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Biomedical subjects

P Singh

Publications and source records attributed to P Singh.

At least 19 recordsLinked to original sources
PubMed2026

Reduced Length of ADT and ARTA With XRT in High-Risk Prostate Cancer (RELAX): A Randomised Controlled Trial.

AIM: To assess the efficacy of a short, intensified regimen of androgen deprivation therapy (ADT) and androgen receptor-targeted agent (ARTA) with curative-intent external beam radiotherapy (XRT) for high-risk prostate cancer (HRPCa) staged with prostate specific membrane antigen (PSMA) imaging. MATERIALS AND METHODS: The RELAX (Reduced Length of ADT and ARTA with XRT in high-risk prostate cancer) trial is a multicentre, phase II randomised non-inferiority trial comparing 9 months of ADT and 6 months of ARTA against the standard 24-month ADT, with definitive dose-escalated hypofractionated pelvic radiotherapy for PSMA-staged non-metastatic HRPCa. The primary endpoint is 5-year disease-free survival (DFS), defined from randomisation to first biochemical or clinico-radiological recurrence or any-cause death. Secondary endpoints include biochemical failure-free survival, metastasis-free survival, overall survival, testosterone recovery, treatment-related adverse effects, and patient-reported outcomes. Participants are monitored with serial serum PSA and testosterone levels, CTCAE and PRO-CTCAE assessments, and PSMA-PETCT at recurrence. The non-inferiority margin is set at 10% absolute difference from an expected 5-year DFS of 85% in the standard arm, with intention-to-treat analysis. The trial is ethics board approved and funded by institutional intramural grant, and registered on clinicaltrials.gov (NCT06818682). RESULTS: The planned accrual of 206 participants commenced in February 2025, with nearly a third of enrolment completed till date. CONCLUSION: The RELAX trial incorporates contemporary standards of PSMA-based staging, dose-escalated hypofractionated radiotherapy, and ARTA for HRPCa. The results are expected to inform the efficacy of a shorter, intensified androgen suppression strategy against the prevailing standard of long-term ADT for these patients.

Humans↗
PubMed1992

A novel bombesin receptor antagonist (2258U89), potently inhibits bombesin evoked release of gastrointestinal hormones from rats and dogs, in vitro and in vivo.

Several bombesin-receptor antagonists are available that inhibit secretory and growth effects of bombesin, in vitro. In the present study, we examined the effects of a new class of bombesin receptor antagonists (modified GRP(15-27) peptides, with D-Pro26 and D-Ala24 moieties), on bombesin mediated effects, in vivo and in vitro. Of the 10 different compounds tested, BW-10 or 2258U89 ([de-NH2)Phe19,D-Ala24,D-Pro26 psi(CH2NH)Phe27]-GRP(19-27)) was most potent towards inhibiting bombesin binding to rat pancreatic acinar cancer cells with an ID50 of 0.5 nM. BW-10 (1 and 10 nM) significantly inhibited the gastrin response to 1 nM bombesin, from isolated rat stomach, in vitro, in a dose-dependent fashion. BW-10 (10-100 nmol/kg) was equally effective at significantly inhibiting bombesin evoked gastrin release in anesthetized rats, in vivo. [D-Phe6]Bombesin(6-13)-propylamide (BIM), a member of another class of antagonists, reported previously to be the most potent antagonist, in vitro, on the other hand, enhanced bombesin provoked gastrin release in rats. The antagonistic effects of BIM, in vivo, may thus be more selective. Intravenous infusion of BW-10 (10 nmol/kg/h) partially depressed gastrin and pancreatic polypeptide and completely abolished insulin released in response to bombesin, in conscious dogs. These results suggest that BW-10 functions as one of the most potent bombesin receptor antagonists, in vitro and in vivo, which could potentially be used as a therapeutic compound in treatment of some human diseases.

Animals↗
PubMed1992

Characterization of gastrin binding to colonic mucosal membranes of guinea pigs.

Gastrin has significant growth and metabolic effects on colonic mucosal cells. It is, however, not known if gastrin receptors are present on colonic mucosal cells that may directly mediate the reported biological effects of gastrin. In the present studies, the presence of specific gastrin binding sites on colonic mucosal membranes was investigated and the binding sites were further characterized. Crude membranes from colonic mucosa of guinea pigs were analyzed for specific binding to gastrin by our published procedures. A significant number (14.7 +/- 1.8 fmoles/mg protein) of high affinity gastrin binding sites (Kd = 0.49 +/- 0.05 mM) were measured, that were specific for binding gastrin/CCK related peptides and demonstrated negligible binding affinity for all other unrelated peptides examined. In addition a large number of low-affinity (Kd = approximately 1 microM) binding sites were present. In order to further characterize the molecular size of gastrin binding proteins, we used the chemical cross-linking methods, and observed at least four bands of gastrin binding proteins (GBPs) (approximately 33, 45, 80 and 250 KDa), both under reducing and non-reducing conditions, indicating that these proteins were not sub-units of forms linked by disulfide bonds. Interestingly, majority of the specific gastrin binding sites (approximately 70%) were present on the 45 KDa protein, unlike other target cells of gastrin. The presence of N- and O-linked glycosylated moieties were indicated on the 45 KDa protein, based on enzymatic de-glycosylation studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Early stages of gallstone formation in guinea pig are associated with decreased biliary sensitivity to cholecystokinin.

The purpose of this study was to measure differences in gallbladder sensitivity to cholecystokinin (CCK) in vivo during the early stages of gallstone formation and to correlate these findings to gallbladder CCK receptors. Guinea pigs were placed on either a normal diet or a two-week cholelithogenic diet, after which gallbladder emptying pressure to exogenously administered CCK was measured in vivo, according to the presence or absence of gallstones. At all doses of CCK tested (except 10(-10) mol/kg), the gallbladder response to CCK of guinea pigs that did not develop gallstones (on the cholelithogenic diet) was more sensitive than that of guinea pigs that did develop gallstones. Neither group was different from guinea pigs on a normal diet. In a second experiment, CCK receptors were measured on gallbladder muscularis from guinea pigs after two weeks on the same diet as in the first experiment. Those guinea pigs that did not develop gallstones had greater concentrations of CCK receptors (149 +/- 9 fmol/mg protein) than those that did develop gallstones (70 +/- 23 fmol/mg protein). Neither group was different from normal diet guinea pigs (119 +/- 57 fmol/mg protein). At the time point measured, there were no differences in the lipid chemistry or protein concentrations of gallbladder bile between the guinea pigs on the cholelithogenic diet that did or did not develop gallstones, or those on normal guinea pig chow. We conclude that the early stages of gallstone formation in guinea pigs are associated with decreased gallbladder sensitivity to CCK and that this change may be due to a lower concentration of CCK receptors on the gallbladder smooth muscle.

Animals↗
PubMed1992

Estradiol is trophic for colon cancer in mice: effect on ornithine decarboxylase and c-myc messenger RNA.

The mitogenic role of estradiol on the growth of colon cancer was examined in mice. Sham-operated or ovariectomized mice were injected with cancer cells and received estradiol treatment. Tumor growth was noted: tumor weights were higher in female than male mice. The growth of the tumors was least in ovariectomized mice and highest in estradiol-treated ovariectomized mice. Tumor messenger RNA (mRNA) levels for ornithine decarboxylase (ODC) and proto-oncogenes c-myc, c-fos, and H-ras were examined. Two transcripts (2.2 and 2.7 kilobase pairs) of ODC were observed. The steady-state mRNA levels for ODC paralleled the changes observed in the weight of the tumors in all groups of animals. Less dramatic changes were observed in c-myc mRNA levels. No significant differences were observed in the mRNA levels for H-ras and c-fos. It thus appears likely that an increase in the ODC mRNA levels and, to a lesser extent, an increase in c-myc mRNA levels may be some of the important mechanisms by which estradiol mediates its growth effects on colon cancer cells in vivo.

Animals↗
PubMed1992

Mobius syndrome with basal ganglia calcification.

Basal ganglia calcification has not been described in Mobius syndrome. A family with two children with Mobius syndrome are reported. Bilateral basal ganglia calcification was seen on computed tomography in both. This is the first family where cerebral involvement has been clearly documented in this syndrome.

Abducens Nerve↗
PubMed1992

Oesophageal motor function before and after healing of oesophagitis.

Forty three patients with reflux oesophagitis were studied to investigate the effect of healing on oesophageal function. All patients underwent oesophageal manometry and transit studies before and after complete healing of oesophagitis. Oesophagitis was treated with omeprazole 40 mg/day for a median duration of 12 weeks. Twenty three patients also had an acid clearance test before and after healing. Thirty eight of the 43 patients had 24 hour oesophageal pH monitoring before treatment and this was repeated after healing (while on omeprazole) in 31 of them. Thirty four volunteers served as controls. All volunteers underwent manometry, 33 had oesophageal transit studies, and 23 had acid clearance test. Patients had significantly reduced lower oesophageal sphincter pressures and distal and middle oesophageal amplitudes, longer durations of contraction, and slower velocity of propagation than the controls (16.5 v 22.5 mm Hg; 52 v 92 mm Hg; 46 v 79 mm Hg; 3.1 v 2.7 seconds; and 3.3 v 4.1 cm/second respectively with the corresponding p values = 0.017; 0.0001; 0.0001; 0.017; and 0.006). Patients had significantly longer transit times (9 v 7 and 17 v 11 seconds: p = 0.027 and 0.002 for erect and supine postures respectively). They also had longer acid clearance times (350 v 288 and 536 v 405 seconds: p = 0.044 and 0.016 for sitting and supine postures respectively). There was no significant change in any of the indices of oesophageal function after healing of oesophagitis (lower oesophageal sphincter pressure = 16.5 v 20; distal amplitude = 52 v 60; middle amplitude = 46 v 49; duration of contraction = 3.1 v 3.1; velocity = 3.3 v 3.3; erect transit time = 9 v 9; supine transit time = 17 v 24; acid clearance test (sitting) = 350 v 371; acid clearance test (supine) = 536 v 645). These results indicate that oesophageal motor dysfunction in reflux oesophagitis is a primary phenomenon.

Adult↗
PubMed1992

Characterization of insulinlike growth factor I receptors in human colon cancer.

A possible role of insulinlike growth factor I (IGF-I) and IGF-I receptors in the proliferation of human colon cancer has, to the best of the authors' knowledge, not been examined as yet. To determine a role of IGF-I in colon cancer, several human colon cancer cell lines and colon cancers were screened for specific binding to 125I-IGF-I. Almost all the human colon cancer cells examined were variably positive for specifically binding 125I-IGF-I. Almost half the colon cancer cell lines examined showed significant growth response to 6.6 nmol/L IGF-I. Dose-dependent growth effects of exogenously added IGF-I (0.05-3.3 nmol/L) were shown in a representative human colon cancer cell line (Colo-205). To determine if IGF-I binding sites on colon cancer cells were similar or different from that described on other cells, the binding affinity, binding specificity, and molecular size of the IGF-I binding sites were characterized in representative human colon cancer cell lines (HCT-116 and Colo-205). The optimal binding assay conditions for measuring maximum number of 125I-IGF-I binding sites on the cells, in vitro, were determined and found to be similar to that described on other cells. Scatchard analysis of the specific binding data showed the presence of a single class of high-affinity binding sites [disassociation constant (Kd) = approximately 1.0-2.0 nmol/L], with a binding capacity of 1.0-2.0 x 10(5) sites per cell. The molecular weight of IGF-I receptors on cell membranes was determined by gel electrophoresis of the affinity cross-linked proteins, followed by autoradiography. A single band of binding proteins with a molecular mass of approximately 300 kilodaltons was evident under nonreducing conditions and separated out into two bands of approximately 240 and approximately 130 kilodaltons under reducing conditions. The 130-kilodalton band represents the alpha subunit of IGF-I receptors, and the 240-kilodalton band may represent aggregates of the receptor subunits that were not reduced completely. The widespread existence of high-affinity binding sites for IGF-I in established human colon cancer cell lines and freshly resected human colon cancers and the proliferative effect of IGF-I in several colon cancer cell lines, in vitro, reflect that IGF-I may be an important endocrine/paracrine/autocrine factor in the growth regulation of colon cancers in situ.

Cell Division↗
PubMed1992

A potent bombesin receptor antagonist inhibits bombesin-stimulated growth of mouse colon cancer cells in vitro: absence of autocrine effects.

Bombesin (BBS) exerts significant effects on the growth of a mouse colon cancer cell line (MC-26) in vitro. The presence of specific binding sites on MC-26 cells for gastrin-releasing peptide (GRP)/BBS-related peptides was recently reported by us. In the present study, we determined that the transcript size of the mRNA species that codes for GRP receptors is 9 kilobase pairs, which is similar to that reported for mouse Swiss 3T3 cells, using the complementary DNA probe for the GRP receptor gene from mouse Swiss 3T3 cells. We next examined the effects of potent GRP receptor antagonists, D-Phe6, bombesin(6-13)-propylamide (D-Phe6,BN(6-13)PA) and Leu13-psi-(CH2NH)Leu14-bombesin (LL-BBS), on BBS-stimulated growth of MC-26 cells in vitro. A possible autocrine role of GRP in the growth of MC-26 cells was also investigated. MC-26 cells were inoculated s.c. into male BALB/c mice, and tumors were harvested 21-28 days postinoculation. Both D-Phe6,BN(6-13)PA and LL-BBS significantly inhibited the binding of 125I-GRP to MC-26 tumor membranes in a dose-dependent manner, with 50% inhibitory concentrations of 4.5 +/- 0.52 nM and 87 +/- 6 nM, respectively. D-Phe6,BN(6-13)PA similarly inhibited the specific binding of 125I-GRP, cross-linked to a approximately 80 kilodalton binding protein on the MC-26 tumor membranes. In order to determine whether the BBS receptor antagonist, D-Phe6,BN(6-13)PA, functioned as an antagonist or an agonist of biological functions, we measured the bioefficacy of D-Phe6,BN(6-13)PA.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Quantitative structure-activity relationship study of some benzodiazepine-receptor ligands having inverse agonist/antagonist and agonist actions.

Quantitative structure-activity relationship (QSAR) analyses of three different series of benzodiazepine ligands, pyridodiindoles, and beta-carbolines, having inverse agonist/antagonist and agonist actions have been performed with a view to understanding their likely mode of action at the benzodiazepine-receptor (BzR). From this study, the in vitro radioligand displacement activities of substituted 7,12-dihydropyrido[3,2-b: 5,4-b']diindoles (Figure 1) were found to be significantly correlated with resonance effect of R-substituents, van der Waals volumes at positions-1 and -3, hydrophobic constant at position-2 and field effect at position-4 of X-substituents. For 3-substituted beta-carbolines, a similar analysis has established that R-substituents at position-3 of beta-carbolines (Figure 2) are involved in strong hydrophobic interaction with some hydrophobic pocket on the receptor. For the analogues of 6-(benzyloxy)-4-(methoxymethyl)-beta-carbolines-3-carboxylic acid ethyl ester (Figure 3), however, the combined hydrophobicities of 6- and 4-substituents were shown to be important in determining ligand binding behaviour. The significant correlations so obtained are in agreement with the proposed models (Figures 4 and 5) of pharmacophores of inverse agonist/antagonist and of agonist sites at the BzR.

Carbolines↗
PubMed1992

Peribulbar anesthesia for primary vitreoretinal surgery.

We prospectively studied the efficacy of peribulbar anesthesia in 76 consecutive patients who underwent vitreoretinal surgery. The mean duration of anesthesia was 124.74 +/- 50.17 minutes, and the mean duration of akinesia, 151.5 +/- 54.45 minutes. Adequate anesthesia and akinesia, independent of the duration of surgery, was obtained in 26 of 33 (78.8%) patients who underwent vitrectomy; 9 of 32 (28.1%) who underwent scleral buckling; and 2 of 11 (18.2%) who underwent vitrectomy combined with scleral buckling. In all, topical and systemic supplementation of drugs for inadequate anesthesia or akinesia allowed 32 of the 33 (97%) vitrectomies, 30 of the 32 (94%) scleral buckling procedures, and all 11 of the combined surgeries to be completed as planned. Three (4%) patients vomited, moved, or were restless, resulting in an operative complication or postponement of surgery. Fifty-eight (76%) said they would desire similar anesthesia if subsequent surgery was needed in the same or fellow eye. We conclude that peribulbar anesthesia should be considered primarily for patients requiring vitreous surgery alone, and as an alternative for patients requiring scleral buckling or combined surgery for whom general anesthesia is contraindicated.

Adult↗
PubMed1992

Growth, behavior, development and intelligence in rural children between 1-3 years of life.

In a rural cohort of 625 children registered from 1981 to 1983 in 10 villages of K.V. Block, Varanasi, 196 children were assessed for physical growth, development, intelligence and concept development between 1 and 3 years of age. Home environment was also assessed using Caldwell Home inventory. These rural children remained below 3rd centile of NCHS standard for weight, height, skull and mid-arm circumferences throughout the study. Malnourished children scored poorly in all the areas of development, i.e., motor, adaptive, language and personal social, 9% in Grade I and 16.6% children in Grade II + III had IQ less than 79 (inferior). Concept for color shape and size was poorly developed in malnourished children. Maternal involvement and stimulation was strongly associated with better behavior development and intelligence. Multiple regression analysis showed that the effect of home environment on development and intelligence was of a higher magnitude as compared to status and family variables and nutritional status during 1-3 years of age.

Adult↗
PubMed1992

Toxic effects of ackee oil (Blighia sapida L) following subacute administration to rats.

Subacute intraperitoneal administration of the lipid portion of the unripe ackee arillus, referred to as "ackee oil", resulted in marked neutropenia (p less than 0.001) and increase in platelets (p less than 0.01) without anaemia, in rats. Blood urea, sodium and aspartate aminotransferase levels were significantly decreased but glucose and bilirubin levels were similar to those of controls. The lungs showed areas of petechial haemorrhages and a dose-related perivascular and peribronchial mononuclear cell infiltration. The pulmonary toxicity may be interpreted as a hypersensitive reaction to ackee oil. Further research is in progress on the neutropenic effects of ackee oil.

Animals↗
PubMed1992

Role of vagal and sinoaortic baroreflexes in circulatory adjustments to passive head up tilt.

To evaluate the contribution of vagal and sinoaortic baroreflexes in circulatory adjustments anaesthetized rabbits were subjected to 70 degree head up tilt with (i) both reflexes intact; (ii) after elimination of sinoaortic reflexes; (iii) after elimination of vagal reflexes; and (iv) after elimination of both categories of reflexes. The results suggest that vagal mediated baroreflexes from cardiopulmonary baroreceptors contribute significantly in circulatory adjustments to passive head up tilt while sinoaortic baroreflexes play the major role.

Animals↗
PubMed1991

High-affinity binding sites for bombesin on mouse colonic mucosal membranes.

Bombesin (BBS) has specific biological effects on colonic mucosal cells, but the presence of BBS receptors on colonic mucosa have not been described to-date. In the present study we examined the mouse colonic mucosal membranes for the presence of specific binding sites for BBS/gastrin releasing peptides (GRP), and characterized the binding kinetics and molecular weight of the specific binding proteins. The radiolabeled ligand (125I-Tyr4-BBS), in the absence or presence of a 1000-fold excess of BBS, was used to establish the optimal binding assay conditions of time, pH and temperature for measuring the maximum number of specific binding sites for BBS related peptides. Under the optimal binding assay conditions, BBS displaced the binding of 125I-Tyr4-BBS in a dose-related manner. A single class of high-affinity binding sites (Kd = 0.23 +/- 0.02 nM) for BBS were measured, with a binding capacity of 27.3 +/- 4.6 fmoles/mg membrane protein. The binding sites were specific for binding BBS/GRP related peptides, since all structurally related peptides inhibited the binding of 125I-Tyr4-BBS in a dose-dependent manner, while structurally unrelated peptides did not compete for the 125I-Tyr4-BBS binding sites. The relative binding affinity (RBA) of BBS/GRP related peptides was determined to be in the order of GRP (14-27) = GRP (18-27) greater than GRP (1-27) greater than neuromedin B greater than BBS. The BBS-receptor antagonists, [Leu13-psi-(CH2NH) Leu14]-BBS (LL-BBS) and D-Phe6, BN(6-13) propylamide (D-Phe6, BN(6-13)-PA), inhibited the specific binding of 125I-Tyr4-BBS to colonic mucosal membranes in a dose-dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗