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Biomedical subjects

R Dhir

Publications and source records attributed to R Dhir.

At least 37 records · Page 2Linked to original sources
PubMed1998

Identification of nuclear matrix protein alterations associated with renal cell carcinoma.

PURPOSE: Neoplastic transformation, including renal cell carcinoma (RCC), is always accompanied by changes in nuclear morphology. Nuclear grading of RCC is based on characteristic alterations in nuclear shape, size, area and other morphologic parameters. The nuclear matrix, which forms the skeleton of the nucleus, determines nuclear morphology. Alterations in nuclear matrix protein (NMP) composition specific to tissue and cancer type have been described in a variety of human cancers. We conducted a study to analyze the nuclear matrix protein composition of renal cell carcinoma and compare it to that of normal renal tissue and renal cell carcinoma cells grown in culture. MATERIALS AND METHODS: We analyzed the nuclear matrix protein composition of RCC tumor tissue and that of normal kidney tissue obtained from seventeen patients undergoing radical nephrectomy for RCC. We also analyzed the NMP composition of two renal cancer cell lines (A-498 and 769-P). RESULTS: We were able to identify five different and unique NMPs which were present only in the human RCC tumor samples and were absent in all normal kidney tissue. One NMP was found specifically in the normal kidney tissue. All five RCC specific NMPs were also identified in the nuclear matrix of the two cell lines analyzed. CONCLUSIONS: Five nuclear matrix proteins specific and unique to RCC were identified. These NMPs are different from those previously identified in other tissues and neoplasms. The RCC specific NMPs identified in this study can potentially be used as diagnostic markers for renal cell carcinoma and for therapeutic tumor targeting.

Aged↗
PubMed1998

Prostatic carcinoma with signet ring cells: a clinicopathologic and immunohistochemical analysis of 12 cases, with review of the literature.

Prostatic adenocarcinoma with a signet ring cell (SRC) component is a rare, incompletely characterized variant that must be distinguished from similar tumors of bladder or gastric origin. In this study, we used mucin and immunoperoxidase stains on formalin-fixed, paraffin-embedded sections from 12 prostatic adenocarcinomas with SRC components, with antibodies to prostate-specific antigen (PSA), cytokeratins, MIB-1, bcl-2, c-MET, CD44v6, and CD44v7; we performed a comparison study on six bladder and seven gastric carcinomas with SRCs. The prostatic SRC component was always associated with the usual high-grade adenocarcinoma. Both components were positive for PSA, AE1/AE3, and CAM 5.2 (12 cases of 12) and also expressed c-MET (5 cases of 9), CD44v6 (9 of 10), and CDv7 (9 of 10). Only rare cells stained for bcl-2 (3 cases of 9). The mean MIB-1 proliferation index was 8%. Intracellular mucin was identified (periodic acid-Schiff with diastase predigestion (PAS-D) in 9 cases of 10, mucicarmine in 5 of 10, alcian blue in 6 of 10). Bladder and gastric tumors were positive for PSA (3 cases of 6 and 2 of 7, respectively), using a polyclonal antibody, and for bcl-2 (5 cases of 6, 2 of 7), c-MET (6 of 6, 6 of 7), CD44v6 (5 of 6, 6 of 7), and CD44v7 (4 of 6, 4 of 7), with mean MIB-1 proliferation indices of 15 and 35%, respectively. All were negative for cytokeratin 34 beta E12. We conclude that prostatic adenocarcinomas with SRC components are typically accompanied by high-grade adenocarcinoma; are variably positive for mucin, with PAS-D being the most sensitive stain; show expression of PSA, cytokeratins, MIB-1, bcl-2, c-MET, and CD44 similar to that shown by high-grade adenocarcinoma components; have a low MIB-1 proliferation index; and are not always distinguishable from SRC components of bladder and stomach carcinomas with any of the above stains, including PSA.

Aged↗
PubMed1997

Perineural invasion in transitional cell carcinoma and the effect on prognosis following radical cystectomy.

OBJECTIVES: The relationship between perineural invasion and prognosis has been demonstrated to be poor in a number of malignancies. This has not been evaluated in the bladder. We performed a study to determine the occurrence of nodal metastases, extranodal metastases, and disease-free survival in patients with perineural invasion (PNI) and/or angiolymphatic invasion (ALI) in transitional cell carcinoma of the bladder (TCCB) from radical cystectomy specimens. METHODS: A retrospective review of 27 patients treated with radical cystectomy for TCCB was conducted. Comparisons were performed between three groups: PNI with or without ALI (PNI +/- ALI, 12 patients), ALI alone (8 patients), and a control group (no PNI or ALI) (7 patients). RESULTS: The mean patient age was 70 years (range 49 to 83). The overall median follow-up period was 11 months (range 1 to 32). PNI +/- ALI was predominantly found in Stage T3b disease (14 of 20 [70%] cases). The overall 1-year disease-free survival was 48%, 67%, and 83% for the PNI +/- ALI, ALI alone, and control groups, respectively. Nodal metastases (for all stages combined) were found in 6 of 12 (50%), 3 of 8 (38%), and 1 of 7 (14%) patients in the PNI +/- ALI, ALI alone, and control groups, respectively. Similarly, extranodal metastatic disease was found in 5 of 12 (42%), 4 of 8 (50%), and 1 of 7 (14%) patients in the PNI +/- ALI, ALI alone, and control groups, respectively. The percentage of deaths for the PNI +/- ALI, ALI only, and control groups were 33%, 50%, and 14%, respectively. CONCLUSIONS: In TCCB, perineural invasion with or without angiolymphatic invasion and angiolymphatic invasion alone are associated with a higher incidence of nodal and extranodal metastases and death.

Aged↗
PubMed1997

Vitamin D inhibition of prostate adenocarcinoma growth and metastasis in the Dunning rat prostate model system.

OBJECTIVES: Risk factors for prostate cancer (PCa)-related mortality include old age, black race, and residence in northern latitudes. The objectives of this study are to examine the in vitro and in vivo effects of 1,25-dihydroxycholecalciferol (1,25-D3) and less-hypercalcemic analogues on the Dunning rat prostate adenocarcinoma model. METHODS: To evaluate the effect of 1,25-D3 on PCa in vitro, we used the highly metastatic Mat-lylu (MLL) and moderately metastatic R3327-AT-2 (AT-2) Dunning prostate cell lines, and examined effects on growth, clonogenicity, differentiation, and cell cycle. In vivo analysis included examination of the effects of these compounds on tumor growth and metastasis. RESULTS: Using both the 3-day MTT and 7-day clonogenic assay, 1,25-D3 demonstrated a growth inhibitory effect with a concentration for 50% inhibition (IC50) of approximately 20 microM for both MLL and AT-2. Cell cycle analysis of treated MLL cells (10 microM 1,25-D3 for 48 hours) had 25% more cells in the G0/G1 phase than did control cells. To examine the in vivo effect of 1,25-D3 and the less hypercalcemic vitamin D analogue, Ro25-6760 (or 6760), on MLL PCa growth and metastasis, tumors (5 x 10(5) cells) were implanted subcutaneously into the flank of Copenhagen rats on the same day that treatment was initiated with 1,25-D3 (1 microgram) or 6760 (1 or 5 micrograms); rats received treatment three times a week. After 3 weeks, 1,25-D3 and 6760 (5 micrograms dosing) resulted in an inhibition of tumor volume and a reduction in the number and size of lung metastases. CONCLUSIONS: These preclinical studies demonstrate the profound in vitro, or in vivo, or both antiproliferative and differentiating effects of 1,25-D3 and 6760 on PCa and suggest that these drugs may have potential beneficial effects in the treatment of advanced PCa.

Adenocarcinoma↗
PubMed1997

CD44 Expression in Benign and Neoplastic Human Prostates.

Background: CD44, a major cell surface receptor for hyaluronic acid, is a family of ubiquitous cell surface glycoproteins. Altered levels of CD44 expression, seen in many epithelial neoplasms, have prognostic implications. Expression of standard and variant isoforms of CD44 was assessed in normal and neoplastic human prostate tissue and culture cells to evaluate as a marker for malignant transformation. Methods and Results: Expression of CD44s, CD44R, v5, v6, v7/8 and v10 was assessed in prostate tissue (benign and malignant) and cell lines (DU-145, PC-3, LNCaP, p69) and primary cultures of normal prostates and adenocarcinoma cells obtained from prostatectomies using reverse transcriptor polymerase chain reaction, Western blotting, and immunofluorescence. No CD44 expression was seen in LNCaP cells. p69, DU-145, and PC-3 cells expressed CD44s and CD44R. p69, cells demonstrated a 1000-bp-long form of CD44 mRNA, unique to this normal cell line. Both normal and neoplastic prostatic tissue demonstrated CD44s on Western blotting. Conclusions: In agreement with previous studies, prostatic adenocarcinoma cells, except LNCaP, expressed CD44s. Different patterns of CD44 expression were seen in benign and neoplastic prostate. Benign prostate exhibited higher v5 protein levels, whereas neoplastic prostates demonstrated higher CD44s expression. CD44s expression was identified in all neoplastic prostates as compared with only 50% of the benign prostates. No significant difference in expression of the other variants assessed (v6, v7, v7/8, and v10) was observed in the benign and neoplastic prostates.

Journal Article↗
PubMed1995

A correlative study of in vivo and in vitro labeling index using bromodeoxyuridine in human brain tumors.

The labeling index (LI) of 216 cases of human brain tumors was determined by the immunohistochemical technique with monoclonal antibody to bromodeoxyuridine (BrdU). The proliferative potential of 110 cases was estimated using the intra-operative intravenous infusion of BrdU at a dose of 200 mg/sq m. In another 106 cases, the in vitro technique of incubating freshly resected tumor tissue fragments with 100 microM bromodeoxyuridine was used. The BrdU LI in these tumors was then correlated with the histological types and the data as determined by both the in vivo and in vitro BrdU incorporation were compared. The results indicate that although in vivo and in vitro techniques could possibly provide equivalent data in some histologic types, a clear statistically valid proof however is not apparent from this study.

Adolescent↗
PubMed1995

Orbital neurofibrosarcoma: a case report.

Malignant peripheral nerve sheath tumours of orbit is rare entity. Only sixteen cases are reported in world literature. Bengin schwannomas of the orbit are found in 1.5 to 18 percent of patients with von Recklinghausen's disease (VRD) and form 1 percent of all orbital tumours1. The incidence of malignant transformation in VRD is varies from 5-15 percent of all the cases1.

Female↗
PubMed1994

Primary cerebellopontine angle choroid plexus papilloma: a case report and review of literature.

A case of primary choroid plexus papilloma of the cerebellopontine (CP) angle is described in a 28 years old man. He presented with hearing loss, right facial palsy and spastic quadriparesis (4/5). He also had markedly increased intracranial pressure. CT scan revealed a large high attenuating lesion in right CP angle with gross hydrocephalus. The patient was operated with the clinical and radiological diagnosis of right sided acoustic tumor with brainstem compression. Radical tumour excision was performed, seven days following VP shunt. Patient had immediate postoperative deterioration followed by a steady recovery. The possibility of a secretory choroid plexus papilloma is discussed.

Adult↗
PubMed1993

Modulatory effects on substrate specificity of independent mutations at the serine939/941 position in predicted transmembrane domain 11 of P-glycoproteins.

The serine residue located at position 939 and 941 in the predicted transmembrane segment 11 of P-glycoprotein (P-gp) encoded by mouse mdr3 and mdr1, respectively, appears to be important for interaction of chemotherapeutic drugs and reversal agents with P-gp. To further understand the role of this residue in this process and to identify the structural requirements involved, we have replaced this serine residue by alanine, cysteine, threonine, tyrosine, tryptophan, and aspartic acid and tested the effect of these mutations on the overall activity and substrate specificity of mdr1 and mdr3. All mutant proteins could be expressed at high levels in the membrane fractions of LR73 Chinese hamster cells transfected with the corresponding mutant cDNAs. All introduced mutations had limited effect on the capacity of mdr1 and mdr3 to confer resistance to vinblastine. The modulatory effect of mutations on resistance to colchicine, adriamycin, and actinomycin D was more dramatic. The hydroxyl group of serine did not seem essential for interaction with these drugs since mutant mdr1 and mdr3 bearing alanine or cysteine at that position behaved essentially as wild type, while threonine-bearing mutants showed significantly reduced resistance to these drugs. The insertion at that site of residues with bulkier side chains had more complex effects on P-gp function. While introducing tyrosine, tryptophan, or aspartic acid caused an almost complete loss of colchicine and adriamycin resistance in both mdr1 and mdr3, the replacement to tyrosine or tryptophan had the opposite effect on mdr1 and mdr3 for actinomycin D resistance, causing either a 3-fold increase or a 4-8-fold decrease in resistance to this drug, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Functional analysis of chimeric proteins constructed by exchanging homologous domains of two P-glycoproteins conferring distinct drug resistance profiles.

P-Glycoproteins (P-gps) encoded by the mouse mdr1 and mdr3 (Phe939, mdr3F) genes confer distinct drug resistance profiles. While the mdr1 and mdr3F clones confer comparable levels of vinblastine (VBL) resistance, mdr3F confers actinomycin D (ACT) resistance levels 2-fold greater than mdr1, while mdr1 confers resistance to colchicine at levels 7-fold greater than mdr3F. We wished to identify in chimeric proteins discrete protein domains responsible for the distinct drug resistance profiles of mdr1 and mdr3F. Homologous protein domains were exchanged in hybrid cDNA clones, and the specific drug resistance profiles conferred by chimeric proteins were determined in stably transfected cell clones expressing comparable amounts of wild-type or chimeric P-gps. Immunoblotting experiments showed that all chimeras were found expressed in membrane-enriched fractions of transfected cell clones and all conveyed cellular drug resistance at levels above the background of nontransfected drug-sensitive LR73 cells. For VBL, all chimeric constructs were found to convey similar levels of resistance. For COL and ACT, the levels of resistance conferred by the various chimeras were heterogeneous, being similar to either the parental mdr1 or the parental mdr3F clones, or in many cases being intermediate between the two. The preferential COL and ACT resistance phenotypes of mdr1 and mdr3F, respectively, did not segregate in chimeric proteins with any specific protein segment. Taken together, our results suggest that the preferential drug resistance phenotypes encoded by the mdr1 and mdr3F clones implicate complex interactions between the two homologous halves of the respective P-gp.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Giant lumbosacral nerve sheath tumors.

Cauda equina nerve sheath tumors are usually small, well-encapsulated tumors. Sometimes they may attain very large proportions, cause extensive bony changes, and resemble ependymomas in the cauda equina. They may also infiltrate into adjacent soft tissue planes and retroperitoneal spaces and yet be histologically benign. An awareness of this entity ensures aggressive surgical removal at the time of exploration. Primary neuro-fibrosarcomas or malignant changes in primary nerve sheath tumors of the cauda equina are seen in patients with neurofibromatosis.

Adolescent↗
PubMed1992

Dystrophin test in differential diagnosis of childhood muscular dystrophies.

Two cases of childhood muscular dystrophy are described. One of them had clinical features suggestive of Emery-Dreifuss muscular dystrophy and the other with some features of Prader-Willi syndrome, besides proximal muscle weakness. Muscle biopsy from both cases revealed a clear abnormality of dystrophin, and were diagnosed as having Duchenne muscular dystrophy (DMD) by immunofluorescence examination; that is, absent dystrophin at the membrane of the muscle fibers. The clinical spectrum of DMD-related myopathies and the importance of dystrophin testing in childhood muscular dystrophies is discussed.

Biopsy↗
PubMed1991

A single amino acid substitution strongly modulates the activity and substrate specificity of the mouse mdr1 and mdr3 drug efflux pumps.

Specific protein domains and amino acids responsible for the apparent capacity of P-glycoprotein (mdr) to recognize and transport a large group of structurally unrelated drugs have not been identified. We have introduced a single Ser----Phe substitution within the predicted TM11 domain of mdr1 (position 941) and mdr3 (position 939) and analyzed the effect of these substitutions on the drug-resistance profiles of these two proteins. Mutations at this residue drastically altered the overall degree of drug resistance conveyed by mdr1 and mdr3. The modulating effect of this mutation on mdr1 and mdr3 varied for the drugs tested: it was very strong for colchicine and adriamycin and moderate for vinblastine. For mdr1, the Ser941----Phe941 substitution produced a unique mutant protein that retained the capacity to confer vinblastine resistance but lost the ability to confer adriamycin and colchicine resistance. These results strongly suggest that the predicted TM11 domain of proteins encoded by mdr and mdr-like genes plays an important role in the recognition and transport of their specific substrates.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

Na,K-ATPase isoform expression in sheep red blood cell precursors.

Isoform expression of mammalian red cell Na,K-ATPase was analyzed using messenger RNA isolated from red cell precursor-enriched bone marrow of anemic sheep. Expression of the catalytic alpha subunit was analyzed using rat isoform-specific cDNA probes and expression of the beta 1 subunit, using a sheep beta 1-specific cDNA probe. RNA isolated from sheep kidney and brain were analyzed concurrently. In the red cell, as in the kidney, messenger RNA encoding only one isoform (alpha 1) of the catalytic subunit is detected; neither of the other isoforms (alpha 2 or alpha 3) could be detected. This holds true for bone marrow of sheep of either the low potassium or high potassium phenotype. Relative to the expression of alpha 1, beta subunit-specific message (beta 1) was extremely low in the red cell compared to either kidney (less than 5%) or brain (less than 3%). Using a rat cDNA probe specific for a beta 1-like subunit, beta 2, message was detected in brain but not in either kidney or bone marrow.

Animals↗
PubMed1990

Structural and functional characterization of the mouse multidrug resistance gene family.

The mouse multidrug resistance (mdr) gene family is composed of three closely related genes mdr1, mdr2 and mdr3. To clarify the role of these three genes in the emergence of multidrug resistance and to initiate a structure-function analysis of the corresponding proteins, we have isolated full length cDNA clones corresponding to their respective cellular RNA transcripts. Sequence analyses indicate that the three encoded polypeptides are highly similar sharing the same predicted structural features and a high degree of sequence homology (85% to 92%). The three genes are contiguous on a 625 kb chromosomal segment and appear to result from two consecutive gene duplication events. Hybridization studies with gene specific probes in independently derived multidrug resistant cell lines and transfection experiments with full length cDNA clones indicate that mdr1 and mdr3 but not mdr2 overexpression can induce multidrug resistance. In transfected cells, multidrug resistance is linked to a decreased drug accumulation and an concomitant increased ATP-dependent drug efflux. Mutational analysis indicates that both predicted ATP binding domains in mdr1 are absolutely essential for biological activity. The study of chimeric proteins constructed between biologically active mdr1 and inactive mdr2 indicate that both ATP binding domains of mdr2 are functional and suggest that transmembrane domains of mdr1 are essential for the drug resistance phenotype conferred by this protein. Finally, although mdr1 and mdr3 can confer multidrug resistance, drug survival characteristics of mdr1 and mdr3 transfectants indicate that both proteins have overlapping but distinct substrate specificities.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Rhinosporidiosis in India: a case report and review of literature.

A 21-year-old male from Kerala, south India, who had been living in Chandigarh for the last 4 years presented with a nasal polyp in the left nasal cavity. On histopathological examination, it was found to be due to rhinosporidiosis. This disease is not uncommon in south India, but few case reports have been documented from north India. This paper presents a case report of rhinosporidiosis from the Government Medical College and Hospital, Chandigarh, and a review of literature of the disease.

Adult↗