Biomedical subjects
Publications and source records attributed to G Ramesh.
The use of high voltage radiotheraphy in pelvi malignancies has led to a common complication which is radiation . proctitis. Treatment with rectal formalin is simple and effective and can be done as a day care procedure. The use of formalin dab was assessed as a day care procedure in our surgical unit in which ten patients were prospectively evaluated. Outcome of these patients was encouraging.
Synthesis of mixed imine-amine pyrrolobenzodiazepine (PBD) dimers that are comprised of DC-81 and secondary amine (N10) of DC-81 subunits tethered to their C8 positions through alkanedioxy linkers (comprised of three and five carbons) is described. These noncross-linking unsymmetrical molecules exhibit significant DNA minor groove binding ability and one of them 5b linked through the pentanedioxy chain exhibits efficient DNA binding ability (DeltaTm=11.0 degrees C) when compared to naturally occurring DC-81, 1 (DeltaTm=0.7 degrees C). The imine-amine PBD dimers exhibit promising in vitro antitumor activity in a number of human cancer cell lines.
Two types of benzimidazoles have been synthesized and linked to DC-81 at C8-position through different alkyl chain spacers. These PBD conjugates have exhibited remarkable DNA-binding affinity, and a representative compound shows promising in vitro anticancer activity.
The synthesis of novel A-C8/C-C2-exo unsaturated alkoxyamido-linked pyrrolo[2,1-c][1,4]benzodiazepine dimers is reported and these dimers show significant DNA binding affinity and they also exhibit moderate anticancer activity.
Pyrrolobenzodiazepine hybrids linked to acridone/acridine ring systems at C8-position have been designed and prepared that exhibit significant DNA-binding affinity, and a representative compound shows promising in vitro anticancer activity.
Pyrene-linked pyrrolobenzodiazepine hybrids have been synthesized that exhibit potential anticancer activity in a number of human tumour cell lines. These hybrids also exhibit much enhanced DNA-binding ability in comparison to the parent pyrrolobenzodiazepine ring system (DC-81).
The appearance of virus-specific CD4(+) and/or CD8(+) T lymphocytes in peripheral blood of captive juvenile rhesus macaques (Macaca mulatta) was observed following rotavirus infection. These cell-mediated immune responses were measured following experimental or natural infection after rotavirus was isolated from stool specimens of asymptomatic animals. The virus isolated was a new strain of simian rotavirus that we named TUCH (for Tulane University and Cincinnati Children's Hospital). Restimulation of peripheral T lymphocytes by inactivated double- or triple-layered TUCH rotavirus particles containing either VP6 or VP4 and VP7 on their respective surfaces resulted in increased quantities of interleukin-6 (IL-6) and IL-12 in cell culture supernatants. Recall responses to rotavirus by CD4(+) and CD8(+) T lymphocytes were associated with accumulation of intracellular IL-6 and gamma interferon. Antigen presentation of TUCH rotavirus to lymphocytes was mediated via differentiated cultures of monocyte-derived dendritic (HLA-DR(+)) cells. This is the first report demonstrating cell-mediated immune responses to rotavirus in nonhuman primates. Further exploration of rhesus macaques in vaccine trials with human rotavirus vaccine candidates is the major objective of future studies.
The synthesis of new A-C8/C-C2 alkoxyamido-linked pyrrolo[2,1-c][1,4]-benzodiazepine dimers have been described in this report. These dimers exhibit significant DNA-binding ability with moderate anticancer activity.
Synthesis of C2 and C2-C8 linked pyrrolobenzodiazepine-naphthalimide hybrids have been prepared that exhibit significant DNA-binding affinity and cytotoxicity.
The facile synthesis of C-8 methanesulphonate substituted pyrrolobenzodiazepines is described. These have been prepared by linking the methanesulphonate at C-8 position with alkanol spacer and their in vitro cytotoxicity have been described.
Chrysene-linked pyrrolobenzodiazepine hybrids have been prepared that possess cytotoxicity in some cancer cell lines. They also exhibit promising DNA-binding affinity and this is supported by molecular modeling studies.
New sequence selective mixed imine-amide pyrrolobenzodiazepine (PBD) dimers have been developed that are comprised of DC-81 and dilactam of DC-81 subunits tethered to their C8 positions through alkanedioxy linkers (comprised of three to five and eight carbons). Thermal denaturation studies show that after 18 h of incubation with calf thymus DNA at a 5:1 DNA/ligand ratio, one of them (5c) increases the DeltaT(m) value by 17.0 degrees C. Therefore, these unsymmetrical molecules exhibit significant DNA minor groove binding affinity and 5c linked through the pentanedioxy chain exhibits efficient DNA binding ability that compares with the cross-linking DSB-120 PBD dimer (DeltaT(m) = 15.4 degrees C). Interestingly, this imine-amide PBD dimer has been linked with a five carbon chain linker unlike DSB-120, which has two DC-81 subunits with a three carbon chain linker, illustrating the effect of the noncross-linking aspect by introducing the noncovalent subunit. The binding affinity of the compounds has been measured by restriction endonuclease digestion assay based on inhibition of the restriction endonuclease BamHI. This study reveals the significance of noncovalent interactions in combination with covalent bonding aspects when two moieties of structural similarities are joined together. This allows the mixed imine-amide PBD dimer with a five carbon chain linker to achieve an isohelical fit within the DNA minor groove taking in to account both the covalent bonding and the noncovalent binding components. This has been supported by molecular modeling studies, which indicate that the PBD dimer with a five carbon chain linker gives rise to maximum stabilization of the complex with DNA at the minor groove as compared to the other PBD dimers with three, four, and eight carbon chain linkers. The energy of interaction in all of the complexes studied is correlated to the DeltaT(m) values. Furthermore, this dimer 5c has significant cytotoxicity in a number of human cancer cell lines.
The design and facile synthesis of C-8 alkylamino substituted pyrrolo[2,1-c][1,4]benzodiazepines is described. These have been prepared by linking the amines at C-8 position with propane spacer to improve solubility in water, and their in vitro cytotoxicity studies have been carried out.
The facile synthesis of C-8 linked pyrrolobenzodiazepine-naphthalimide hybrid analogues is described. The compounds are prepared with varying degrees of linker length in order to probe the structural requirements for optimal in vitro anti-tumour activity. Some of these new hybrid compounds showed higher cytotoxic activity than the existing natural and synthetic pyrrolo[2,1-c][1,4]benzodiazepines.
The molecular regulation of mammalian peri-implantation development is complex and difficult to study in vivo. We successfully cultured hamster blastocysts through hatching and peri-attachment stages, using a chemically defined medium, HECM-2h. Using this system, we showed that a species-specific, embryonic cysteine-like protease is involved in blastocyst hatching and that the process is modulated by growth factors. In particular, heparin binding-epidermal growth factor (HB-EGF) or leukemia inhibitory factor (LIF) enhance blastocyst hatching, and the former also improves attachment and trophoblast outgrowth. We observed interesting changing patterns of expression of mRNA and/or immunoreactive protein for EGF, HB-EGF, LIF and transforming growth factor-beta (TGF-beta) in the embryo and/or endometrial tissue, during peri-implantation development. Together, it appears that hamster blastocyst hatching, attachment and trophoblast outgrowth are regulated by autocrine and/or paracrine growth factors, produced by the embryo-endometrial tissues.
Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are naturally occurring compounds isolated from various Streptomyces species. The PBDs exert their biological activity through covalent binding and exhibit cytotoxicity. Extensive studies have been carried out on the synthetic strategies of PBDs, and a sound understanding of structure activity relationships within this class of compounds has been developed. The PBDs have shown to interfere with the interaction of endonuclease enzymes of DNA and block the transcription by inhibiting RNA polymerase in a sequence specific manner. These processes have been thought to account for the biological activity of PBDs. The PBDs have also been used as a scaffold to attach different type of moieties leading to novel sequence selective DNA cleaving and cross-linking agents. The design and synthesis of C8-linked PBD dimers and other hybrids of PBDs has given a new insight towards the development of molecules with enhanced DNA binding affinity and sequence specificity compared to the naturally occurring PBDs. This improvement in the biological profile has been explained on the basis of certain factors like DNA cross-linking and doubling of DNA binding sites. There seems to be enough potential for further changing the substitution pattern and to design structurally modified PBDs by retaining the PBD core intact. In this review both the synthetic strategies and the structure-activity relationships, particularly the DNA binding and cytotoxicity studies of PBDs have been discussed.
A young boy presented with history of abdominal trauma. History and initial clinical findings suggested a soft tissue injury. Due to increasing abdominal pain and fever, we proceeded with an exploratory laparotomy with a diagnosis of intra-abdominal injury, at which we found a perforated appendix. Appendicitis following blunt abdominal trauma needs high index of suspicion.
This study was designed to assess the production of nitric oxide (NO) by neutrophils in bronchial asthma. Thirty asthmatic patients (ten each of mild, moderate and severe asthma) and ten healthy controls were included in the study. Neutrophils from peripheral venous blood were stimulated with latex, and production of nitrite (an NO metabolise) and L-citrulline (a co-product of NO) was studied. It was postulated that peripheral blood neutrophils, being in a primed or activated state in asthma, would reflect the changes occurring in bronchial tree neutrophils. Nitrite and L-citrulline production by neutrophils was significantly higher in asthmatics (p < 0.001) and increased with disease severity. A strong negative correlation was observed between peak expiratory flow and both nitrite (r = -0.87, p < 0.001) and L-citrulline (r = -0.88, p < 0.001) production. It is concluded that nitric oxide production by neutrophils is increased in bronchial asthma and can possibly contribute to airway narrowing and disease severity.