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.

An orthotopic mouse model of hepatocellular carcinoma with underlying liver cirrhosis

Abstract: Subcutaneous xenografts have been used for decades to study hepatocellular carcinoma (HCC). These models do not reproduce the specific pathophysiological features of HCCs, which occur in cirrhotic livers that show pronounced necroinflammation, abnormal angiogenesis and extensive fibrosis. As these features are crucial for studying the role of the pathologic host microenvironment in tumor initiation, progression and treatment response, alternative HCC models are desirable. Here we describe a syngeneic orthotopic HCC model in immunocompetent mice with liver cirrhosis induced by carbon tetrachloride (CCl4) that recapitulates key features of human HCC. Induction of substantial hepatic fibrosis requires 12 weeks of CCl4 administration. Intrahepatic implantation of mouse HCC cell lines requires 30 min per mouse. Tumor growth varies by tumor cell line and mouse strain used. Alternatively, tumors can be induced in a genetically engineered mouse model. In this setting, CCl4 is administered for 12 weeks after tail-vein injection of Cre-expressing adenovirus (adeno-Cre) in Stk4(-/-)Stk3(F/-) (also known as Mst1(-/-)Mst2(F/-); F indicates a floxed allele) mice, and it results in the development of HCC tumors (hepatocarcinogenesis) concomitantly with liver cirrhosis.

PDGF-D Improves Drug Delivery and Efficacy via Vascular Normalization, But Promotes Lymphatic Metastasis by Activating CXCR4 in Breast Cancer

Abstract: Purpose: Unlike platelet-derived growth factor-B (PDGF-B), the role of PDGF-D in tumor progression or treatment is largely unknown. To this end, we determined the role of PDGF-D in breast cancer progression, metastasis, and response to chemotherapy. Experimental Design: We first examined PDGF-D expression in human breast carcinomas by immunohistochemical (IHC) staining. To mimic high PDGF-D expressing tumors, we stably transfected the breast cancer cell lines MDA-MB-231 and 4T1 with pdgf-d cDNA, and implanted these tumor cells orthtopically into nude mice. We monitored tumor growth by caliper measurement and bioluminescence imaging. We also used short hairpin RNA interference (shRNAi) and imatinib to block PDGF-D/PDGFRβ signaling. Finally, we studied the effect of PDGF-D on doxorubicin delivery and efficacy. Results: Human breast cancers express high levels of PDGF-D. Overexpression of PDGF-D promoted tumor growth and lymph node metastasis through increased proliferation, decreased apoptosis, and induction of CXCR4 expression. Blockade of CXCR4 signaling abolished PDGF-D–induced lymph node metastasis. Furthermore, overexpression of PDGF-D increased perivascular cell coverage and normalized tumor blood vessels. As a result, PDGF-D overexpression facilitated tissue penetration of doxorubicin and enhanced its treatment efficacy. Conclusions: PDGF-D is highly expressed in human breast cancer and facilitates tumor growth and lymph node metastasis, making it a potential target in breast cancer. At the same time, PDGF-D increases drug delivery and hence improves the efficacy of chemotherapy through vessel normalization. Therefore, judicious use of PDGF-D/PDGFRβ blockers would be necessary to minimize the adverse effects on concomitantly administered cytotoxic therapies. Clin Cancer Res; 17(11); 3638–48. ©2011 AACR .

Fluorescence ratio imaging of interstitial pH in solid tumours: effect of glucose on spatial and temporal gradients.

Abstract: Tumour pH plays a significant role in cancer treatment. However, because of the limitations of the current measurement techniques, spatially and temporally resolved pH data, obtained non-invasively in solid tumours, are not available. Fluorescence ratio imaging microscopy (FRIM) has been used previously for noninvasive, dynamic evaluation of pH in neoplastic tissue in vivo (Martin GR, Jain RK 1994, Cancer Res., 54, 5670-5674). However, owing to problems associated with quantitative fluorescence in thick biological tissues, these studies were limited to thin (50 microns) tumours. We, therefore, adapted the FRIM technique for pH determination in thick (approximately 2 mm) solid tumours in vivo using a pinhole illumination-optical sectioning (PIOS) method. Results show that (1) steep interstitial pH gradients (5 microns resolution), with different spatial patterns, exist between tumour blood vessels; (2) pH decreased by an average of 0.10 pH units over a distance of 40 microns away from the blood vessel wall, and by 0.33 pH units over a 70 microns distance; (3) the maximum pH drop, defined as the pH difference between the intervessel midpoint and the vessel wall, was positively correlated with the intervessel distance; (4) 45 min following a systemic glucose injection (6 g kg-1 i.v), interstitial pH gradients were shifted to lower pH values by an average of 0.15 pH units, while the spatial gradient (slope) was maintained, when compared with preglucose values. This pH decrease was not accompanied by significant changes in local blood flow. pH gradients returned to near-baseline values 90 min after glucose injection; (5) interstitial tumour pH before hyperglycaemia and the glucose-induced pH drop strongly depended on the local vessel density; and (6) sodium bicarbonate treatment, either acute (1 M, 0.119 ml h-1 for 3 h i.v.) or chronic (1% in drinking water for 8 days), did not significantly change interstitial tumour pH. Modified FRIM may be combined with other optical methods (e.g. phosphorescence quenching) to evaluate non-invasively the spatial and temporal characteristics of extracellular pH, intracellular pH and pO2 in solid tumours. This will offer unique information about tumour metabolism and its modification by treatment modalities used in different cancer therapies.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

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。

Bevacizumab plus irinotecan, fluorouracil, and leucovorin for 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.

SPAdes, a new genome assembly algorithm and its applications to single-cell sequencing ( 7th Annual SFAF Meeting, 2012)

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.