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S Sundaresan

Publications and source records attributed to S Sundaresan.

At least 19 recordsLinked to original sources
PubMed2001

N-Phthaloyl gamma-aminobutyric acid affects biochemical circadian rhythms in Wistar rats.

N-Phthaloyl gamma-aminobutyric acid (P-GABA) was administered to Wistar rats and 24 hr rhythms of glucose, cholesterol, total protein and lactic acid levels in blood were studied under semi-natural light dark conditions. P-GABA administration caused desynchronisation of the rhythms; while glucose and lactic acid rhythms were advanced, cholesterol and total protein rhythms were delayed. Since GABA is being involved in conveying dark information to the clock, exogenous administration of P-GABA may reduce the photic information received by the clock. The results could be explained by slightly less than 1 hr daily delays (or) advances respectively which would bring the peak times to the points 21 days after the start of administration.

Animals↗
PubMed2000

Evidence for cytotoxic T lymphocyte response against human lung cancer: reconstitution of antigenic epitope with peptide eluted from lung adenocarcinoma MHC class I.

BACKGROUND: Cancer-associated, major histocompatibility complex (MHC)-restricted peptide antigens have been elucidated in human melanomas and ovarian, breast, and renal carcinomas; but relatively little is known about lung cancer antigens. METHODS: To work toward delineation of lung cancer-associated antigens, we developed tumor infiltrating lymphocytes (TILs), peripheral blood mononuclear cell-derived cytolytic T cell lines (CTL), autologous lung cancer cell lines, and normal lung cell lines from 17 patients undergoing lung cancer resections. The TILs and CTL lines were subsequently evaluated for markers of activation and specific lysis of autologous or allogeneic lung cancer cell lines or both. RESULTS: Freshly isolated TILs contained a more activated T cell population compared with the patients' peripheral blood T cells as evidenced by an increased expression of HLA-DR, CD25, and CD45RO. TILs isolated from 15 patients lysed allogeneic lung cancer lines. TILs lysed autologous lung cancer but not autologous normal lung or Epstein-Barr virus transformed B cell lines (B-LCL) in 4 of 8 cases tested, suggesting tumor specificity. A CTL line (RHPBL57.1) was generated from peripheral blood mononuclear cells of an HLA-A24(+) patient by stimulation against an established HLA-A24(+) allogeneic lung cancer cell line. RHPBL57.1 lysed the lung cancer cell line in an HLA-A24-restricted manner. Moreover, RHPBL57.1 specifically lysed autologous B-LCL pulsed with peptides, eluted from MHC class I and isolated from the HLA-A24(+) lung cancer cell line. CONCLUSIONS: TILs isolated from patients with lung cancer are predominantly an activated population of T cells with evidence of tumor and MHC class I-restricted lysis. Furthermore, we provide evidence for a lung cancer-associated, MHC class I-bound peptide antigen(s) that reconstitutes the epitope recognized by a lung cancer specific CD8(+) T cell line derived from a patient with lung cancer.

Adenocarcinoma↗
PubMed1999

Development of ELISA-detected anti-HLA antibodies precedes the development of bronchiolitis obliterans syndrome and correlates with progressive decline in pulmonary function after lung transplantation.

BACKGROUND: Development of anti-HLA antibodies after lung transplantation (LT) is thought to play an important role in the etiology of bronchiolitis obliterans syndrome (BOS). However, a cause-effect relationship between anti-HLA antibodies and BOS has not been established. This study was conducted to determine the temporal relationship between the development of anti-HLA antibodies and BOS after LT, and to determine the antigenic specificity of the antibodies developed in BOS patients. METHODS: Sera from 15 BOS+ LT patients and 12 BOS- LT patients were obtained before LT and collected again at 6, 12, 24, 36, and 48 months after LT. Anti-HLA antibodies were detected by the PRA-STAT ELISA system and by complement-dependent cytotoxicity assays. Anti-HLA reactivity was further characterized by flow cytometry and absorption/elution with human platelets. RESULTS: When analyzed by ELISA, 10 of 15 BOS+ patients developed anti-HLA antibodies, whereas 0 of 12 BOS- patients developed anti-HLA antibodies (P<0.001). When analyzed by complement-dependent cytotoxicity, only 2 of 15 BOS+ patients developed anti-HLA antibodies and 1 of 12 BOS- patients developed anti-HLA antibodies (P = 0.99). There was a significant difference of 20.1 months between the time of anti-HLA antibody detection and the time of BOS diagnosis (P = 0.005). A progressive decrease in pulmonary function correlated with a progressive increase in the anti-HLA reactivity 36 months after LT. The anti-HLA reactivity was directed to one of the donor HLA class I antigens and to other unrelated HLA class I antigens. No anti-HLA reactivity was found against HLA class II molecules. CONCLUSIONS: Our study indicates that anti-HLA class I antibodies play an important role in the pathogenesis of BOS and that monitoring of anti-HLA class I antibody development by a highly sensitive assay such as the PRA-STAT ELISA after LT can provide an early identification of an important subset of LT patients with an increased risk of developing BOS.

Antibodies↗
PubMed1999

Development of bronchiolitis obliterans syndrome despite blood chimerism in human lung transplant recipients.

Bronchiolitis Obliterans Syndrome (BOS) remains the overwhelming obstacle to the success of lung transplantations (LTx). The presence of donor-specific microchimerism (DSM) and its association with lung allograft function is not well defined. To investigate the relationship between chimerism and BOS, blood was obtained from 21 LTx recipients. Genomic DNA was isolated from patient blood, and PCR-based techniques were used to identify recipient and donor HLA-DR. Fifty percent of the LTx recipients with BOS exhibited DSM at "T1" time post transplant, and 40% at one year follow-up (T2). However, 54% exhibited DSM in the BOS-free group at T1, and 44% at T2. Of the BOS-free, DSM-positive patients at T1, 29% developed BOS by T2. In contrast, 50% of BOS-free DSM-negative patients 50% developed BOS (P > 0.05). Double LTx had a higher prevalence of DSM (73%) and a lower prevalence of BOS (46%) than single LTx (50% and 80% respectively, P > 0.05). One-HLA-DR-antigen-matched LTx recipients show a low prevalence of DSM compared to non-matched (P < 0.05). This study demonstrates that the development of BOS in LTx recipients could also occur in the presence of blood chimerism.

Adult↗
PubMed1999

The biology of human epidermal growth factor receptor 2.

Our understanding of the normal signaling mechanisms and functions of human epidermal growth factor receptor 2 (HER2) and other members of the HER family, namely epidermal growth factor receptor, HER3, and HER4, is growing rapidly. Activation of these receptors results in a diverse array of signals through the formation of homodimeric and heterodimeric receptor complexes; HER2 is the preferred dimerization partner for the other HERs. These oligomeric receptor complexes activate distinct signaling pathways, such as the Ras-MAPK and PI3-kinase pathways. These, in turn, affect various cellular processes. Recent gene deletion experiments in mice point to an important role for HER2 in cardiac and neural development, and evidence from other studies indicates that HER2 is involved in normal breast growth and development. Thus, HER2 is a key component of a complex signaling network that plays a critical role in the regulation of tissue development, growth, and differentiation.

Animals↗
PubMed1999

Favorable results after sleeve lobectomy or bronchoplasty for bronchial malignancies.

BACKGROUND: Sleeve lobectomy and bronchoplasty are established alternatives to pneumonectomy for bronchial malignancies involving a main bronchus. However, potential bronchial anastomotic complications have deterred the general application of these types of resection. Some reports have contained a mixture of non-small cell lung cancer (NSCLC) and tumors of low-grade malignancy, making it difficult to assess the long-term results of these procedures as an alternative to pneumonectomy for lung cancer. METHODS: We retrospectively reviewed our experience with sleeve lobectomy and bronchoplasty for bronchial malignancies from January 1988 to September 1998 separating NSCLC (n = 58) from tumors of low-grade malignancy (n = 19). We compared the overall results between sleeve lobectomy and pneumonectomy (n = 142) performed for NSCLC over the same time interval. RESULTS: For NSCLC, after sleeve lobectomy, the operative mortality was 5.2% (3 of 58 patients) and the overall 5-year actuarial survival was 37.5%. After pneumonectomy, the operative mortality was 4.9% (7 of 142 patients) and the overall 5-year actuarial survival was 35.8%. For tumors with low-grade malignancy, there was no operative mortality after sleeve lobectomy or bronchoplasty and the 5-year actuarial survival was 100%. Major bronchial anastomotic complications occurred in 3 patients among the 77 patients who underwent sleeve resection. CONCLUSIONS: Sleeve resection can be performed with a low risk of bronchial anastomotic complication. The long-term survival after sleeve resection for NSCLC is similar to pneumonectomy. Excellent results are obtained after sleeve resection for low-grade malignancies.

Adenocarcinoma↗
PubMed1998

HLA-A locus mismatches and development of antibodies to HLA after lung transplantation correlate with the development of bronchiolitis obliterans syndrome.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) is the most common cause of morbidity and mortality after lung transplantation (LT). A retrospective analysis of clinical and immunologic variables were done to identify those that might predict the development of BOS. METHODS: Of 112 LT performed over a 42-month interval, 94 survived at least 3 months and form the basis of this analysis. There was a minimum of 21 months follow-up. BOS was defined on the basis of declining spirometry (FEV1 <80% of baseline) and/or the presence of histologic obliterative bronchiolitis. All variables analyzed were subjected first to a univariate analysis; those variables appearing to carry significance were then subjected to a multivariate logistic regression analysis. RESULTS: Univariate analysis revealed the following to be predictors of the development of BOS: age (the probability of developing BOS declined with advancing age); donor/recipient HLA-A locus mismatch, with actuarial freedom from BOS being significantly greater with no A-locus mismatches versus cases with one or two mismatches (P=0.031); and development of anti-HLA antibodies after transplantation (P=0.006 vs. recipients without detectable antibodies). In multivariate analysis, only HLA locus mismatch and development of anti-HLA antibodies were significant independent predictors of the development of BOS. The remaining clinical variables (gender, type of LT, indication for LT, graft ischemic time, use of cardiopulmonary bypass, cytomegalovirus) and immunologic variables (crossmatch, frequent early acute rejection) did not correlate with the development of BOS. CONCLUSIONS: These data suggest that BOS is the result of an immune process, that differences at the HLA-A locus may play an important role in this process, and antibody-mediated injury may play a role in BOS.

Adult↗
PubMed1998

Lung transplantation.

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Bronchiolitis Obliterans↗
PubMed1998

Tracheal mucoepidermoid carcinoma in a 7-year-old child.

Mucoepidermoid cancers are rare tumors that arise from the serous and mucous glands of the upper airway and salivary glands. Patients, especially children, with tumors that arise in the trachea and upper airways are often misdiagnosed as asthmatic and are treated with bronchodilators without resolution. A 7-year-old girl who had been diagnosed as asthmatic was subsequently found to have a mucoepidermoid tumor of the trachea. She underwent a successful tracheal resection and remains tumor free on follow-up bronchoscopy at 16 months.

Carcinoma, Mucoepidermoid↗
PubMed1998

Effect of development of antibodies to HLA and cytomegalovirus mismatch on lung transplantation survival and development of bronchiolitis obliterans syndrome.

OBJECTIVE: A retrospective analysis was performed to examine the role of HLA antibodies and cytomegalovirus mismatch on the development of bronchiolitis obliterans syndrome and survival after lung transplantation. METHODS: Of 339 consecutive lung transplantations performed over a 102-month interval, 301 patients survived at least 3 months. There was a minimum follow-up period of 13 months. Bronchiolitis obliterans syndrome was defined as a decline in forced expiratory volume in 1 second less than 80% of posttransplantation baseline and/or histologic presence of obliterative bronchiolitis and was defined as occurring "early" if documented within 3 years of transplantation. Variables analyzed included preoperative donor and recipient cytomegalovirus status and the development of antibodies to human leukocyte antigens after transplantation. Microcytotoxicity was used to determine the presence of antibodies to human leukocyte antigens. Variables were subjected to Kaplan-Meier analysis to determine their impact on freedom from bronchiolitis obliterans syndrome and survival. RESULTS: The development of antibodies to human leukocyte antigens after transplantation correlated significantly with bronchiolitis obliterans syndrome (P = .02). The development of antibodies to human leukocyte antigens did not affect survival (P = .33) unless they were detected within 2 years of transplantation (P = .04). There was greater frequency of early bronchiolitis obliterans syndrome in cytomegalovirus seronegative patients who received allografts from seropositive donors compared with all other combinations (P = .02). There was also a trend toward worse survival of cytomegalovirus seronegative patients who received allografts from seropositive donors (P = .13). CONCLUSION: These data suggest that bronchiolitis obliterans syndrome is the result of an immune-mediated process in which HLA antibodies and cytomegalovirus may play a significant role.

Actuarial Analysis↗
PubMed1998

Pediatric and adult lung transplantation for cystic fibrosis.

OBJECTIVE: This paper was undertaken to review the experience at our institution with bilateral sequential lung transplantation for cystic fibrosis. METHODS: Since 1989, 103 bilateral sequential lung transplants for cystic fibrosis have been performed (46 pediatric, 48 adult, 9 redo); the mean age was 21 +/- 10 years. Cardiopulmonary bypass was used in all but one pediatric (age <18) transplant, and in 15% of adults. RESULTS: Hospital mortality was 4.9%, with 80% of early deaths related to infection. Bronchial anastomotic complications occurred with equal frequency in the pediatric and the adult populations (7.3%). One- and 3-year actuarial survival are 84% and 61%, respectively (no significant difference between pediatric and adult age groups; average follow-up 2.1 +/- 1.6 years). Mean forced expiratory volume in 1 second increased from 25% +/- 9% before transplantation to 79% +/- 35% 1 year after transplantation. Acute rejection occurred 1.7 times per patient-year, with most episodes taking place within the first 6 months after transplantation. The need for treatment of lower respiratory tract infections occurred 1.2 times per patient in the first year after transplantation. Actuarial freedom from bronchiolitis obliterans was 63% at 2 years and 43% at 3 years. Redo transplantation was performed only in the pediatric population and was associated with an early mortality of 33%. Eight living donor transplants (four primary transplants, four redo transplants) were performed with an early survival of 87.5%. CONCLUSION: Patients with end-stage cystic fibrosis can undergo bilateral lung transplantation with morbidity and mortality comparable to that seen in pulmonary transplantation for other disease entities.

Actuarial Analysis↗
PubMed1998

The impact of bronchiolitis obliterans on late morbidity and mortality after single and bilateral lung transplantation for pulmonary hypertension.

Primary pulmonary hypertension (PPH) is a rare cardiovascular disease with a variable course; however, in general, its prognosis is poor. Among the various treatment options available, transplantation (initially heart-lung transplantation, and later isolated single or bilateral lung transplantation) has become an accepted modality. Heart-lung transplantation is necessary only in a minority of patients because right ventricular recovery has been gratifying after isolated lung transplantation. Furthermore, the scarcity of suitable donor organs mandates the achievement of the maximal number of heart and lung transplants from the limited donor pool. Available published data show that both single and bilateral lung transplantation are suitable alternatives for the majority of patients with pulmonary hypertension. Bronchiolitis obliterans syndrome (BOS), the main cause of late mortality and morbidity in lung transplant recipients, affects pulmonary hypertensive patients as it does other recipient subgroups. The available data regarding the impact of BOS on single versus bilateral lung recipients with pulmonary hypertension are somewhat scanty. Although some have suggested that BOS is more prevalent among PPH recipients, this is not uniformly supported through the literature. Other reports have documented severe ventilation-perfusion imbalance associated with graft dysfunction secondary to BOS in single lung transplant recipients with PPH. Despite this, there are no available data to document a significant survival benefit for PPH patients receiving bilateral versus single lung transplantation. Our own transplantation experience at Washington University in St. Louis with pulmonary hypertension shows a trend toward better survival in bilateral lung recipients, although this difference is not significant. Ultimately, both single and bilateral lung replacement seem to be satisfactory transplant options in PPH. Both recipient groups are affected by BOS, and longer follow-up of larger numbers of patients may document superior survival and functional outcome with bilateral lung replacement.

Actuarial Analysis↗
PubMed1998

Bronchiolitis obliterans.

Hospital survival rates in experienced lung transplantation centers exceed 90%, but late survival for lung allograft recipients is clouded by bronchiolitis obliterans syndrome (BOS). Bronchiolitis obliterans is the characteristic pathological feature of this late syndrome of chronic lung allograft dysfunction, which is thought to represent chronic lung allograft rejection. BOS seems to affect all lung transplant recipients, including single, bilateral, and heart-lung transplantation patients. Although specific symptoms are lacking, patients typically experience worsening respiratory debilitation, with the characteristic physiological hallmark being airflow limitation, as evidenced by progressive decline in several spirometric parameters. Because the clinical and functional aspects of this syndrome are not always coexistent with the typical pathology, a staging and classification system was devised that allows for diagnosis of BOS even in the absence of bronchiolitis obliterans. Data from Stanford University, featuring very prolonged follow-up, have shown that actuarial freedom from OB is only 29% at 5 years post lung transplantation. Overwhelming experimental evidence suggest that OB is the result of an immune-mediated process, and therefore the usual treatment for this condition has been to increase the maintenance immunosuppression regimen, and to further augment immunosuppression using a variety of strategies. Most of these strategies have been effective in achieving some reduction in the rate of decline in graft function, although true "cure" of BOS has been rare. Re-transplantation has been the most aggressive therapeutic strategy for OB, but for a number of logistic reasons, is applicable for only a tiny minority of lung transplant recipients with OB.

Bronchiolitis Obliterans↗
PubMed1998

Biological response to ErbB ligands in nontransformed cell lines correlates with a specific pattern of receptor expression.

The human epidermal growth factor receptor (HER or ErbB) family consists of four distinct members, including the epidermal growth factor (EGF) receptor (EGFR, HER1, or ErbB1), ErbB2 (HER2 or neu), ErbB3 (HER3), and ErbB4 (HER4). Activation of these receptors plays an important role in the regulation of cell proliferation, differentiation, and survival in several different tissues. Binding of a specific ligand to one of the ErbB receptors triggers the formation of specific receptor homo- and heterodimers, with ErbB2 being the preferred signaling partner. We analyzed the levels of various ErbB receptor messenger RNAs in a series of nontransformed cell lines by real time quantitative RT-PCR. The cell lines chosen were derived from a variety of tissues, including pancreas, lung, heart, and nervous system. Further, we measured biological responses in these cell lines upon treatment with EGF, betacellulin, and two types of neuregulins, heregulin and sensory and motor neuron-derived factor. All cell lines examined expressed detectable levels of ErbB2. High levels of expression of ErbB3 were correlated with responsiveness to heregulin and sensory and motor neuron-derived factor, whereas high levels of EGFR expression were correlated with responsiveness to EGF and betacellulin. Moreover, the sensitivity of a cell line to ErbB ligands was also correlated with the levels of expression of the appropriate ErbB receptors in that cell line. These results are consistent with our hypothesis that appropriate biological responsiveness to ErbB ligands is determined by the levels of expression of specific ErbB receptor combinations within a given tissue.

Animals↗
PubMed1998

Temporal oscillations of phosphatases in N-phthaloyl gamma-aminobutyric acid treated rats.

N-pathaloyl gamma-aminobutyric acid (P-GABA) was administered to Wistar and 24 hr rhythms of acid and alkaline phosphatases were studied under light-dark conditions. P-GABA administration advanced the peak times of phosphatases. Since GABA is being involved in conveying dark information to the clock, exogenous administration of P-GABA might reduce the photic information received by the clock. The results could be explained by slight daily advances which would bring the peak times to the points 21 days after the start of administration.

Acid Phosphatase↗
PubMed1998

Increased expression of HDJ-2 (heat shock protein 40) and heat shock protein 70 in biopsy specimens of transplanted human lungs.

BACKGROUND: Heat shock proteins are expressed during several forms of stress and inflammation. This study was done to determine whether the expression of heat shock protein HDJ-2 (heat shock protein 40), heat shock protein 60, and heat shock protein 70 are increased during rejection in human pulmonary allografts. METHODS: Thirty-five transbronchial biopsy specimens were obtained from adult lung transplant recipients. Histologic analysis and assessment of heat shock protein HDJ-2, heat shock protein 60, and heat shock protein 70 mRNA expression was performed. Total RNA was extracted, reverse transcribed, and amplified by polymerase chain reaction with oligonucleotide primers specific for the heat shock proteins. The identity of the amplified message was verified by Southern blot and slot blot analysis. RESULTS: The expression of heat shock protein HDJ-2 was significantly higher in samples from lung transplant recipients undergoing rejection when compared with recipients without rejection or infection. Heat shock protein 70 expression was also increased in rejection. Expression of heat shock protein 60 did not show any increase in recipients with no evidence of rejection and infection or transplant recipients with rejection or infection. Serial analysis of heat shock protein HDJ-2 and heat shock protein 70 obtained in biopsy specimens during and after rejection showed a decrease of heat shock protein HDJ-2 and heat shock protein 70 expression after resolution of lung rejection. CONCLUSION: Our data demonstrate that the expression of heat shock protein HDJ-2 and heat shock protein 70 increases during lung rejection. However, only heat shock protein HDJ-2 was able to differentiate between rejection and infection. Measurement of heat shock protein HDJ-2 in transbronchial biopsy specimens may assist in the differential diagnosis between rejection and infection in lung transplant recipients.

Carrier Proteins↗
PubMed1998

The impact of cytolytic therapy on bronchiolitis obliterans syndrome.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) is the major cause of morbidity and death after lung transplantation. Therapy has focused on augmented immunosuppression with a variety of agents. Although transient responses are often achieved, sustained remission has been unusual. The outcome of cytolytic therapy for BOS at our center has been analyzed and is reported. METHODS: Between July 1988 and July 1994, 233 patients underwent lung transplantation at Barnes-Jewish Hospital. Among 207 recipients (88.8%) who survived more than 3 months, 81 recipients (39%) had development of BOS; 48 of these patients underwent 64 courses of treatment with a cytolytic agent (antilymphocyte globulin, antithymocyte globulin, or OKT3 monoclonal antibody). The cases of BOS were retrospectively analyzed to determine the impact of cytolytic therapy. RESULTS: The 4-year survival rate was significantly greater in recipients without BOS than in those with BOS (82.8% vs 46.0%; p < .05). Various clinical factors, including diagnosis, forced expiratory volume in 1 second at onset of BOS, presence or absence of pathologically proven bronchiolitis obliterans, type of transplant operation, cytomegalovirus serologic status, and cytomegalovirus pneumonia, were examined, but no significant predictor of survival after the development of BOS was discerned. The mean decrement in forced expiratory volume in 1 second was significantly reduced by cytolytic therapy (-23.5% +/- 2.3% in the 3 months before therapy vs -9.9% +/- 3.5% in the 3 months after the therapy; p < .002). Nevertheless, the stage of BOS progressed over time in spite of therapy in most cases, and only 4 recipients (4.9%) with BOS remained in a lower BOS stage 2 years after treatment. CONCLUSIONS: Recipients with BOS had a significantly lower survival rate than recipients without BOS. No predictor of survival after the onset of BOS was identified. Although cytolytic therapy decreased the rate of decline in pulmonary function in the 3 months after treatment, the stage of BOS ultimately progressed in most patients.

Antilymphocyte Serum↗