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Rakesh K. Jain

Bio: Rakesh K. Jain is an academic researcher from Harvard University. The author has contributed to research in topics: Angiogenesis & Vascular endothelial growth factor. The author has an hindex of 200, co-authored 1467 publications receiving 177727 citations. Previous affiliations of Rakesh K. Jain include Government Medical College, Thiruvananthapuram & University of Oslo.


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TL;DR: Administration of trebananib plus F OLFIRI did not prolong PFS compared with placebo plus FOLFIRI, and Toxicities were manageable and consistent with those known for FolFIRI and trebanAnib.
Abstract: A randomised, double-blind, placebo-controlled phase 2 study of trebananib (AMG 386) in combination with FOLFIRI in patients with previously treated metastatic colorectal carcinoma

63 citations

Journal ArticleDOI
TL;DR: A new method for determining the relative importance of convection versus diffusion in macromolecular transport across tumor microvessel walls is developed.
Abstract: Objective: To develop a new method for determining the relative importance of convection versus diffusion in macromolecular transport across tumor microvessel walls.Methods: The human colon adenocarcinoma LS174T was transplanted in the dorsal skinfold chamber in a severe combined immunodeficient (SCID) mouse. The vasculature at the tumor surface was exposed by carefully removing the glass window of the chamber. A tumor microvessel was randomly selected, which was ∼20–40 μm in diameter, embedded in the connective tissue 10–12 μm below the surface of the tumor. The vessel was cannulated with a micropipette and perfused with fluorescein isothiocyanate (FITC)-labeled bovine serum albumin (BSA) at different perfusion pressures. The fluorescence intensity was recorded on videotapes via a video system attached to the fluorescence microscope for offline analysis. The apparent vascular permeability was determined based on the time-dependence of fluorescence intensity and the vessel diameter.Results: The apparent v...

63 citations

Journal ArticleDOI
TL;DR: In this article, a systematic procedure for synthesizing chemical complexes in which toxicology aspects are incorporated in addition to the economic considerations based on previous, work by Grossmann et al.
Abstract: A systematic procedure is presented for synthesizing chemical complexes in which toxicology aspects are incorporated in addition to the economic considerations Based on previous, work by Grossmann ...

63 citations

Journal ArticleDOI
TL;DR: It is found that tuning the drug release kinetics and binding affinities leads to improved delivery of the drug and suggests that smaller nanoparticles achieve better treatment outcome.
Abstract: Conventional drug delivery systems for solid tumors are composed of a nano-carrier that releases its therapeutic load. These two-stage nanoparticles utilize the enhanced permeability and retention (EPR) effect to enable preferential delivery to tumor tissue. However, the size-dependency of the EPR, the limited penetration of nanoparticles into the tumor as well as the rapid binding of the particles or the released cytotoxic agents to cancer cells and stromal components inhibit the uniform distribution of the drug and the efficacy of the treatment. Here, we employ mathematical modeling to study the effect of particle size, drug release rate and binding affinity on the distribution and efficacy of nanoparticles to derive optimal design rules. Furthermore, we introduce a new multi-stage delivery system. The system consists of a 20-nm primary nanoparticle, which releases 5-nm secondary particles, which in turn release the chemotherapeutic drug. We found that tuning the drug release kinetics and binding affinities leads to improved delivery of the drug. Our results also indicate that multi-stage nanoparticles are superior over two-stage nano-carriers provided they have a faster drug release rate and for high binding affinity drugs. Furthermore, our results suggest that smaller nanoparticles achieve better treatment outcome.

63 citations

Journal ArticleDOI
TL;DR: The solid-phase synthesis of a library of moenomycin disaccharide analogues and the identification of novel antibacterial agents from this library is described.
Abstract: The increase in bacterial resistance to conventional chemotherapy has resulted in a resurgent interest in the discovery and development of antibacterial agents.1-4 The search for novel antibiotics active against resistant phenotypes is increasingly focused on identification of novel chemotypes or antibiotics with novel mechanisms of action.5,6 The bacterial cell wall is an attractive target for developing novel antibacterial agents. The cell wall of both Gram-positive and Gram-negative bacteria is essential for cell viability. Of the many enzymes involved in bacterial cell wall biosynthesis, only transpeptidases responsible for cross-linking the growing glycan chain are targeted by existing clinically useful chemotherapeutic agents. As a strategy for developing novel antibacterial agents that would be effective against resistant phenotypes, we focused on the transglycosylase enzyme activity associated with the penicillin-binding proteins (PBPs). This activity functions to lengthen the peptidoglycan polymer and may also be required to initiate synthesis of a new chain. Our approach for developing novel inhibitors of transglycosylase focused on exploring moenomycin A (1) (Chart 1) as a lead. The moenomycins are a family of natural product antibiotics which are known to inhibit the synthesis of bacterial cell wall peptidoglycan through inhibition of transglycosylase.7-11 Moenomycin A is a pentasaccharide containing a long lipid attached to the reducing sugar (F) through a phosphoglycerate unit. By degradation studies and limited directed analogue synthesis, Welzel and co-workers showed that cell wall inhibitory activity was retained in a disaccharide core structure 2.12-22 In addition, they showed that certain structural elements were important for retaining transglycosylase inhibitory activity. The activity of moenomycin-derived disaccharides encouraged us to investigate the construction and screening of a library of disaccharides related to moenomycin A with the goal of identifying novel bacterial transglycosylase inhibitors. Access to a library of moenomycin disaccharides required that we develop a general solid-phase synthetic strategy that would allow us to explore carbohydrate diversity and chemical diversity at sites known to be linked to biological activity. Welzel had shown that the carbamate at C-3, the amide at C-2′, and the phosphoglycerate moiety at C-1 were important in overall biological activity.12-22 However, structural variations at these sites were never explored. The complexity of the moenomycin disaccharide system in combination with our desire to investigate multiple structural variations combinatorially posed a formidable synthetic challenge. Although solution syntheses of several moenomycin-type disaccharides had been reported by Welzel and others, these syntheses lacked the generality and efficiencynecessaryforconstructingcomplexlibraries.12-22 In this paper, we describe the solid-phase synthesis of a library of moenomycin disaccharide analogues and the identification of novel antibacterial agents from this library. Our basic synthetic approach envisioned constructing appropriately functionalized and protected disaccharide lactols that would allow us to explore modifications at C-1, C-3, and C-2′ and explore limited variation in the * Address for correspondence: Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, P.O. Box 5100, Wallingford, CT 06492-7660. E-mail: sofiam@bms.com. © Copyright 1999 by the American Chemical Society

62 citations


Cited by
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Journal ArticleDOI
04 Mar 2011-Cell
TL;DR: Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.

51,099 citations

28 Jul 2005
TL;DR: PfPMP1)与感染红细胞、树突状组胞以及胎盘的单个或多个受体作用,在黏附及免疫逃避中起关键的作�ly.
Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1(PfPMP1)与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用,在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员,通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

18,940 citations

Journal ArticleDOI
TL;DR: Attention is focussed on the ROS/RNS-linked pathogenesis of cancer, cardiovascular disease, atherosclerosis, hypertension, ischemia/reperfusion injury, diabetes mellitus, neurodegenerative diseases, rheumatoid arthritis, and ageing.

12,240 citations

Journal ArticleDOI
TL;DR: The addition of bevacizumab to fluorouracil-based combination chemotherapy results in statistically significant and clinically meaningful improvement in survival among patients with metastatic colorectal cancer.
Abstract: background Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has shown promising preclinical and clinical activity against metastatic colorectal cancer, particularly in combination with chemotherapy. methods Of 813 patients with previously untreated metastatic colorectal cancer, we randomly assigned 402 to receive irinotecan, bolus fluorouracil, and leucovorin (IFL) plus bevacizumab (5 mg per kilogram of body weight every two weeks) and 411 to receive IFL plus placebo. The primary end point was overall survival. Secondary end points were progression-free survival, the response rate, the duration of the response, safety, and the quality of life. results The median duration of survival was 20.3 months in the group given IFL plus bevacizumab, as compared with 15.6 months in the group given IFL plus placebo, corresponding to a hazard ratio for death of 0.66 (P<0.001). The median duration of progressionfree survival was 10.6 months in the group given IFL plus bevacizumab, as compared with 6.2 months in the group given IFL plus placebo (hazard ratio for disease progression, 0.54; P<0.001); the corresponding rates of response were 44.8 percent and 34.8 percent (P=0.004). The median duration of the response was 10.4 months in the group given IFL plus bevacizumab, as compared with 7.1 months in the group given IFL plus placebo (hazard ratio for progression, 0.62; P=0.001). Grade 3 hypertension was more common during treatment with IFL plus bevacizumab than with IFL plus placebo (11.0 percent vs. 2.3 percent) but was easily managed. conclusions The addition of bevacizumab to fluorouracil-based combination chemotherapy results in statistically significant and clinically meaningful improvement in survival among patients with metastatic colorectal cancer.

10,161 citations

01 Jun 2012
TL;DR: SPAdes as mentioned in this paper is a new assembler for both single-cell and standard (multicell) assembly, and demonstrate that it improves on the recently released E+V-SC assembler and on popular assemblers Velvet and SoapDeNovo (for multicell data).
Abstract: The lion's share of bacteria in various environments cannot be cloned in the laboratory and thus cannot be sequenced using existing technologies. A major goal of single-cell genomics is to complement gene-centric metagenomic data with whole-genome assemblies of uncultivated organisms. Assembly of single-cell data is challenging because of highly non-uniform read coverage as well as elevated levels of sequencing errors and chimeric reads. We describe SPAdes, a new assembler for both single-cell and standard (multicell) assembly, and demonstrate that it improves on the recently released E+V-SC assembler (specialized for single-cell data) and on popular assemblers Velvet and SoapDeNovo (for multicell data). SPAdes generates single-cell assemblies, providing information about genomes of uncultivatable bacteria that vastly exceeds what may be obtained via traditional metagenomics studies. SPAdes is available online ( http://bioinf.spbau.ru/spades ). It is distributed as open source software.

10,124 citations