Development of Analytical Methods and Their Validation for Bioactive Molecules and APIs

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Telomerase a prognostic marker an therapeutic target

Malignant glioma is the most common and aggressive form of tumours and is usually refractory to therapy. Telomerase and its altered activity, distinguishing cancer cells, is an attractive molecular target in glioma therapeutics. The aim of this thesis was to silence telomerase at the genetic level with a view to highlight the changes caused in the cancer proteome and identify the potential downstream pathways controlled by telomerase in tumour progression and maintenance. A comprehensive proteomic study utilizing 2D-DIGE and MALDI-TOF were used to assess the effect of inhibiting two different regulatory mechanisms of telomerase in glioma. RNAi was used to target hTERT and Hsp90α. Inhibition of telomerase activity resulted in down regulation of various cytoskeletal proteins with correlative evidence of the involvement of telomerase in regulating the expression of vimentin. Vimentin plays an important role in tumour metastasis and is used as an indicator of glioma metastasis. Inhibition of telomerase via sihTERT results in the down regulation of vimentin expression in glioma cell lines in a grade specific manner. While, 9 of 12 glioblastoma tissues (grade IV) showed vimentin to be highly expressed, its expression was absent in lower grades and normal tissues. This suggests that vimentin can be potentially used as a glioma progressive marker. This is the first study to report the potential involvement of telomerase in the regulation of vimentin expression. This study also identified that combination therapy, comprising siRNA targeted towards telomerase regulatory mechanisms and the natural product Epigallocatechin-3-gallate (ECGC), results in decreased cell viability producing comparable results to that of other chemotherapeutic drugs

Study of Seismic Base Isolation of Bridge Considering Soil Structure Interaction

In this paper, a comprehensive study of seismic response of base isolated bridge is made by varying different parameters such as soil stiffness, embedment depth, hydrodynamic pressure and earthquake response spectrum. The object is to determine effect of soil-structure interaction on seismic response when isolation by elastomeric bearing is provided between superstructure and substructure. Elastomeric bearing is seen to be effective in reducing seismic response of substructure on rocky site. The increase in embedment depth also causes reduction in bending moments and shear forces in the substructure. The use of elastomeric bearing in place of Rocker-Roller bearing is seen to be beneficial from seismic considerations

On the origin of the artesian groundwater and escaping gas at Narveri after the 2001 Bhuj earthquake

At Narveri, north of Khavada in the Great Rann of Kachchh, an outflow of groundwater continued even more than four months after the Bhuj earthquake of 26 January 2001, although at a considerably reduced rate compared to that immediately following the earthquake. Air or gas bubbling through the freshly oozing water has also been observed. We had collected a large number of samples from different parts of Gujarat, where post-earthquake groundwater outpourings were reported. Narveri, however, was the only site where the samples showed dissolved helium concentrations, significantly above the air equilibration value. Based on measurements of helium, radon, chloride, sulphate and sodium concentrations and temperature, we suggest that the flowing water and escaping gases at Narveri have a deep confined source with a reservoir age in excess of ~ 104 years

Objective Assessment of Physiologic Alterations Associated with Hemodynamically Significant Patent Ductus Arteriosus in Extremely Premature Neonates

Delay in closure of ductus arteriosus in postnatal life may lead to serious consequences and complications in an extremely premature neonate secondary to hemodynamic alterations in regional blood flow pattern in various organs. Despite the widespread recognition amongst neonatologists to identify a hemodynamically significant patent ductus arteriosus (hsPDA) early in the postnatal course, there is lack of consensus in its definition and thus the threshold to initiate treatment. Echocardiographic assessment of PDA shunt size and volume combined with neonatologists\u27 impression of clinical significance is most frequently used to determine the need for treatment of PDA. Common clinical signs of hsPDA utilized as surrogate for decreased tissue perfusion may lag behind early echocardiographic signs. Although echocardiogram allows direct assessment of PDA shunt and hemodynamic alterations in the heart, it is limited by dependence on pediatric cardiologist availability, interobserver variation and isolated time point assessment. Electrical cardiometry (EC) is a non-invasive continuous real time measurement of cardiac output by applying changes in thoracic electrical impedance. EC has been validated in preterm newborns by concomitant transthoracic echocardiogram assessments and may be beneficial in studying changes in cardiac output in premature newborns with hsPDA. Alterations in perfusion index derived from continuous pulse oximetry monitoring has been used to study changes in cardiac performance and tissue perfusion in infants with PDA. Near infrared spectroscopy (NIRS) has been used to objectively and continuously assess variations in renal, mesenteric, and cerebral oxygen saturation and thus perfusion changes due to diastolic vascular steal from hsPDA in preterm neonates. Doppler ultrasound studies measuring resistive indices in cerebral circulation indicate disturbance in cerebral perfusion secondary to ductal steal. With recent trends of change in practice toward less intervention in care of preterm newborn, treatment strategy needs to be targeted for select preterm population most vulnerable to adverse hemodynamic effects of PDA. Integration of these novel ways of hemodynamic and tissue perfusion assessment in routine clinical care may help mitigate the challenges in defining and targeting treatment of hsPDA thereby improving outcomes in extremely premature neonates

Medical research and ethics - Revisited

Ethics in the medical research is known since many years; however, there have been new developments in this area recently. A phenomenal improvement in the health-care system, leading to increased life expectancy, and thereby, newer lifestyle and other health-related diseases has opened avenues for newer drugs and health-care technology. However, these have to be tried and tested in the context of the disease epidemiology, health-care delivery and of course, medical ethics. Monitoring and evaluation of the treatment regimes of well documented effective medicines is also required. This is the core of medical research. With the ever increasing concept of evidence-based medical system, and thereby, a rapid rise in the number of clinical trials; the role of medical ethics is potentially increasing to keep the patient