-kappaB activation. These cellular events correlate with a significant survival advantage in TN versus T mice after CLP. These data suggest that a specific COX-2 inhibitor not only suppresses PGE(2), but normalizes proinflammatory cytokines after trauma through changes that may partly be mediated via transcriptional events. This correlates with significantly increased survival in TN mice given a septic challenge and suggests that COX-2 inhibitors contribute to modulating the inflammatory response and improving survival after trauma.

Animals↗
PubMed2001

Comparative analysis of IFN-gamma B7.1 and antisense TGF-beta gene transfer on the tumorigenicity of a poorly immunogenic metastatic mammary carcinoma.

Cancer progression is attributed in part to immune evasion strategies that include lack of co-stimulation, down-regulation of cell surface MHC molecules, and secretion of immunosuppressive factors, such as transforming growth factor-beta (TGF-beta). Gene therapy has been employed to counter these mechanisms of immune evasion by transference of B7.1, IFN-gamma or antisense TGF-beta genes into tumor cells, resulting in cell surface expression of B7.1, upregulation of MHC class I and class II molecules, or elimination of tumor-derived TGF-beta, respectively. Although each of these transgenes has been shown to alter tumorigenicity in murine models, a direct comparison of their efficacy has not been performed. In this study, we have employed a very aggressive, poorly immunogenic and highly metastatic mammary model, 4T1, to compare the efficacy of B7.1, IFN-gamma and antisense TGF-beta gene transfer in stimulating an anti-tumor response. We demonstrate that both IFN-gamma and antisense TGF-beta gene expression significantly reduced the tumorigenicity of these cells compared to mock transduced cells, with IFN-gamma having a greater effect. In contrast, B7.1 gene transfer did not affect the tumorigenicity of 4T1 cells. The anti-tumor response directed against antisense TGF-beta-expressing 4T1 tumors was mediated by CD4+ and CD8+ T cells. However, CD8+ T cells, and not CD4+ T cells, appeared to mediate the anti-tumor response against IFN-gamma-expressing tumors. Treatment of tumor-bearing animals with IFN-gamma or antisense TGF-beta gene-modified tumor cell vaccines reduced the number of clonogenic metastases to the lungs and liver compared to treatment with mock-transduced cells. Finally, in a residual disease model in which the primary tumor was excised and mice were vaccinated with irradiated tumor cells, treatment of mice with vaccinations consisting of 4T1 cells expressing both antisense TGF-beta and IFN-gamma genes was the most effective in prolonging survival.

Animals↗
PubMed2006

Early initiation of salvage hormone therapy influences survival in patients who failed initial radiation for locally advanced prostate cancer: A secondary analysis of RTOG protocol 86-10.

PURPOSE: We examined overall and disease-specific survival outcomes both from the time of initial treatment and from the start of salvage hormone therapy (HT), by the extent of disease progression at the time salvage HT was started in patients treated on RTOG Protocol 86-10. METHODS: [corrected] With a median follow-up of 9.0 years, 247 patients (54%) had received subsequent salvage HT. The overall survival (OVS) and disease-specific survival (DSS) were compared by the extent of disease progression at the time salvage HT was started. RESULTS: For those patients with distant metastases (DM) present at the start of salvage HT, the OVS and DSS were significantly reduced when compared to [corrected] those with DM absent at the time salvage HT was started (OVS at 8 years, 31% vs. 58%; DSS at 8 years, 38% vs. 65%). A statistically significant increase in DSS was observed among the 143 patients with DM absent when patients with prostate-specific antigen (PSA) less than 20 were compared with those with PSA greater than 20 at the time salvage HT was started. CONCLUSION: [corrected] The DSS and the OVS of the relapsed patient are decreased in those with more extensive disease at the time of salvage HT. However, because this protocol could not evaluate the effect of posttreatment PSA velocity on outcomes, which is likely a better predictor of long-term success with salvage HT, these results cannot be taken to demonstrate that early salvage HT in patients with long posttreatment PSA doubling times is necessary for longer survival.

Analysis of Variance↗
PubMed2006

Defining high risk prostate cancer with risk groups and nomograms: implications for designing clinical trials.

PURPOSE: Death from prostate cancer is usually preceded by metastases and it usually occurs in men with high risk disease who experienced biochemical failure with a short prostate specific antigen doubling time. We developed a model for determining disease specific survival in prostate cancer. MATERIALS AND METHODS: We used the model for defining high risk prostate cancer that was developed by the Radiation Therapy Oncology Group and combined it with the Kattan nomogram for predicting the risk of metastases. We selected 414 Radiation Therapy Oncology Group intermediate and high risk patients who were treated with external beam radiotherapy alone. Excluded were patients with low risk disease. The Kaplan-Meier product limit method was used to estimate the probability of freedom from biochemical failure, overall survival and disease specific survival. RESULTS: A significant difference was observed in freedom from biochemical failure, disease specific survival and overall survival among the 3 tertiles created by the nomogram using the cutoff points less than 8.5%, 8.5% to 15% and greater than 15% (p <0.001, 0.0002 and 0.0003, respectively). Only the risk of metastases using the categorized nomogram score (less than 8.5% and 8.5% to 15% vs greater than 15%), not preradiotherapy prostate specific antigen or Radiation Therapy Oncology Group risk (Radiation Therapy Oncology Group 2 vs 3), was a significant predictor of disease specific and overall survival for intermediate/high risk patients and intermediate/high risk with 15% or less risk for metastases. CONCLUSIONS: We combined a risk group stratification scheme for disease specific survival with a nomogram predicting the risk of metastases and created a model that may be useful for designing phase III trials with metastases and disease specific survival as study end points.

Clinical Trials as Topic↗
PubMed2001

Overlapping CRE and E-box promoter elements can independently regulate COX-2 gene transcription in macrophages.

Macrophage cyclooxygenase-2 (COX-2) transcription is mediated through the collaboration of different promoter elements. Here, the role of an overlapping cyclic AMP responsive element (CRE)/E-box was investigated. Nuclear proteins bound both the CRE and E-box, which synergized with other promoter elements to induce COX-2 transcription. Endotoxin induced binding of nuclear proteins to the CRE and E-box and each element independently induced higher COX-2 transcription levels than the overlapping CRE/E-box. Transcription factors associated with the CRE binding complex included c-Jun and CRE binding protein and with the E-box binding complex USF-1; their overexpression significantly induced COX-2 transcription. Therefore, both CRE and E-box promoter elements regulate COX-2 transcription in macrophages.

Animals↗
PubMed2003

Structure-activity relationships in a series of NPY Y5 antagonists: 3-amido-9-ethylcarbazoles, core-modified analogues and amide isosteres.

Beginning with carbazole 1a, the amide and alkyl substituents were optimized to maintain potency while adding solubilizing groups. Efforts to replace the 3-amino-9-ethylcarbazole core, a known carcinogen, used the SAR generated in the carbazole series for guidance and led to the synthesis of a number of core-modified analogues. In addition, an isosteric series, in which the amide was replaced with an imidazole, was prepared. Two potent new series lacking the putative toxicophore were identified from these endeavors.

Amides↗
PubMed2003

Structure-activity relationship studies on 2-heteroaryl-4-arylimidazoles NPY5 receptor antagonists.

A series of 2-heteroaryl-4-arylimidazoles with potent in vitro activity at the NPY5 receptor was developed. Introduction of electron-withdrawing groups on the 4-aryl ring led to a significant improvement of in vitro potency. Several analogues from this series had anorectic activity in rodent feeding models, but were also found to have undesired behavioral effects in spontaneous locomotor activity.

Animals↗
PubMed2003

In vitro and in vivo characterization of 3-[2-[6-(2-tert-butoxyethoxy)pyridin-3-yl]-1H-imidazol-4-yl]benzonitrile hydrochloride salt, a potent and selective NPY5 receptor antagonist.

To investigate the anorectic potential of NPY5 receptor antagonists, we have profiled the in vitro and in vivo properties of 3-[2-[6-(2-tert-butoxyethoxy)pyridin-3-yl]-1H-imidazol-4-yl]benzonitrile hydrochloride salt (1). This compound was found to have excellent NPY5 receptor affinity and selectivity, potent functional antagonism, and good peripheral and central nervous system exposure in rats. This compound attenuated bovine pancreatic polypeptide induced food intake in rats but failed to demonstrate anorectic activity in rodent natural feeding models.

Animals↗
PubMed2001

Smooth muscle differentiation marker gene expression is regulated by RhoA-mediated actin polymerization.

Smooth muscle cell (SMC) differentiation is regulated by a complex array of local environmental cues, but the intracellular signaling pathways and the transcription mechanisms that regulate this process are largely unknown. We and others have shown that serum response factor (SRF) contributes to SMC-specific gene transcription, and because the small GTPase RhoA has been shown to regulate SRF, the goal of the present study was to test the hypothesis that RhoA signaling is a critical mechanism for regulating SMC differentiation. Coexpression of constitutively active RhoA in rat aortic SMC cultures significantly increased the activity of the SMC-specific promoters, SM22 and SM alpha-actin, whereas coexpression of C3 transferase abolished the activity of these promoters. Inhibition of either stress fiber formation with the Rho kinase inhibitor Y-27632 (10 microm) or actin polymerization with latrunculin B (0.5 microm) significantly decreased the activity of SM22 and SM alpha-actin promoters. In contrast, increasing actin polymerization with jasplakinolide (0.5 microm) increased SM22 and SM alpha-actin promoter activity by 22-fold and 13-fold, respectively. The above interventions had little or no effect on the transcription of an SRF-dependent c-fos promoter or on a minimal thymidine kinase promoter that is not SRF-dependent. Taken together, the results of these studies indicate that in SMC, RhoA-dependent regulation of the actin cytoskeleton selectively regulates SMC differentiation marker gene expression by modulating SRF-dependent transcription. The results also suggest that RhoA signaling may serve as a convergence point for the multiple signaling pathways that regulate SMC differentiation.

Actins↗
PubMed1999

Stapled versus sutured gastrointestinal anastomoses in the trauma patient.

BACKGROUND: Construction of gastrointestinal anastomoses by using stapling devices has become a familiar procedure. Most studies have shown no significant differences in complication rates between stapled and sutured anastomoses performed during elective surgery. To date, no study has evaluated the incidence of complications of stapled anastomoses in the trauma patient. The purpose of our study was to determine whether the incidence of postoperative complications differs between stapled and sutured anastomoses after the emergent repair of traumatic bowel injuries. METHODS: A retrospective analysis of the medical and institutional trauma registry records of patients identified to have undergone a gastrointestinal anastomosis in a regional Level I trauma center over a 4-year period. RESULTS: A total of 84 patients with 118 gastrointestinal anastomoses were identified. A surgical stapling device was used to create 58 separate anastomoses, whereas a hand-sutured method was used in 60 anastomoses. A complication was defined as an anastomotic leak verified at reoperation. The ratio of blunt versus penetrating injuries, mean abdominal Abbreviated Injury Scale score, and Injury Severity Score were similar in the two groups. Stapling and suturing techniques were evenly distributed between small and large bowel repairs. Mean intensive care unit length of stay was comparable in both cohorts. However, inpatient length of stay was longer in patients with solely a stapled anastomosis compared with sutured anastomoses. Four of the 58 stapled anastomoses and none of the 60 hand-sewn anastomoses resulted in a clinically significant leak requiring reoperation (relative risk = undefined; 95% confidence interval, 1.14-infinity; p = 0.037). Each anastomotic leak occurred in a separate individual. The only death occurred in the stapled cohort secondary to peritonitis and subsequent sepsis. CONCLUSION: Anastomotic leaks seem to be associated with stapled bowel repairs compared with sutured anastomoses in the traumatically injured patient.

Adult↗
PubMed2002

Timing of femur fracture fixation: effect on outcome in patients with thoracic and head injuries.

BACKGROUND: Optimal timing of femur fracture fixation remains controversial. This study examines the association between the timing of femur fracture fixation and outcome in patients with concomitant chest and head injuries. METHODS: A retrospective review of registry data from a Level I trauma center identified 1362 patients with a femoral shaft fracture over a 12-year period. Patients were categorized into five groups by timing of femur fracture fixation: Group 1, within 24 hours; Group 2, 24 to 48 hours; Group 3, 48 to 120 hours; Group 4, > 120 hours; and Group 5, patients with no operative fixation. Primary outcome measures included morbidity (specifically, pulmonary complications) and mortality. Secondary outcome measures were hospital length of stay, intensive care unit length of stay, and discharge Glasgow Coma Scale score. Subsets of patients were examined including all patients with multiple injuries (Injury Severity Score > 15), chest trauma (Chest Abbreviated Injury Scale score > or = 2), and head trauma (Head Abbreviated Injury Scale score > or = 2). RESULTS: Acute respiratory distress syndrome, pneumonia, hospital length of stay, and intensive care unit length of stay were lowest in the group fixed within 24 hours, even in patients with concomitant head or chest trauma. Fixation between 2 and 5 days was associated with a significantly increased incidence of acute respiratory distress syndrome, pneumonia, and fat embolization syndrome in patients with concurrent chest trauma (p < 0.0001). In head-injured patients, discharge Glasgow Coma Scale score was highest in the group fixed within 24 hours. Timing of operative fixation did not affect mortality. CONCLUSION: Our data show that early femur fracture fixation (< 24 hours) is associated with an improved outcome, even in patients with coexistent head and/or chest trauma. Fixation of femur fractures at 2 to 5 days was associated with a significant increase in pulmonary complications, particularly with concomitant head or chest trauma, and length of stay. Chest and head trauma are not contraindications to early fixation with reamed intramedullary nailing.

Adult↗
PubMed1993

Effect of fasting on hepatocytes cold stored in University of Wisconsin solution for 24 hours.

Although there have been improvements in liver preservation, liver dysfunction still remains a serious consequence of liver transplantation. This may be related to cold ischemic injury since the incidence of dysfunction increases with longer preservation times. However, even some livers preserved for short periods of time (less than 15 hr) develop liver dysfunction. One possible cause may be the lack of adequate nutritional support, and the donor may be exposed to prolonged periods of hyponutrition. In this study, we have compared the effects of fasting on functions of hepatocytes isolated from the rat. Hepatocytes were cold stored in University of Wisconsin solution for 24 hr and analyzed at the end of preservation as well as at the end of rewarming in Krebs-Henseleit buffer for 120 min. The glycogen content of fed cells was 1.57 mumol/mg protein and this was reduced by 95% in cells from fasted rats. After cold storage and rewarming, hepatocytes from fasted rats lost 84.2 +/- 2.5% of the total cellular lactate dehydrogenase versus only 32.7 +/- 3.8% (P < 0.001) in cells from fed rats. Also, ATP and reduced glutathione content of fasted cells were significantly reduced, free fatty acids were higher (P = 0.0154), and protein synthesis was reduced to 41% of controls (versus only 88% in fed cells), although there were no differences in phospholipid content. When hepatocytes from fasted rats were rewarmed in Krebs-Henseleit buffer containing fructose (10 mM), lactate dehydrogenase release was reduced from 80% to 34.4 +/- 0.2% and ATP content was significantly higher with fructose than without. Hepatocytes from fasted rats, therefore, are more sensitive to cold ischemic injury than cells from fed rats. The increased sensitivity appears related to the lack of glycogen as a source of substrates for metabolism during rewarming. This is supported by the fact that addition of fructose, which is metabolized readily by hepatocytes through glycolysis, suppressed rewarming injury to cells from fasted rats. The nutritional status of the donor, therefore, may play a pivotal role in the results of liver preservation and transplantation. Effective donor nutritional management may reduce the incidence of liver dysfunction after transplantation.

Adenosine↗
PubMed2001

Suppression of macrophage nitric oxide production by melanoma: mediation by a melanoma-derived product.

The tumour-bearing state is known to induce immune dysfunction that contributes to increased infectious complications and tumour progression. However, the mechanisms underlying this immunosuppression remain unclear. This study investigated in a murine model the effects of melanoma growth on nitric oxide (NO) production by peritoneal macrophages in vivo and in vitro. B16 and K1735 melanoma cells were inoculated subcutaneously into C57BL/6 and C3H/HeN mice, respectively. Stimulated NO production by elicited peritoneal macrophages was examined in control and melanoma- bearing mice. An in vitro system was established to assess the effects of co-culturing melanoma cells (B16 and K1735) or melanoma-conditioned medium with normal peritoneal macrophages on subsequent NO production. NO production was significantly suppressed in macrophages from melanoma-bearing mice. Co-culture of normal macrophages with melanoma cells in a transwell system or with melanoma-conditioned media in vitro reproduced the defects observed in vivo without affecting macrophage viability, pointing to a melanoma-derived product as the basis for the observed suppression of NO production. This inhibition required RNA and protein synthesis and was dose and time dependent. Using inhibition profiles and neutralizing antibodies, it was demonstrated that this melanoma inhibitory activity was distinct from known NO inhibitors. Preliminary characterization attributed this activity to a melanoma-secreted protein moiety.

Animals↗
PubMed2002

The TB structural genomics consortium: providing a structural foundation for drug discovery.

Structural genomics, the large-scale determination of protein structures, promises to provide a broad structural foundation for drug discovery. The tuberculosis (TB) Structural Genomics Consortium is devoted to encouraging, coordinating, and facilitating the determination of structures of proteins from Mycobacterium tuberculosis and hopes to determine 400 TB protein structures over 5 years. The Consortium has determined structures of 28 proteins from TB to date. These protein structures are already providing a basis for drug discovery efforts.

Acyltransferases↗