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Biomedical subjects

G Natarajan

Publications and source records attributed to G Natarajan.

At least 19 recordsLinked to original sources
PubMed1998

Myc/p53 interactions in transgenic mouse mammary development, tumorigenesis and chromosomal instability.

We have examined defects in mammary development and tumorigenesis in a transgenic model expressing the c-myc gene under the MMTV-LTR promoter. The stochastic tumors which arise from hyperplastic ductal and lobular lesions in this model are characterized by high rates both of apoptosis and of chromosomal instability. Since the p53 gene product is thought to be central in the maintenance of genomic integrity, in part due to its ability to induce apoptosis in cells harboring DNA damage, we examined its expression and possible mutation. Initially, we observed that unmutated p53 is strongly expressed in premalignant mammary glands and in mammary tumors derived from the MMTV-c-myc strain. We then mated the MMTV-myc strain to a p53-deficient strain as a means of examining the effect of this lesion on mammary development and tumorigenesis in the context of c-myc overexpression. A lack of both p53 alleles in the presence of c-myc overexpression resulted in a dramatic hyerplastic alteration in mammary gland development. Specifically, in female bitransgenic MMTV-c-myc/p53 null mice (MMTV-myc/p53(-/-)), lobular hyperplasias were observed at almost every ductal end bud as early as 32 days of age. In contrast, only mild ductal and lobular hyperplasias were seen in MMTV-myc mice that contained both p53 alleles (MMTV-myc/p53(+/+)); an intermediate phenotype occurred in mice with a single intact (MMTV-myc/p53(+/-)) p53 allele. Mammary carcinomas arose with a high frequency in MMTV-myc/p53(+/-) mice; the tumors were comparable in frequency, histology and apoptotic index to the tumors in MMTV-myc/p53(+/+) mice. Also, as previously observed (Elson et al., 1995), lymphomas arose with extremely short latency in MMTV-myc/p53(-/-) mice, precluding study of the fate of their hyperplastic mammary lesions in situ. The frequency of p53 mutations in MMTV-myc/p53(+/+) and MMTV-myc/p53(+/-) mammary tumors and in cell lines derived from these tumors was examined by direct sequencing. No point mutations or deletions in p53 were observed in mammary tumors or cell lines from either genotype. Finally, a detailed chromosomal analysis using multicolor spectral karyotyping (SKY) revealed that there were multiple chromosomal alterations in the c-myc-overexpressing cells that contained either one or two unmutated p53 alleles. Variable ploidy changes, a common translocation of chromosome 11, and other chromosomal aberrations were observed. Our data thus support an interaction between c-Myc and p53 in mammary development, but suggest that loss of p53 is required neither for c-myc-dependent tumorigenesis nor for c-myc-dependent chromosomal instability.

Animals↗
PubMed1998

Helix-coil transitions in DNA by novel Pt(II) complexes: a pH melting study.

Recent reports have shown that pH could also be used as a melting factor to monitor helix-coil transitions in DNA; the results being comparable to those obtained by Tm studies. The rapidity with which the method can be performed to obtain similar transition curves, and elimination of the evaporation factor (at high temperatures as seen in Tm studies) is one of the advantages offered by this technique. With regard to its suitability in studying DNA-drug interactions, the addition of platinum (II) complexes changed the Pm (pH of melting) in a predictable manner thereby confirming the destabilization of bases in DNA. In the present study, melting profiles of calf thymus DNA modified by certain chloro substituted platinum complexes have been generated using pH as a denaturing factor. These novel platinum complexes have been recently shown to have potential tumour inhibiting properties too. Diammine diaqua platinum (active form of the anti tumour drug cisplatin) was coupled to beta poly-L-malate (a bioresorbable polymer synthesized by a myxomycete), L-malate and L-succinate. At a constant Pt:P ratio (0.2), the extent of damage to DNA by these complexes in comparison to cisplatin was cisPt>SuccPt>MalPt>PMA-Pt>carboplatin. Given the similarity of the side groups of these platinum compounds with that of carboplatin (a successful second generation analog of cisplatin), interesting variations have been obtained in the DNA melting profiles, the implications of which have been discussed in the present study.

Animals↗
PubMed1997

Glucocorticoids inhibit E-selectin expression by targeting NF-kappaB and not ATF/c-Jun.

E-selectin, an adhesion molecule expressed on the surface of activated endothelial cells, is essential for leukocyte rolling on endothelium which leads to extravasation in the process of inflammation. Induction of E-selectin expression by proinflammatory stimuli such as TNF-alpha or LPS is reduced markedly in the presence of dexamethasone, a synthetic glucocorticoid and potent anti-inflammatory agent. We have investigated the molecular mechanism underlying dexamethasone-mediated E-selectin repression in porcine aortic endothelial cells. Reduced E-selectin protein expression is paralleled by a decrease in E-selectin mRNA and is based on changes in transcription rate. Analysis of the E-selectin promoter revealed that induction by proinflammatory stimuli as well as repression by dexamethasone are mediated by the same promoter region containing three closely spaced binding sites for nuclear factor (NF)-kappaB and an element, NF-ELAM-1 (endothelial leukocyte adhesion molecule-1), constitutively occupied by ATF and c-Jun. NF-ELAM-1 contributes to maximal promoter activity, but does not confer glucocorticoid inhibition, as demonstrated by site-directed mutagenesis. In contrast, transcription directed by the E-selectin NF-kappaB elements is reduced strongly in the presence of dexamethasone, thus identifying NF-kappaB as the primary target for glucocorticoid-mediated E-selectin repression.

Animals↗
PubMed1996

The intron-exon structure of the porcine E-selectin-encoding gene.

We have cloned and sequenced the gene encoding porcine E-selectin. The gene comprises 12 exons and 11 introns. Two pseudoexons are contained within intron 4 and intron 6. These sequences are similar to the corresponding exons in the human E-selectin sequence; however, they are not present in the porcine E-selectin-encoding cDNA. Transcription starts at position -498 relative to the translation initiation site. The first ATG is located within exon 2. Translation stops in exon 11 leaving exon 12 untranslated in its entirety.

Amino Acid Sequence↗
PubMed1994

Comparison of three techniques of esophagectomy within a residency training program.

Residency training programs commonly emphasize a single technique of esophagectomy, as the safety and the efficacy of teaching or performing more than one type of esophagectomy are unclear. Between 1986 and 1992, 248 patients were explored for possible esophageal resection. Thoracic surgical residents or fellows performed major components of all resections. Two hundred twenty-one patients (adenocarcinoma, 146; squamous cell carcinoma, 72; and other, 3) underwent transthoracic esophagectomy (n = 134), transhiatal esophagectomy (n = 42), or total thoracic esophagectomy (n = 45), a resectability rate of 89.1% (221/248). Complications occurred in 75% of patients with transthoracic esophagectomy, in 69% with transhiatal esophagectomy, and in 80% with total thoracic esophagectomy. The overall operative mortality rate was 6.8% (15/221). Patients with a cervical anastomosis had a higher leak rate (13%) than those with an intrathoracic anastomosis (6%). Median survival was 22 months (19% 5-year survival) and did not differ by operation type or stage. No patient with unresectable disease (n = 27) survived longer than 10 months. Survival for patients with adenocarcinoma stages 3 and 2a suggested a trend toward improved survival after transthoracic esophagectomy despite similar rates of local and distant recurrence. Transthoracic esophagectomy, transhiatal esophagectomy, and total thoracic esophagectomy performed within a residency training program have similar morbidity, mortality, and recurrence rates as those in other modern series. A specific technique of esophagectomy can be selected for individual patients. Survival and sites of recurrence primarily reflect disease stage, not the technique of esophagectomy used.

Adenocarcinoma↗
PubMed1993

Extended resection of pulmonary metastases: is the risk justified?

Extended resection of pulmonary metastases by pneumonectomy or by pulmonary resection en bloc with chest wall or other thoracic structures (diaphragm, pericardium, superior vena cava) is infrequently performed as survival benefit is presumed low. Between 1981 and 1992, 38 patients underwent extended resection for pulmonary metastases (24 men, 14 women; average age, 48 years) from various primary neoplasms. Thirty-three patients (33/38, 87%) had complete resection. Five-year actuarial survival was 25.4%. Mortality was 5.3% (2/38) and occurred in patients undergoing pneumonectomy (2/19, 10.5%). Nineteen patients underwent pneumonectomy, and 19 patients had other assorted resections: pulmonary resection en bloc with chest wall in 11 and pulmonary resection en bloc with other thoracic structures in 8. Actuarial median survival (median, 27 months) did not differ between patients having pneumonectomy and those having pulmonary resection en bloc with chest wall or other thoracic structures. Initial disease-free interval (median) was no different between those patients undergoing pneumonectomy (32 months) or other type resection (35 months; p = 0.16). Median survival for extended resection as the initial operation for pulmonary metastases was 28 months compared with 14 months for all others (p = 0.095). Pneumonectomy for pulmonary metastases may be performed with operative risk equivalent to pneumonectomy for primary bronchogenic carcinoma. Patients may safely undergo extended resection of pulmonary metastases by pneumonectomy or in continuity with chest wall or other thoracic structures. Despite advanced localized metastatic disease, some patients achieve long-term survival after pneumonectomy and extended resection for pulmonary metastases.

Actuarial Analysis↗
PubMed1992

Five-year survival after pulmonary metastasectomy for adult soft tissue sarcoma.

Determinants of 5-year survival were evaluated after complete resection of pulmonary metastases from adult soft-tissue sarcomas. Fifty-eight patients had complete resection (median survival 25 months, P = 0.0002), with a 25.8% absolute 5-year survival (15 of 58 patients); six patients had unresectable disease (median survival 6 months) and were excluded from additional analysis. Eleven patients remain disease free, with a median follow-up of 76 months. Significant independent prognostic indicators associated with improved survival (P less than 0.05) included metastasis doubling time of 40 days or greater (median survival 37 months versus 15 months if less than 40 days); unilateral disease on preoperative radiography (33 months versus 15 months if bilateral disease); three or fewer nodules on preoperative computed tomography (40 months versus 14 months if 4 or more nodules); two nodules or fewer resected (40 months versus 17 months if 3 or more nodules resected), and tumor histology (33 months for malignant fibrous histiocytoma versus 17 months for all others). Multivariate analysis identified the number of nodules detected by computed tomography preoperatively as having significant prognostic value.

Adult↗
PubMed1992

Long-term survival after resection of pulmonary metastases from carcinoma of the breast.

Resection of isolated pulmonary metastases may yield improved survival in select patients. Between 1981 and 1991, 44 women (median age, 55 years) with a history of breast cancer underwent 47 thoracotomies with no operative deaths and only three minor postoperative complications (3/47, 6.4%). Confirmation of the metastatic origin of the lung lesion was made by direct histological comparison with the primary. Three patients had benign nodules and were excluded, and 4 patients had less than complete resection at thoracotomy. The median survival after thoracotomy of the remaining 37 patients with completely resected metastases was 47 +/- 5.5 months, and their actuarial 5-year survival was 49.5%. Patients with a disease-free interval of longer than 12 months had a longer survival (median survival, 82 +/- 6 months; 5-year survival, 57%) than patients with a disease-free interval of 12 months or less (median survival, 15 +/- 3.6 months; 5-year survival, 0%) (p = 0.004). Patients with estrogen receptor-positive status (n = 14) tended to have longer survival after resection than patients with estrogen receptor-negative status (n = 15) (median survival, 81 +/- 9 months versus 23 +/- 6 months, respectively; p = 0.098). Other clinical variables analyzed did not predict survival after thoracotomy. We conclude that resection of pulmonary metastases in patients with breast cancer can be done safely and may result in long-term survival for a substantial number of patients. Patients with a disease-free interval of longer than 12 months have an excellent prognosis after complete resection.

Adult↗
PubMed1991

Efficacy of pulmonary metastasectomy for recurrent soft tissue sarcoma.

To evaluate surgical results of resection of second (recurrent) pulmonary metastases from adult soft tissue sarcoma, the survival of 39 patients was analyzed retrospectively. With the exclusion of two patients (one with interval metastases between staged resections and one without histologically proved metastases), three patients were found to have unresectable disease (median survival, 7 months). A significantly (P = 0.0001) longer median survival (28 months) was found for 34 patients whose recurrent metastases were completely resected. The only other factor predicting significantly longer post-thoracotomy survival was resection of a solitary metastatic nodule (median survival, 65 months). Patients who had two or more recurrent nodules resected had a median survival of 14 months only (P = 0.01). Although trends toward longer survival were noted for other prognostic factors, none reached statistical significance. We conclude that the complete resection of a solitary second (recurrent) pulmonary metastatic nodule from adult soft tissue sarcoma predicts long-term survival.

Adolescent↗
PubMed1991

Improved survival after resection of pulmonary metastases from malignant melanoma.

The value of resecting pulmonary metastases from malignant melanoma was retrospectively examined. Between 1981 and 1989, 56 patients (35 men and 21 women with a mean age of 49 years) had 65 pulmonary resections for histologically proven metastatic melanoma after treatment of the primary tumor. In patients undergoing thoracotomy, 50% (28/56) had pulmonary metastases as the initial site of recurrence. Twenty-eight patients (50%) had local-regional recurrence before the development of lung metastases. Eight lobectomies, two segmentectomies, and 55 wedge excisions were done. Fifty-four patients (54/56, 96%) underwent complete resection, and there were no operative deaths. The postthoracotomy actuarial survival was 25% at 5 years (median interval, 18 months). Location of the primary tumor, histology, thickness, Clark level, local-regional lymph node metastases, or type of resection was not associated with improved survival. Patients without regional nodal metastases before thoracotomy had a median survival of 30 months compared with 16 months for all others (p = 0.04). Patients with lung as the site of first recurrence had a median survival of 30 months compared with 17 months for patients with initial local-regional recurrence (p = 0.038, log-rank test). Despite systemic spread, patients with isolated pulmonary metastases from melanoma may benefit from metastasectomy.

Female↗
PubMed1989

Premature mortality and chronic alcoholism: medical examiner cases, New Jersey.

To obtain estimates of premature mortality from nonviolent causes associated with chronic alcoholism, median ages at death were calculated for 994 Essex County, New Jersey Medical Examiner cases aged 25 or older classified as (1) 'nonabusers' or (2) alcoholics whose underlying cause of death was natural disease and (3) those who died of chronic alcoholism. Alcohol-associated mortality accounts for considerable years of potential life lost. Differences in its life-shortening effects according to sex, race, and natural disease versus chronic alcoholism as underlying and/or contributing cause(s) of death are analyzed. Criteria for classifying cases as alcoholics were: (1) autopsy findings attributable to alcoholism; (2) case information that the decedent was a 'known alcoholic', or ever had any health or other related problems because of drinking; or, (3) alcohol-specific disease or condition attributable to alcoholism as underlying or contributing cause of death. Nonabusers were cases not classified as alcoholics and/or other drug abusers. Nonabusers had the oldest median age at death, followed by alcoholics who died of (1) natural disease and (2) chronic alcoholism. Female nonabusers were older than their male counterparts, whereas female alcoholics whose underlying cause of death was natural diseases or chronic alcoholism were younger than male alcoholics with the same underlying cause. Median age at death was considerably lower for blacks than whites in all subgroups, with consistently greater race than sex differences. Evidence is presented which supports the accelerated development of alcoholism symptoms and associated illness among women. Aspects of increased mortality risk among alcoholics with natural disease and/or chronic alcoholism as underlying or contributing cause(s) of death are discussed.

Adult↗
PubMed1986

Trends in alcoholism and narcotics abuse from medical examiner data.

To determine trends in alcoholism and narcotics abuse, New Jersey State Medical Examiner cases from Essex County of those age 12 or older during three consecutive 12-month periods from October 1981 to September 1984 (years 1, 2 and 3) were analyzed. Cases were classified as alcoholics or narcotics abusers according to the following criteria: any case record report of drinking problems or narcotics abuse, alcoholism or narcotics abuse indicated in the manner or cause of death or autopsy findings of liver change or pancreatitis due to alcoholism, or toxicology findings of narcotics (unless medically prescribed). The age-eligible cases decreased from 710 in year 1 to 691 in year 2 and 643 in year 3. Decedents classified as alcoholics rose from 18% in year 1 to 25% in years 2 and 3. The proportions classified as narcotic abusers and those with both conditions were relatively constant, averaging 7 and 5%, respectively, over the 3 years. Substance abuse itself was the manner of death for alcoholics and most of those with both conditions; 38% of the narcotics abusers were homicide victims. There were no appreciable demographic changes among substance abusers during this period.

Accidents↗
PubMed1982

Idiopathic long QT syndrome: association of ventricular tachycardia with alternating left and right bundle branch block.

A case of sporadic long QT syndrome with ventricular tachycardia characteristic of torsades de pointes is presented. The ECG revealed sinus rhythm with marked prolongation (less than 140%) of QT interval and alternating periods of left and right bundle branch block. The onset of ventricular tachycardia was associated with alternating left and right bundle branch block and the disappearance of bundle branch block coincided with the resolution of ventricular tachycardia. This observation suggests the possibility that heterogeneous repolarization of the bundle branch system contributed to ventricular tachycardia either alone or in combination with dispersion of refractoriness of the ventricular myocardium.

Adolescent↗
PubMed1979

Increased passive stiffness of short-term pressure-overload hypertrophied myocardium in cat.

The passive stress-strain relationship of right ventricular papillary muscles from 10 normal and 9 experimental cats with short-term pressure-overload right ventricular hypertrophy-failure was examined by plotting the logarithm of instantaneous stress (ln sigma) against the natural strain calculated as ln(l/l0) where l = instantaneous length and l0 = length at zero force. Such a stress-strain relationship was well approximated by a linear relationship. The slope K obtained from this linear relationship was higher in the hypertrophy-failure muscles (normal, 15.01 +/- 0.87 (SEM); hypertrophy-failure, 31.79 +/- 4.09; P less than 0.005). The value of the intercept, ln C was similar in the two groups (normal, -4.33 +/- 0.20; hypertrophy-failure, -4.71 +/- 0.10). This analysis indicates the the ln sigma-natural strain relationship is linear in the papillary muscle and the slope of this relationship, an index of stiffness, is increased in hypertrophy-failure muscles. Using a three-element muscle model, it is shown that increased diastolic stiffness may contribute to the decreased systolic performance.

Animals↗