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21.
Shili Xu Alexey N. Butkevich Roppei Yamada Yu Zhou Bikash Debnath Roger Duncan Ebrahim Zandi Nicos A. Petasis Nouri Neamati 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(40):16348-16353
Protein disulfide isomerase (PDI), an endoplasmic reticulum chaperone protein, catalyzes disulfide bond breakage, formation, and rearrangement. The effect of PDI inhibition on ovarian cancer progression is not yet clear, and there is a need for potent, selective, and safe small-molecule inhibitors of PDI. Here, we report a class of propynoic acid carbamoyl methyl amides (PACMAs) that are active against a panel of human ovarian cancer cell lines. Using fluorescent derivatives, 2D gel electrophoresis, and MS, we established that PACMA 31, one of the most active analogs, acts as an irreversible small-molecule inhibitor of PDI, forming a covalent bond with the active site cysteines of PDI. We also showed that PDI activity is essential for the survival and proliferation of human ovarian cancer cells. In vivo, PACMA 31 showed tumor targeting ability and significantly suppressed ovarian tumor growth without causing toxicity to normal tissues. These irreversible small-molecule PDI inhibitors represent an important approach for the development of targeted anticancer agents for ovarian cancer therapy, and they can also serve as useful probes for investigating the biology of PDI-implicated pathways. 相似文献
22.
Madhubala Devi S. Subadani Devi Kaushik Debnath Th. Mira Devi H. Nabachandra Singh 《Indian journal of hematology & blood transfusion》2007,23(3-4):109-111
An autopsy finding of sudden death due to disseminated intra-vascular sickling of RBCs in a young adult male from Madhya Pradesh while undergoing army recruitment rally, is reported because of its rarity in this part of the country. 相似文献
23.
Peptide and non-peptide HIV fusion inhibitors 总被引:10,自引:0,他引:10
24.
In addition to its importance in transfusion, Kell protein is a member of the M13 family of zinc endopeptidases and functions as an endothelin-3-converting enzyme. To obtain information on the structure of Kell protein we built a model based on the crystal structure of the ectodomain of neutral endopeptidase 24.11 (NEP). Similar to NEP, the Kell protein has 2 globular domains consisting mostly of alpha-helical segments. The domain situated closest to the membrane contains both the N- and C-terminal sequences and the enzyme-active site. The outer domain contains all of the amino acids whose substitutions lead to different Kell blood group phenotypes. In the model, the zinc peptidase inhibitor, phosphoramidon, was docked in the active site. Site-directed mutagenesis of amino acids in the active site was performed and the enzymatic activities of expressed mutant Kell proteins analyzed and compared with NEP. Our studies indicate that Kell and NEP use the same homologous amino acids in the coordination of zinc and in peptide hydrolysis. However, Kell uses different amino acids than NEP in substrate binding and appears to have more flexibility in the composition of amino acids allowed in the active site. 相似文献
25.
26.
Objectives: The Department of Health had recently introduced guidelines so that all suspected colorectal cancer patients could be seen by a specialist within two weeks of referral by their general practitioners. The usefulness and practicality of such a decision had been questioned. The aims of this study were to measure the compliance to the guidelines and evaluate the effectiveness of such referrals. Methods: All patients who were referred to the rapid access colorectal clinic between August 2000 and July 2001 were included. Settings: Darlington Memorial Hospital and Bishop Auckland General Hospital, both under South Durham Health Care Trust, were considered for the study. Measures: Date of referral, referring practitioner, time of appointment, reasons for referral, and diagnosis. Results: A total of 239 referrals were made; 96.2% of patients were given appointments within two weeks. Rectal bleed was the commonest (32%) cause for referral. Diverticular disease was the most frequent (29%) condition diagnosed. Altogether 97.4% of referrals were incomplete and 37.6% did not comply with the guidelines. Twenty one colorectal cancers (8.9%) were diagnosed. The early cancer detection rate was 4.6%. Conclusions: This audit showed that compliance to the guidelines was associated with a higher cancer detection rate. The majority of patients received appointments within two weeks. Contrary to some speculations, the number of referrals was not limitless. However a high number of referrals failed to adhere to the guidelines. The cancer (particularly early cancer) detection rate was disappointingly low. This does not reflect an efficient system of referral and potential benefits to patients remain questionable. 相似文献
27.
Debnath AK 《Current pharmaceutical design》2005,11(24):3091-3110
Despite the availability of several classes of drugs against acquired immunodeficiency syndrome (AIDS) caused by human immunodeficiency virus type 1(HIV-1), this deadly disease showing very little sign of containment, especially in Sub-Saharan Africa and South-East Asia. More than 20 million people died since the first diagnosis of AIDS more than twenty years ago and almost 40 million people are currently living with HIV/AIDS. Structure-based drug design effort was immensely successful in identifying several drugs that are currently available for the treatment of HIV-1. Many applications have been reported on the use of quantitative structure-activity relationship (QSAR) studies to understand the drug-receptor interactions and help in the design of more effective analogs. Extensive application was also reported on the application of 3D-QSAR techniques, such as, Comparative Molecular Field Analysis (CoMFA), Comparative Molecular Similarity Analysis (CoMSIA), pharmacophore generation using Catalyst/HypoGen, free-energy binding analysis, GRID/GOLPE, HINT-based techniques, etc. in anti-HIV-1 drug discovery programs in academia and industry. We have attempted to put together a comprehensive overview on the 3D-QSAR applications in anti-HIV-1 drug design reported in the literature during the last decade. 相似文献
28.
J Debnath Sree Ram S Balani I Chakraborty PD Gupta RK Bindal P Sengupta 《Medical Journal Armed Forces India》2005,61(3):249-252
Background
To evaluate the usefulness and limitations of graded compression ultrasonography in the diagnosis of clinically equivocal cases of suspected acute appendicitis at the setting of mid zonal military hospital of India.Methods
A prospective study, graded compression ultrasonography with self localization was carried out with 3.5 MHz convex, 5 MHz convex and 7.5 MHz linear transducers (Wipro GE) in 69 clinically equivocal suspected cases of acute appendicitis. With maximal compression the anteroposterior diameter of appendix was measured from outer to outer wall. The main criterion for diagnosing appendicitis was demonstration of a non compressible appendix with anteroposterior dimension of 7mm or more.Result
Sonologically 36 (52%) cases were diagnosed as appendicitis. Anteroposterior outer diameter of inflamed appendices ranged from 7mm to 21mm (mean 10.5mm). 30 (83%) of 36 patients could accurately self localize the point of maximum tenderness. There were 01 false positive and 04 false negative cases. Sensitivity and specificity were 89.7% and 96.6% respectively. Positive and negative predictive values were 97.2% and 87.8% respectively. Alternative diagnoses were offered in 33 (47.8%) cases. Amongst these 33 cases, 14(42.4%) had abdominal pain of unknown origin. Gynaecologic, urologic and gastrointestinal aetiologies were established in 10(30.3%), 07(21.2%) and 02(6%) cases respectively.Conclusion
Graded compression ultrasonography superadded with self localization is an accurate means of diagnosing/excluding appendicitis in clinically equivocal cases of acute appendicitis and it is of great value in establishing alternative diagnoses.Key Words: Ultrasonography, Acute appendicitis 相似文献29.
Matsuoka Y Shao L Debnath M Lafrancois J Becker A Gray A Aisen P Mathis C Klunk W Duff K 《Current Alzheimer research》2005,2(2):265-268
Amyloid beta (Abeta) has been considered as a primary cause of Alzheimer's disease (AD), and Abeta lowering approaches have been tested. Active immunization against Abeta is one of several promising Abeta-lowering approaches. Two mechanisms have been proposed: enhancement of microglial phagocytosis and Abeta sequestration (also called "peripheral sink"). We hypothesized that Abeta sequestration without immune modulation is sufficient to reduce the brain Abeta load and have demonstrated effective sequestration with Abeta binding agents that do not stimulate an immune reaction. Recent reports from other groups showed two other non-immune related Abeta binding agents, which have no structural relation to compounds we previously tested, reduced brain Abeta after peripheral administration. Congo red is a chemically synthesized small molecule that has binding affinity to Abeta. In the present study, we tested three Congo red derivatives in Abeta plaque-forming mice at an early pathological stage. Unfortunately, peripheral administration for three weeks did not substantially alter brain Abeta load. Optimized Abeta binding agents with high affinity to soluble Abeta are necessary for the sequestration approach. 相似文献
30.
Sarker CB Rahman S Siddiqui NI Huq MH Musa AK Talukder SI Alam KS Debnath CR Kabir AK Saleh FM 《Mymensingh medical journal : MMJ》2004,13(1):88-90
Thoracic actinomycosis represents about one-fourth of all cases of the disease. Isolated pleural effusion due to Actinomycosis is rare. We report a case of right sided pleural effusion with discharging sinus in the right anterior chest wall. Actinomycosis was suspected and confirmed by microscopic identification of "sulfur granules" in the discharge of the sinus tract and also identification of gram-positive filamentous bacteria in the specimen of discharging sinus. The patient improved clinically and radiologically after treatment with intravenous penicillin G followed by oral penicillin and aspiration of pleural fluid. 相似文献