QSAR based therapeutic management of <Emphasis Type="Italic">M. tuberculosis</Emphasis>

Mycobacterium tuberculosis is responsible for severe mortality and morbidity worldwide but, under-developed and developing countries are more prone to infection. In search of effective and wide-spectrum anti-tubercular agents, interdisciplinary approaches are being explored. Of the several approaches used, computer based quantitative structure activity relationship (QSAR) have gained momentum. Structure-based drug design and discovery implies a combined knowledge of accurate prediction of ligand poses with the good prediction and interpretation of statistically validated models derived from the 3D-QSAR approach. The validated models are generally used to screen a small combinatorial library of potential synthetic candidates to identify hits which further subjected to docking to filter out compounds as novel potential emerging drug molecules to address multidrug-resistant tuberculosis. Several newer models are integrated to QSAR methods which include different types of chemical and biological data, and simultaneous prediction of pharmacological activities including toxicities and/or other safety profiles to get new compounds with desired activity. In the process, several newer molecules have been identified which are now being assessed for their clinical efficacy. Present review deals with the advances made in the field highlighting overall future prospects of the development of anti-tuberculosis drugs.     

Magnetic resonance spectroscopy and perfusion weighted imaging as predictors for tumor response to gamma knife radiosurgery: A single center experience

Objective

To test the hypothesis that hemodynamic and metabolic characteristics of intracranial neoplasms detected with magnetic resonance spectroscopy and perfusion weighted imaging are efficient predictors of tumor response to radiosurgery.

Methods

Fifty-four patients with 59 intracranial neoplasms, who underwent evaluation with echoplanar PW and MRS imaging prior to gamma knife radiosurgery were selected for this retrospective analysis. The mean irradiation dose was 13.76 Gy. The mean follow up after GNR constituted 24 months. Predictive diagnostic accuracy was calculated with standard formulas. The association of tumor response to radiosurgery with pretherapeutic MRI parameters was estimated using the Mann–Whitney U test.

Results

Significant association was found between the perfusion and hemodynamic parameters of intracranial neoplasms and the outcome of GKR. Diagnostic accuracy of multimodel MRI was 89% among low grade and 65% among high grade neoplasms. The overall accuracy was 81%. Normalized rCBV, choline, NAA and lipid contents and Chol/cr and NAA/cr were statistically different between low and high grade neoplasms (p < 0.001).

Conclusion

MR perfusion and spectroscopic results provided information that were predictive of the outcome of radiosurgery in this patient pool, increased the diagnostic accuracy of conventional MRI in defining tumor type and grade and may play an important role in pre-therapeutic planning for radiosurgery.     

XPS analysis of poly[(3-hydroxybutyric acid)-co-(3-hydroxyvaleric acid)] film surfaces exposed to an allylamine low-pressure plasma

Homogeneous and stable layers were deposited through allylamine plasma polymerization (75 W, 100 Pa, 15 min) onto poly[(3-hydroxybutyric acid)-co-(3-hydroxyvaleric acid)] (91 : 9 wt.-%) (P(HB-co-9%HV)) film surfaces, XPS analysis using take-off angles of 20° and 70° and performed 10 days and 20 days after plasma treatment gives information on the composition (in atom%) of the modified surface: C, 62.74; N, 19.60; O, 17.65. The unexpected oxygen percentage is weaker if argon plasma pretreatment (25 W, 40 Pa, 5 min) is applied. Then, a succinct mechanism is proposed. The study of changes in element ratios and binding energy values shows that the majority of incorporated functional groups seem to be amide and imine groups.     

Interaction of CD154 with different receptors and its role in bidirectional signals

In addition to its classical receptor, CD40, it is now well established that CD154 also binds αIIbβ3, α5β1, and αMβ2 integrins. Although these integrins are all members of the same family, they bind CD154 differently. The current investigation aims to analyze the interaction of CD154 with α5β1 and αMβ2 and investigate its role in bidirectional signals in various human cell lines. Results obtained herein indicate that the CD154 residues involved in the interaction with α5β1 are N151 and Q166, whereas those involved in αMβ2 binding are common to residues required for CD40, namely Y145 and R203. Soluble CD40/CD154 or αMβ2/CD154 complexes do not interfere with the binding of CD154 to α5β1‐positive cells, but inhibit the binding of CD154 to CD40‐ or αMβ2‐positive cells, respectively. Ligation of CD154 on CD154‐positive cells with soluble CD40, αIIbβ3, α5β1, or αMβ2 stimulates intracellular signaling, including MAPK phosphorylation. Given that CD154 exists as a trimer, our data strongly suggest that CD154 may bind concomitantly to two receptors of the same or different family, and biologically activate cells expressing both receptors. The characterization of CD154/receptor interactions helps the identification of new therapeutic targets for the prevention and/or treatment of CD154‐associated autoimmune and inflammatory diseases.     

Neoplastic lesions in CADASIL syndrome: report of an autopsied Japanese case

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is one of the most common heritable causes of stroke and dementia in adults. The gene involved in the pathogenesis of CADASIL is Notch3; in which mutations affect the number of cysteine residues in its extracellular domain, causing its accumulation in small arteries and arterioles of the affected individuals. Besides the usual neurological and vascular findings that have been well-documented in CADASIL patients, this paper additionally reports multiple neoplastic lesions that were observed in an autopsy case of CADASIL patient; that could be related to Notch3 mutation. The patient was a 62 years old male, presented with a past history of neurological manifestations, including gait disturbance and frequent convulsive attacks. He was diagnosed as CADASIL syndrome with Notch3 Arg133Cys mutation. He eventually developed hemiplegia and died of systemic convulsions. Autopsy examination revealed-besides the vascular and neurological lesions characteristic of CADASIL- multiple neoplastic lesions in the body; carcinoid tumorlet and diffuse idiopathic pulmonary neuro-endocrine cell hyperplasia (DIPNECH) in the lungs, renal cell carcinoma (RCC), prostatic adenocarcinoma (ADC) and adenomatoid tumor of the epididymis. This report describes a spectrum of neoplastic lesions that were found in a case of CADASIL patient that could be related to Notch3 gene mutations.