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Biomedical subjects

R Reddy

Publications and source records attributed to R Reddy.

At least 145 records · Page 8Linked to original sources
PubMed1994

Phase I trial of low dose N-phosphonacetyl-L-aspartic acid and high dose 5-fluorouracil administered concomitantly with radiation therapy for unresectable localized adenocarcinoma of the pancreas.

BACKGROUND: Preclinical and clinical data suggest that N-phosphonacetyl-L-aspartic acid (PALA) can augment the cytotoxic effects of 5-fluorouracil (5-FU). In addition, the combination of 5-FU and radiation therapy has been used with success in prolonging survival and providing palliation of symptoms in patients with advanced unresectable pancreatic carcinoma. This Phase I study was undertaken to determine the feasibility and evaluate the qualitative and quantitative toxicities of PALA and escalating doses of 5-FU administered concomitantly with radiation therapy in patients with locally advanced nonmetastatic pancreatic adenocarcinoma. METHODS: Ten previously untreated patients with advanced nonmetastatic adenocarcinoma of the pancreas were treated with 250 mg/m2 of PALA given as an intravenous bolus followed 24 hours later by 5-FU, which was given by continuous 24-hour infusion every week. The 5-FU doses were assigned according to a Phase I drug escalation (1000 mg/m2, 1300 mg/m2, and 1700 mg/m2). Radiation therapy was delivered concurrently with chemotherapy at a dose of 180 cGy per fraction (900 cGy per week) over 6 1/2 weeks. PALA and 5-FU were continued weekly after the end of radiation therapy, with disease assessments made every 8 weeks. Chemotherapy was continued until the disease progressed. RESULTS: All 10 patients were evaluable. The maximum tolerated dose (MTD) of 5-FU was 1300 mg/m2. Two of the four patients treated at the 1700 mg/m2 dose level experienced dose-limiting toxicities, nausea/vomiting and mucositis, respectively. Toxicities were mild to moderate at the 1000 mg/m2 and 1300 mg/m2 dose levels. Two patients treated with 5-FU at the 1300 mg/m2 dose level had complete responses, and one patient treated at the 1700 mg/m2 dose level had a partial response. The median survival was 12.5 months, and four patients survived more than 1 year. CONCLUSIONS: PALA and 5-FU administered concomitantly with radiation therapy is an active regimen in locally advanced, unresectable pancreatic cancer. Dose-limiting toxicities are nausea/vomiting and mucositis. The MTD of 5-FU is 1300 mg/m2. The regimen is well tolerated and administered in an outpatient setting.

Adenocarcinoma↗
PubMed1994

Purification of human U6 small nuclear RNA capping enzyme. Evidence for a common capping enzyme for gamma-monomethyl-capped small RNAs.

To understand the mechanism of gamma-monomethyl (meppp) cap formation, we attempted to identify and purify the U6 small nuclear RNA capping enzyme. Although more than one protein was cross-linked to U6, 7SK, B2, or plant U3 RNA, only one protein of approximately 130 kDa was common to all four meppp-capped RNAs; 5 S RNA, which is an uncapped RNA, was not cross-linked to this protein. In addition to specific cross-linking with meppp-capped RNAs, an approximately 130-kDa protein was also cross-linked to 3H-labeled AdoMet. We purified the capping enzyme from a HeLa cell S-100 extract by several successive chromatographic steps, and an approximately 130-kDa protein was purified along with the capping activity. The capping activity and the approximately 130-kDa protein also cosedimented on a glycerol gradient. The purified enzyme catalyzed meppp cap formation of U6, 7SK, B2, and plant U3 RNA, and this enzyme is probably responsible for the capping of multiple RNAs in vivo. The capping activity is distinct from U6 snRNA N6-adenosine methyltransferase, and this is the first methyltransferase to be purified that methylates gamma-phosphate residues in RNAs.

Catalysis↗
PubMed1994

Human RNaseP RNA and nucleolar 7-2 RNA share conserved 'To' antigen-binding domains.

RNase P in both prokaryotes and eukaryotes is a ribonucleoprotein that cleaves tRNA precursors to generate the 5' termini of the mature tRNAs. Many patients with autoimmune diseases produce antibodies against a 40 kDa protein (designated To or Th antigen) which is an integral component of eukaryotic RNaseP as well as nucleolar 7-2 RNP which is identical to the mitochondrial RNA processing (MRP) RNP. Interestingly, the To antigen found in human cells and the C5 protein, the only protein component of E. coli RNaseP, are antigenically related. In this study, we show that a 56 nucleotide-long sequence, corresponding to nucleotides 20-75 near the 5' end of human RNaseP RNA, is sufficient to bind the To antigen. We previously showed that the human To antigen binds to a short distinct structural domain near the 5' end of human 7-2/MRP RNA. There is no obvious primary sequence homology between the To antigen binding sites in RNaseP RNA and 7-2/MRP RNA; however, these sequences are capable of assuming a similar secondary structure which corresponds to the recently proposed 'cage' structure for RNaseP RNAs and 7-2/MRP RNA (Forster and Altman (1989) Cell 62: 407-409). These data are supportive of the idea that these two RNAs may have evolved from a common progenitor molecule.

Antibodies↗
PubMed1994

Multiple-quantum filters of spin-3/2 with pulses of arbitrary flip angle.

The influence of inhomogeneous RF fields on the double- and triple-quantum filtering of spin-3/2 nuclei in the presence of biexponential relaxation is analyzed. In this analysis, spherical tensor operators have been used for density-matrix calculations. In the presence of inhomogeneous RF fields, it is shown that the three-pulse triple-quantum filter (TQF) without a refocusing 2 theta pulse (with delta omega = 0) is on average about 100% more sensitive than the corresponding double-quantum filter (DQF), and in the case of four-pulse DQF and TQF with a refocusing 2 theta pulse (with delta omega not equal to 0), two relaxation coefficients f(1)11(tau) and f(1)33(tau) also contribute to the observed DQ and TQ coherences. It is also shown that the three-pulse filters are more sensitive than the corresponding four-pulse filters. In both three- and four-pulse cases, when used with surface coils, these filters act as depth pulses and thus yield spatial localization. The experimental results obtained with homogeneous RF coils are in excellent agreement with the theoretical results.

Equipment Design↗
PubMed1994

Abnormal growth of cultured skin fibroblasts associated with poor premorbid history in schizophrenic patients.

The relations of abnormal growth of cultured skin fibroblasts, as manifest in prolonged doubling time, and a history of impaired childhood premorbid functioning, separately for social and school (instrumental) functioning were examined in 22 schizophrenic patients. Prolonged doubling time (> 2 weeks) was significantly associated with poorer childhood social functioning, even after controlling for variance due to age, sex, race, and age at onset of illness. Doubling time was not associated with school performance scores. The findings indicate that the cellular or molecular process(es) underlying abnormal growth of skin fibroblasts may be involved in, or associated with, aberrant biological processes that contribute to early dyssocial behavior in schizophrenic patients.

Adult↗
PubMed1994

Serum antibodies to nicotinic acetylcholine receptors in schizophrenic patients.

Although elevated serum levels of antibodies to the nicotinic acetylcholine receptor (nAChR) have been reported in neuroleptic treated patients with tardive dyskinesia, such antibodies have not been determined in comparable nondyskinetic patients. Using a toxin-binding inhibition assay, we examined serum anti-nAChR antibody levels in 17 DSM-III-R chronic schizophrenic patients, seven of whom had persistent tardive dyskinesia, and 10 normal controls. On the average, anti-nAChR antibody levels were significantly higher in schizophrenic patients than in normal controls, but but not differ between patients with and without tardive dyskinesia and was not related to age, sex, or duration of illness in patients.

Adult↗
PubMed1994

Autoantibodies in sclerosing cholangitis against a shared peptide in biliary and colon epithelium.

BACKGROUND/AIMS: A strong association exists between ulcerative colitis and primary sclerosing cholangitis (PSC). Previously, the presence of a unique epitope shared by colon and biliary epithelial cells was shown by using the novel monoclonal antibody (MAb) 7E12H12 developed against a colonic epithelial protein. In the present study, the presence of circulating autoantibody in PSC against this peptide was examined. METHODS: Sera from 16 patients with PSC, 13 with primary biliary cirrhosis, 6 with secondary biliary stricture, and 6 with chronic liver diseases and 10 normal subjects were used. An inhibition immunoperoxidase assay using the 7E12H12 MAb was developed against sections of bile duct and gallbladder. Sera were also examined in an enzyme-linked immunosorbent assay (ELISA) against the gallbladder extract enriched in 7E12H12-reactive protein. RESULTS: About two thirds of the sera from patients with PSC blocked the binding of 7E12H12 MAb on the bile duct and gallbladder, whereas non-PSC sera did not. In the ELISA, 93% of PSC sera had circulating immunoglobulin G antibodies against the enriched gallbladder extract. The reactivity of sera from the PSC group was significantly (P < 0.01 to P < 0.0001) higher than in each of the non-PSC groups. CONCLUSIONS: Sera from patients with PSC contains autoantibodies against a cross-reactive peptide shared by colon and biliary epithelial cells.

Adult↗
PubMed1994

Compilation of small RNA sequences.

This is an update containing small RNA sequences deposited in GenBank recently. Over four hundred small RNA sequences are available in this and earlier complications.

Animals↗
PubMed1994

A phase II trial of recombinant leukocyte interferon plus doxorubicin in patients with hepatocellular carcinoma.

A Phase II trial of combination therapy with recombinant leukocyte interferon (alpha IFN) and doxorubicin was performed in patients with unresectable hepatocellular carcinoma. alpha IFN was administered at a starting dose of 20 x 10(6) U/m2 intramuscularly or subcutaneously with doxorubicin 20 mg/m2 intravenously weekly x 3 weeks followed by a 2-week period rest. There were 22 patients entered into the study. Among the 21 patients, there were 2 partial responses (10%), one minor response, and one patient had stable disease. Toxicity was generally tolerable, with fever, fatigue, and myelosuppression being the most common side effects. This combination of weekly recombinant leukocytic interferon and doxorubicin has modest and limited activity in hepatocellular carcinoma.

Adult↗
PubMed1994

Hepatitis C in liver transplantation: preliminary study of prognostic factors.

At the University of Miami liver transplantation for chronic liver disease in HCV-positive patients has shown good results, with a 92% patients survival rate (follow up 8 to 57 months, median 21). None the less, we found that a large number of patients are expected to develop serious histological graft damage and may need retransplantation, which may place a further strain on the already scarce donor resources. We have conducted a preliminary investigation on the importance of parameters which may correlate with the prognosis of HCV grafts. We found no impact of HLA match or typing. An interesting hypothesis, which deserves further investigation, is that some HCV strains could be more virulent than others and play a role as an independent risk factor. We have identified six strains among our patients and the BK serotype shows a trend to be associated with a worse outcome. We have found that patients developing and maintaining higher liver enzyme levels (ALT and GGT) after transplant and those with higher levels of viremia may be at risk to develop serious damage to their grafts.

Adolescent↗
PubMed1994

Capping signals correspond to the 5' end in four eukaryotic small RNAs containing gamma-monomethylphosphate cap structure.

In eukaryotic cells, the gamma-monomethylphosphate cap structure has been identified in four small RNAs, namely, U6, 7SK, B2, and plant U3 RNAs. In this study, we show that in the case of 7SK and B2, as well as in plant U3 RNAs, the 5' stem-loop followed by a short single-stranded region serves as the capping signal. We previously showed that the nucleotides 1-25 of mouse U6 snRNA, also comprised of a stem-loop followed by a short single-stranded region, function as the capping signal. These data show that capping signals in all four RNAs have common features. The length of the stem-loop among these capped RNAs varied from 20 to 108 nucleotides, with no significant variation in the capping efficiency. In addition to the capping signal, we also observed a minimum RNA length requirement of about 15-25 nucleotides following the stem-loop for efficient capping in vitro. The capping signal in plant U3 snRNA corresponds to the additional 5' stem-loop found in U3 RNAs from plants and lower eukaryotes but absent in U3 RNA from higher animals. Consistent with this observation, the human U3 RNA that lacks the additional 5' stem-loop was not a suitable substrate for capping when compared to U6 snRNA.

Animals↗
PubMed1994

Cholera toxin acts as a potent adjuvant for the induction of cytotoxic T-lymphocyte responses with non-replicating antigens.

Cholera toxin (CT) is a strong systemic and mucosal adjuvant that greatly enhances IgG and IgA immune responses, but its adjuvant effects for cellular immunity, particularly class I-restricted cytotoxic T lymphocyte (CTL) responses, are less well understood. In the present report, CT and the purified non-toxic B component (CTB) were assessed for their ability to facilitate class I-restricted CTL induction to soluble proteins as well as to permit sensitization of target cells for CTL-mediated lysis. Priming for ovalbumin (OVA)-specific CTL occurred following oral exposure to a combination of OVA with CT plus CTB. In addition, CTB mixed with soluble proteins and administered intravenously primed mice for antigen-specific class I-restricted CTL. Target cells could also be sensitized for CTL-mediated killing following their exposure to soluble antigen and CTB in vitro. These results indicate that combinations of CT and CTB not only enhance antibody responses, but also have an immunomodulating effect to allow sensitization and priming for antigen-specific class I-restricted CTL.

Adjuvants, Immunologic↗
PubMed1993

Nonrandom association of free iron with membranes of sickle and beta-thalassemic erythrocytes.

To further define the nature of abnormal iron deposits on the membranes of pathologic red blood cells, we have used sickle cell anemia (HbSS), HbSC, and beta-thalassemic erythrocytes (RBCs) to prepare inside-out membranes (IOM) and insoluble membrane aggregates (AGGs) containing coclustered hemichrome and band 3. Study of IOM from HbSC and thalassemic patients showed that amounts of heme iron and, especially, free iron were much higher in patients who had undergone surgical splenectomy. The membrane AGGs from HbSS and beta-thalassemic RBCs contained much more globin than heme, with this discrepancy being variable from patient to patient. Although these AGGs were enriched (compared with the ghosts from which they were derived) for heme, as expected, less than 10% of total ghost heme was recovered in them. Remarkably, these AGGs also were enriched for nonheme iron, markedly so in some patients. Iron binding studies showed that the association of free iron with these hemichrome/band 3 AGGs is explained by the fact that free iron binds to denatured hemoglobin. These results document that free iron is nonrandomly associated with the membranes of sickle and beta-thalassemic RBCs. Whether this plays a causative role in the premature removal of such cells from the circulation remains to be seen.

Anemia, Sickle Cell↗
PubMed1993

Methylphosphate cap structure increases the stability of 7SK, B2 and U6 small RNAs in Xenopus oocytes.

We studied the role of the methylphosphate cap structure in the stability and nucleocytoplasmic transport by microinjecting U6, 7SK and B2 RNAs into the Xenopus oocytes. In every case, the methylphosphate capped RNAs were 3 to 9 times more stable than the uncapped RNAs. When a methylphosphate cap structure was placed on human H1 RNA which is normally not capped, its stability was improved 2-7 fold. These data show that the methylphosphate cap enhances the stability of 7SK, B2, H1 and U6 RNAs. The methylphosphate-capped 7SK RNA was transported into the nucleus from cytoplasm, but remained in the nucleus when injected into the nucleus; in this respect, 7SK RNA exhibited properties previously shown for U6 RNA. Both U6 and 7SK RNAs with ppp on their 5' ends were transported from cytoplasm to the nucleus suggesting that the methylphosphate cap structure is not required for transport of these RNAs across the nuclear membrane.

Animals↗
PubMed1993

Effects of polychlorinated dibenzofurans on compounds in hepatic DNA of female Sprague-Dawley rats: structure dependence and mechanistic considerations.

Previous work indicated that covalent age-dependent DNA modifications of endogenous origin termed I-compounds may represent useful biomarkers for tumor promotion/carcinogenesis, as various tumor promoters/carcinogens, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and phenobarbital, reduce rat I-compound levels in liver, the target organ. The present study addressed the question as to whether polychlorinated dibenzofurans (PCDFs), which are related to TCDD and its congeners with regard to their toxic and biochemical properties, would also affect hepatic I-compound patterns and levels, and whether such effects would be chemical structure-dependent. Female Sprague-Dawley rats were treated once a week with a single dose (100 micrograms/kg) of 1,2,3,7,8-pentachlorodibenzofuran (1,2,3,7,8-PeCDF), 1,2,4,7,8-PeCDF, 2,3,4,7,8-PeCDF, or 2,3,4,6,7,8-hexachlorodibenzofuran (2,3,4,6,7,8-HeCDF) for 4 weeks and liver DNA was analyzed at the end of the last week by 32P-postlabeling assay. No carcinogen-DNA adducts were detected; however, levels of both non-polar and polar I-compounds were reduced in a structure-dependent manner. Potencies increased in the order, control (100%, 122 modifications in 10(9) DNA nucleotides = 1,2,4,7,8-PeCDF (104%) < 1,2,3,7,8-PeCDF (80%) < 2,3,4,7,8-PeCDF (61%) and 2,3,4,6,7,8-HeCDF (61%). Structure-activity relationships for total I-compounds, therefore, paralleled those reported for Ah receptor agonist activity, i.e., compounds that exhibit high cytosolic Ah receptor binding affinities and are also potent inducers of aryl hydrocarbon hydroxylase activity (1,2,3,7,8-PeCDF, 2,3,4,7,8-PeCDF, and 2,3,4,6,7,8-HeCDF) were active, while 1,2,4,7,8-PeCDF, which is a less potent Ah receptor agonist, was inactive. Polar I-compounds responded to a greater extent than did non-polar ones and, in general, individual I-compounds were affected differentially, thus decreased formation or increased removal of I-compounds played a role in the observed effects of the toxins on DNA. It is proposed that Ah receptor-mediated enzyme induction, particularly of cytochrome P450, is involved in reduced hepatic I-compound formation and that subnormal I-compound levels may contribute to tumor promotion.

Animals↗
PubMed1993

Spectral localization of arbitrarily shaped regions of interest (SLASH) using single voxel signals.

A method for obtaining localized spectra from arbitrarily shaped regions of interest is described. When a sample consists of homogeneous compartments or domains, spectra localized in each compartment can be obtained from signals of single voxels with regular shapes by solving a set of simultaneous linear equations. Experimental demonstrations on a phantom and on human brain in vivo for a two compartment, two voxel case are presented. The issue of signal-to-noise ratio is also discussed.

Brain↗
PubMed1993

Enhancement of age-related increases in DNA I-compound levels by calorie restriction: comparison of male B-N and F-344 rats.

Caloric restriction (CR), known to extend median and maximum life spans, improve resistance to carcinogenesis, and significantly retard age-associated degenerative diseases in rodents, was previously reported to modulate levels of indigenous, age-dependent DNA modifications, called I-compounds, in male Brown-Norway (B-N) rats. Since profiles of these adduct-like derivatives are species-, strain-, sex-, and tissue-specific, we explored this apparent CR/I-compound relationship in a comparative study between male B-N and male Fischer 344 (F-344) rats, the latter having a shorter life expectancy and high incidence of renal disease. Control animals were fed NIH-31 diet ad libitum (AL), while the caloric intake of CR animals was limited to 60% of AL, starting at 3.5 months. Liver and kidney DNA from 1, 8, 12, 16, 24 (AL, CR), and 30 (CR only) month old rats was analyzed by 32P-postlabeling. Corresponding tissues from the two strains yielded similar DNA profiles. Total liver I-compound levels displayed 2.3-4.6-fold age-dependent increases from 1 to 24 months, and kidney values at 24 months were 5.2-8 times higher than those at 1 month. In both strains, I-compound levels of CR animals were higher, up to 2-fold, than in age-matched AL rats. Regression analyses indicated linear relationships between most CR relative adduct labeling values (both total and individual fractions) and age, whereas many AL values exhibited this type of link with log age. These findings confirm that a correlation exists between CR and I-compound levels, and, given the above physiological benefits of CR, indicate that I-compounds represent biomarkers of aging with potential utility in intervention studies.

Aging↗