Search PubMed⌕ Search

Biomedical subjects

J A Roth

Publications and source records attributed to J A Roth.

At least 19 recordsLinked to original sources
PubMed1995

Evaluation of end points of serial drug testing in patients with sustained ventricular tachycardia after healing of acute myocardial infarction.

Serial electrophysiologic drug testing was used to guide antiarrhythmic therapy in a consecutive series of 150 patients with clinical sustained ventricular tachycardia (VT) or cardiac arrest and inducible monomorphic VT. All patients had coronary artery disease and a history of myocardial infarction. For patients with clinical sustained VT, drug responders and partial drug responders (VT slowed by drug to rate < 150 beats/min, with systolic blood pressure > or = 90 mm Hg) had similar total mortality rates (2-year actuarial survival 100% and 94%, p = NS), which were statistically different from that of patients with drug inefficacy (2-year survival 67%). Partial drug responders had high arrhythmia recurrence rates, similar to those of patients with drug inefficacy. For cardiac arrest survivors, the results of electrophysiologically guided drug testing did not predict prognosis. Patients with a change in mode of VT induction during antiarrhythmic therapy had a favorable prognosis (no deaths during follow-up).

Adult↗
PubMed1995

Altered expression of the p50 subunit of the NF-kappa B transcription factor complex in non-small cell lung carcinoma.

Recent studies have implicated a role for the p50 subunit of the NF-kappa B transcription factor complex in tumorigenesis. Therefore, we investigated the expression of the p50 subunit of the NF-kappa B transcription factor complex in paired normal and non-small cell lung carcinoma (NSCLC) tissues. Here we show that nine of 11 (81.8%) fresh NSCLC tissues expressed from two- to 20-fold higher levels of the p50 subunit than normal lung tissue. Thirteen NSCLC cell lines also exhibited high levels of p50. Alterations in the normal NF-kappa B/rel pathway of regulation may play a role in the genesis of NSCLC.

Carcinoma, Non-Small-Cell Lung↗
PubMed1995

Cell cycle arrest and inhibition of tumor cell proliferation by the p16INK4 gene mediated by an adenovirus vector.

The p16INK4 (MTS1) gene has many features of a tumor suppressor gene. It maps to 9p21, a region of frequent loss of heterozygosity in a variety of tumor types. It encodes an inhibitor of cyclin-dependent kinase 4, and its homozygous deletion is common in tumor-derived cell lines. To examine its tumor suppressive function and its potential in cancer gene replacement therapy, wild-type p16INK4 was expressed in an adenovirus-derived gene delivery system and introduced into lung cancer cell lines that do not express p16INK4. Expression of the introduced p16INK4 blocked tumor cell entry into S phase of the cell cycle and inhibited tumor proliferation both in vitro and in vivo. These observations strongly support that p16INK4 is a tumor suppressor gene and is a candidate for cancer gene replacement therapy.

Adenoviridae↗
PubMed1995

Long-term outcomes and modes of death of patients treated with nonthoracotomy implantable defibrillators.

Long-term outcomes of all patients who underwent nonthoracotomy implantable cardioverter-defibrillator (ICD) implantation at our institution from April 1991 to October 1994 were studied using the intention-to-treat analysis. Of 94 consecutive patients, 81 underwent nonthoracotomy ICD implantation and 13 underwent thoracotomy (for concomitant surgery in 11 and unavailability of nonthoracotomy leads in 2). Six of 81 patients had a high defibrillation threshold, 4 subsequently underwent thoracotomy, and 2 were treated with amiodarone. Surgical mortality was 0%. The duration of follow-up was 20 +/- 13 months, and was > 12 months in 74% of 67 living patients. Actuarial survival rates at 1 and 2 years were, respectively, 98% and 94% for sudden death and 91% and 83% for total mortality. Deaths during long-term follow-up were mostly due to nonsudden cardiac or noncardiac deaths. Two-year mortality rates were 12% and 25% in patients with ejection fraction > or = 30% and < 30%, respectively. Thus, instances of sudden death and surgical mortality are very few in patients with nonthoracotomy ICDs. Deaths during long-term follow-up are mostly due to nonsudden cardiac and noncardiac deaths. Therefore, ICD therapy may have greater impact on survival in patients with lower risks of nonsudden cardiac and cardiac death (e.g., younger patients with minimal heart disease) than in patients with severe cardiac or noncardiac disease. Prospective studies are needed to address this question.

Actuarial Analysis↗
PubMed1995

Insulin-like growth factor-I improves mucosal structure and function in transplanted rat small intestine.

The transplanted small intestine develops significant mucosal atrophy, impaired nutrient and water absorption, and increased bacterial translocation to mesenteric lymph nodes in rats maintained on elemental diets or total parenteral nutrition. This study determined the effects of administration of an peptide growth factor (insulin-like growth factor-I[IGF-I]) on the mucosal structure and barrier function of rat small bowel isografts. Thirty-six adult Lewis rats underwent either resection of the distal 60% of the small bowel and proximal colon followed by a 40-cm orthotopic jejunal isograft or proximal small bowel transection and distal small bowel resection to leave an analogous length of small intestine in control animals. All rats received an isocaloric, isonitrogenous, polymeric diet (200 kcal/kg/day, 2 gN/kg/day) by gastrostomy and were infused with either IGF-I (2.4 mg/kg/day) or vehicle by osmotic pumps subcutaneously. After 10 days of treatment, jejunal crypt cell production, mucosal morphometric indices, glucose and water absorption, body weight, and bacterial translocation to mesenteric lymph nodes (MLN) were measured. Jejunal mRNA content for IGF-I, IGF-I receptor, and IGF-binding proteins 3 and 4 (IGFBP-3,4) were determined by Northern blotting. Crypt cell production, villus height, crypt depth, and villus surface area were significantly increased in control and transplanted jejunum of rats infused with IGF-I when compared to animals given vehicle alone. Additionally, jejunal glucose absorption and water absorption were significantly improved in both IGF-I groups when compared with their respective vehicle controls. IGF-I infusion increased body weight in transplanted and control animals and markedly reduced bacterial translocation to MLN after small bowel transplantation. Jejunal levels of IGF-I mRNA were significantly increased in transplanted animals when compared to transected controls. IGF-I treatment significantly increased IGFBP-3 tissue mRNA levels in both transected and transplanted animals. These results demonstrate that IGF-I administration, after small bowel transplantation, improves mucosal structure and absorptive function and reduces bacterial translocation to MLN. IGF-I may have important effects in transplanted small bowel both as an endogenous and administered growth factor.

Animals↗
PubMed1995

Malarial circumsporozoite protein is a novel gene delivery vehicle to primary hepatocyte cultures and cultured cells.

In this report we describe a novel gene delivery system using malaria circumsporozoite (CS) protein as a specific ligand. The CS protein covers the entire surface of sporozoites of malaria parasites. Previous studies have demonstrated that intravenously injected CS protein binds specifically to the basolateral surface of hepatocytes within minutes, indicating the high hepatocyte specificity of CS protein. This characteristic of CS protein prompted us to explore the possibility of using this protein as a liver-specific ligand for hepatic gene delivery vehicle. As an initial step, we investigated the efficacy of CS protein-mediated gene transfer into primary hepatocytes as well as established cell lines. Recombinant CS proteins were chemically conjugated to poly(L-lysine). The CS conjugates were complexed with recombinant plasmid DNA carrying a reporter gene. When the DNA complex was used to transfect primary hepatocytes, a very low level of expression of the reporter gene was observed. The level of expression was greatly enhanced when the cells were cotransfected with adenovirus, which presumably releases the internalized DNA from endosomal entrapment. The CS-mediated gene transfer into the cells required region II+, an evolutionarily conserved amino acid sequence conferring the binding of CS protein to its receptor. CS protein also efficiently mediated gene transfer into a number of cell lines, i.e. HepG2, HeLa, NIH3T3, and K562, but not HL-60, which contains low levels of receptor. Thus, the CS conjugate can be used to deliver DNA into many different cultured cells. Most importantly, the CS conjugate has a potential to be further developed into a liver-specific gene delivery vehicle in vivo.

Amino Acid Sequence↗
PubMed1995

Interdigitating versus concurrent chemotherapy and radiotherapy for limited small cell lung cancer.

PURPOSE: Sequencing and timing of chemotherapy and radiotherapy for limited small-cell lung cancer (LSCLC) was studied in two consecutive trials. METHODS AND MATERIALS: In the interdigitating (IDG) trial, three cycles of COPE (cyclophosphamide 750 mg/M2 i.v. Day 1, vincristine 2 mg i.v. Day 8, cisplatin [DDP] 20 mg/M2 Days 1-3, etoposide 100 mg/M2 i.v. Days 1-3), were followed by thoracic radiation therapy (1.5 Gy bid 5-6 h apart, repeated twice at 3-week intervals) to give 45 Gy in 9 weeks; COPE was given during the intervals and for two more cycles. Operable patients had thoracotomy followed by IDG. Prophylactic cranial irradiation (PCI), 2.0 Gy x 15 fractions with a total dose of 30 Gy in 3 weeks, was given to the complete responders (CR) after completion of chemotherapy. In the concurrent (CON) trial, patients received DDP 60 mg/M2 i.v. Day 1, and etoposide 120 mg/M2 i.v. Days 1-3 for four cycles, every 3 weeks, and concurrent thoracic radiation therapy to 45 Gy with either 1.8 Gy daily, for 5 weeks or 1.5 Gy bid for 3 weeks. Prophylactic cranial irradiation (PCI) was given to the complete responders, 2.5 Gy daily for 2 weeks (25 Gy) (approximately 3 months after the initiation of treatment). RESULTS: The IDG group had 28 evaluable patients with median follow-up of 17.5 months. The CON group had 33 evaluable patients with median follow-up of 21 months. Overall survival rates for IDG patients were 79% at 1 year, 39% at 2 years, 30% at 3 years, and 27% at 4 years compared to 93%, 70%, 51%, and 46%, respectively, for the patients treated with CON (p = 0.01). Loco-regional recurrence (44%) and distant metastasis (48%) was more frequent as the first site of failure in the IDG group compared to the CON group (30% and 30%, respectively). Brain metastases constituted 30% of first metastases with IDG compared to none with CON. Esophagitis was significantly greater with CON. Hematologic and pulmonary toxicity were similar with IDG and CON. One death due to infection was seen in each treatment group. CONCLUSION: Concurrent chemoradiotherapy appears to be more effective than IDG. Earlier administration of PCI with concurrent chemotherapy and thoracic irradiation may reduce the risk of brain metastasis.

Adult↗
PubMed1995

Value of serial carcinoembryonic antigen levels in patients with resectable adenocarcinoma of the esophagus and stomach.

BACKGROUND: Adenocarcinomas of the esophagus and the stomach are highly virulent and remain a major health problem worldwide; 5-year survival rates have not changed in the past 30 years. Recently, preoperative chemotherapy has been used to treat these adenocarcinomas. The authors evaluated the usefulness of serial serum carcinoembryonic antigen (CEA) levels in diagnosing these patients and compared the prognosis of patients with high or normal CEA levels. METHODS: Ninety consecutive patients with potentially resectable adenocarcinoma of the esophagus or stomach treated with preoperative chemotherapy were evaluated. Serum CEA levels were determined before registration, after each chemotherapy course, every 3 months for the first year after completion of all therapy, and every 6 months thereafter for 5 years. RESULTS: The CEA positivity rate before chemotherapy was 22.2% (20/90); after chemotherapy, it dropped to 10.9% (9/82). An increasing CEA level predicted relapse and correlated well with liver, lung, or pleural involvement in some patients. Most patients with peritoneal involvement did not show elevated levels of CEA. Clinical responses correlated with declining levels of CEA in the patients who showed a negative conversion in CEA level after chemotherapy. CONCLUSIONS: An elevated serum CEA level enabled early detection of relapse in the absence of clinical symptoms in patients with adenocarcinoma of the esophagus or the stomach. The level of CEA was also useful in monitoring the response to chemotherapy in patients who had a high CEA level before treatment. Although the pre- and postchemotherapy CEA-positive group had a higher relapse rate than that of other group, the CEA level did not predict resectability or survival. Future research with labeled monoclonal anti-CEA antibodies may prove useful for certain groups of patients.

Adenocarcinoma↗
PubMed1995

In vivo molecular therapy with p53 adenovirus for microscopic residual head and neck squamous carcinoma.

Developing gene therapy strategies may allow contemporary medicine to reassess its management of solid malignancies. We have demonstrated previously that the wild-type p53 adenovirus (Ad5CMV-p53) suppressed the growth of established tumors of the head and neck. In this paper we develop a microscopic residual model which mimics the postsurgical environment of head and neck cancer patients with advanced disease. Using this squamous cell carcinoma of the head and neck model, we prevented the establishment of tumors in nude mice in which tumor cells had been s.c. implanted by transiently introducing exogenous wild-type p53 via an adenoviral vector 2 days following tumor cell implantation. These effects were vector dose dependent but independent on the endogenous wild-type or mutated p53 status of the cells. Importantly, karyotypically normal and nontumorigenic fibroblast cell lines are inert to the p53 adenovirus treatment. These results pave the ground work for further development of molecular therapy for head and neck cancer and other solid malignancies.

Adenoviridae↗
PubMed1995

Pectin improves colonic function in rat short bowel syndrome.

Short bowel syndrome is characterized by weight loss, diarrhea, and malabsorption. Pectin, a highly fermentable fiber, improves small and large bowel mucosal structure, prolongs intestinal transit, and decreases diarrhea. This study determined if the addition of citrus pectin to an enteral liquid diet (LD) improved structure and absorptive function in the rat jejunum and colon following massive intestinal resection. Twenty-one male Sprague-Dawley rats underwent placement of gastrostomy tube for isocaloric, isonitrogenous feeding and either 60% small bowel and cecal resection or small bowel transection with anastomosis. Animals in each group were then randomly and equally assigned to receive either LD (Enercal Plus, Wyeth) or LD supplemented with 2% citrus pectin for 7 days. Study variables included body weight change, percentage of stool solidity, jejunal villous height (JVH) and crypt depth, colonic crypt depth (CCD), and colonic short-chain fatty acid content (SCFA). Jejunal [14C]glucose absorption and colonic [3H]H2O absorption were measured by a dual in vivo perfusion assay. Resection significantly (P < 0.05) decreased body weight, stool solidity, and colonic SCFA content; enlarged structure (JVH, CCD); and increased absorptive function in the remaining bowel. Pectin significantly decreased (P < 0.05) body weight loss, increased (P < 0.05) stool solidity, and improved (P = 0.05) colonic water absorption following resection without significantly altering mucosal structure. It is concluded that pectin improves colonic absorptive function following massive bowel resection in the rat.

Animals↗
PubMed1995

High expression of adhesion molecules/activation markers with little interleukin-2, interferon gamma, and tumor necrosis factor beta gene activation in fresh tumor-infiltrating lymphocytes from lung adenocarcinoma.

Little is known about the activation level of tumor-infiltrating lymphocytes (TIL) in human lung adenocarcinoma. We investigated the activation of fresh TIL at cellular and molecular levels and compared it with autologous and healthy normal peripheral blood lymphocytes (PBL) for baseline level. TIL were extracted from 12 primary lung adenocarcinomas by mechanical disruption without enzyme use and isolated by double-density Ficoll gradients. Flow-cytometry analysis of TIL subset distribution revealed that the majority was composed of T lymphocytes, and double labeling with alpha-CD3 and adhesion/activation markers revealed T cell subsets expressing CD49a, CD49b, CD54, and CD15, each of which was almost absent in autologous T peripheral blood lymphocytes (T-PBL). Moreover, the proportions of T-TIL expressing CD58, CD65, or CD25 were increased severalfold compared to T-PBL. Lymphokine gene activation in TIL was assessed by mRNA reverse transcriptase/polymerase chain reaction (RT-PCR) and primers for interleukin(IL)-2, IL-4, interferon (IFN) gamma, granulocyte/macrophage-colony-stimulating factor (GM-CSF), and tumor necrosis factor (TNF) beta. Semiquantitative comparisons between patients' TIL and PBL and healthy normal and activated PBL were performed by computerized image analysis. RT-PCR gel band products were quantified in relative units as a function of their size and intensity. TIL expressed detectable lymphokine mRNA but seemed poorly activated with respect to the total number of lymphokine genes and the amount of mRNA compared with alpha-CD3-activated healthy PBL. IL-2, IFN gamma, and TNF beta did not appear to be expressed at higher levels in TIL than in autologous or healthy normal PBL. However, two-thirds of the patients had TIL distinguishable from autologous PBL by specific expression of GM-CSF and from healthy normal PBL by expression of IL-4. These results show that lung adenocarcinoma TIL populations had little lymphokine gene activation despite the presence of several T cell subsets expressing different adhesion/activation markers. The lack or deficient combination of lymphokine production may be a factor that prevented efficient activation of TIL in these tumors.

Adenocarcinoma↗
PubMed1995

Prediction of electrophysiologic study results in patients treated with amiodarone.

To identify whether electrophysiologic study results during early-phase amiodarone therapy can be predicted by previous electrophysiologic study, we reviewed the electrophysiologic data of 50 patients with inducible sustained ventricular arrhythmias who underwent 4.3 +/- 1.3 drug trials before being given amiodarone. Study results during testing with agents of the modified Vaughan Williams Ia classification were compared with data obtained after 2 weeks of amiodarone therapy. Partial response by electrophysiologic study was defined as well-tolerated ventricular tachycardia < 150 beats/min associated with a blood pressure > or = 90 mm Hg. Significant slowing in the rate of induced ventricular tachycardia was seen during therapy with both Ia agents and amiodarone, although there was a trend toward greater slowing during amiodarone treatment (180 +/- 45 beats/min vs 164 +/- 65 beats/min; p = 0.09). Two of three patients with noninducible ventricular tachycardia during amiodarone showed profound ventricular tachycardia slowing during Ia therapy. Thirty-eight of 50 patients demonstrated concordance of electrophysiologic study results with regard to achieving partial response criteria. Twenty patients died during a mean follow-up period of 37 +/- 29 months; 7 of the 10 sudden deaths occurred in patients who did not meet partial response criteria. We conclude that patients with inducible sustained ventricular arrhythmias failing serial drug testing with Ia agents only rarely have their ventricular tachycardia suppressed during amiodarone therapy. Partial response criteria are often concordant between testing on agents of the Ia classification and amiodarone, and there was no significant difference in survival in patients based on their partial response status.

Aged↗
PubMed1995

Survival in early-stage non-small cell lung cancer.

The duration of survival in early-stage lung cancer (stages I and II) varies between reports in the literature. Several reasons account for this: patient population heterogeneity, inconsistent staging, anatomic variability, dissimilar tumor morphology, and unpredictable tumor biology. This report addresses some of the issues in early-stage non-small cell lung cancer that relate to variability between estimates of survival in end stage reporting. We review several large series since the introduction of the International Staging System in 1986 and other selected, contemporary reports that address end results in patients with pathologic stage I or stage II lung cancer. Overall survival for patients with pathologic stage I disease is 64.6% (range, 55% to 72%) and 41.2% for patients with stage II disease (range, 29% to 51%). Reducing morphologic differences by placing patients in groups based on the TNM subset and refinement in categorization by matching TNM subsets based on histology and other factors can improve considerably homogeneity and enhance prognostic predictability. The development of more accurate measures for predicting prognosis may serve to clarify the roles of primary and adjuvant treatment, particularly in those patients with early-stage disease associated with poor prognostic factors in whom the potential for long-term survival is reduced.

Biomarkers, Tumor↗
PubMed1995

Monocyte function in cattle experimentally infected with bovine immunodeficiency-like virus.

The effects of bovine immunodeficiency-like virus (BIV) on monocyte function were examined in experimentally infected cattle and in monocytes infected in vitro. Infection with the R29 isolate of BIV appeared to have relatively little effect on monocyte function in cattle during the first 2 years postinfection (PI). For the first 4 to 8 months post infection, monocyte phagocytosis of Staphylococcus aureus tended to be lower (P = 0.06) in BIV infected calves than in control animals. After 8 months PI, however, phagocytosis became equal between the two groups. Random and chemotactic migration and antibody-dependent cell-mediated cytotoxicity (ADCC) did not appear to be affected by BIV infection. Monocytes from BIV infected cattle were able to respond to in vitro treatment with interferon gamma similarly to monocytes from control cattle. Although experimental infection with BIV R29 resulted in minimal effects on monocyte function, this result could have been due either to a low virus burden in vivo or because BIV is intrinsically unable to affect monocyte function. To distinguish between these possibilities, monocytes from control, uninfected cattle were treated with BIV virus in vitro. Treatment of normal monocytes with cell-free virus significantly (P < 0.05) increased phagocytosis and random and chemotactic migration and decreased ADCC, in a dose-dependent manner. It appears, therefore, that the normal function of peripheral blood monocytes in the BIV R29 infected animals may be due to a low virus burden rather than to the inability of BIV to affect monocyte function. The in vitro infection results also raise the possibility that the function of monocyte derived cells at local sites of BIV replication may be altered.

Animals↗
PubMed1995

Feasibility of five courses of pre-operative chemotherapy in patients with resectable adenocarcinoma of the oesophagus or gastrooesophageal junction.

The purpose of this study was to examine the feasibility of administering all chemotherapy pre-operatively to patients with resectable adenocarcinoma of the oesophagus or gastrooesophageal junction. 32 patients with potentially resectable adenocarcinoma of the oesophagus or gastrooesophageal junction were studied in a stepwise fashion in which combination chemotherapy with cisplatin, high-dose arabinoside and 5-fluorouracil was administered. In the first part, 15 patients were to receive three chemotherapy courses pre-operatively and two chemotherapy courses postoperatively. In the second part, the next 15 patients were to receive all five chemotherapy courses pre-operatively, provided there was an objective response after three courses. Endoscopic ultrasonography was also performed, when feasible, prior to chemotherapy and surgery, and in some patients sequentially between chemotherapy courses. All of the 14 assessable patients in the first group tolerated all three courses of pre-operative chemotherapy, and 86% of patients in this group completed all protocol chemotherapy. In the second group, 9 of 18 (50%) assessable patients tolerated all five courses of preoperative chemotherapy, and 100% of patients in this group received all protocol chemotherapy. The median number of chemotherapy courses for the entire group (32 patients) was five (range one to five). Forty-one per cent (13/32) of patients had a major response to chemotherapy. Sixty-nine per cent (or 76% of 29 patients taken to surgery) had a curative resection. One patient had a pathological complete response. The median survival time of 32 patients was 17 months (range 2-36+ months). 14 patients (37%) remain alive at a median follow-up time of 26+ months. There was a correlation between endoscopic ultrasonographic tumour and nodal stage and pathological tumour and nodal stages in 16 patients. The tumour stage correlation was higher (75%) than the nodal stage correlation (62%). Our data suggest that it is feasible to administer five courses of cisplatin-based chemotherapy to patients with potentially resectable adenocarcinoma of the oesophagus or gastrooesophageal junction. More effective chemotherapy regimens that might result in higher pathological complete response rates and acceptable toxic effects are needed.

Adenocarcinoma↗
PubMed1995

Molecular events in lung cancer.

The observation that genes contributing to the process of malignant transformation are altered forms of genes normally present in eukaryotic cells initiated many of the advances that have increased our understanding of lung carcinogenesis at the molecular level. The gene families implicated in carcinogenesis include dominant oncogenes and tumor suppressor genes. Proto-oncogenes (normal homologue of the oncogene) participate in critical cell functions, including signal transduction and transcription. Only a single mutant allele is required for malignant transformation. Primary modifications in the dominant oncogenes that confer gain of transforming function include point mutations, amplification, translocations, and rearrangements. A second recently described gene family is the tumor suppressor genes. Tumor suppressor genes appear to require homozygous loss of function either by mutation, deletion, or a combination of these. Some tumor suppressor genes appear to play a role in the governance of proliferation by regulation of transcription. The identification of specific genes that contribute to the development of the cancer cell presents an opportunity to use these genes and their products as prevention and treatment targets.

Cell Transformation, Neoplastic↗