Showing papers by "Rakesh K. Jain published in 2009"
TL;DR: This work introduces optical frequency domain imaging (OFDI) as an intravital microscopy that circumvents the technical limitations of multiphoton microscopy and provides unprecedented access to previously unexplored, crucial aspects of tissue biology.
Abstract: Intravital multiphoton microscopy has provided powerful mechanistic insights into health and disease and has become a common instrument in the modern biological laboratory. The requisite high numerical aperture and exogenous contrast agents that enable multiphoton microscopy, however, limit the ability to investigate substantial tissue volumes or to probe dynamic changes repeatedly over prolonged periods. Here we introduce optical frequency domain imaging (OFDI) as an intravital microscopy that circumvents the technical limitations of multiphoton microscopy and, as a result, provides unprecedented access to previously unexplored, crucial aspects of tissue biology. Using unique OFDI-based approaches and entirely intrinsic mechanisms of contrast, we present rapid and repeated measurements of tumor angiogenesis, lymphangiogenesis, tissue viability and both vascular and cellular responses to therapy, thereby demonstrating the potential of OFDI to facilitate the exploration of physiological and pathological processes and the evaluation of treatment strategies.
716 citations
TL;DR: The current challenges in establishing biomarkers of antiangiogenic therapy are discussed, a number of potential systemic, circulating, tissue and imaging biomarkers have emerged from recently completed phase I–III studies, and all of them need to be validated prospectively.
Abstract: No validated biomarkers currently exist for appropriately selecting cancer patients for antiangiogenic therapy. A number of potential systemic, circulating, tissue and imaging biomarkers have emerged as suitable candidate biomarkers, but all require prospective validation. The authors discuss the current challenges in establishing biomarkers, the advantages and disadvantages of systemic, circulating, tissue and imaging biomarkers, and the future opportunities for validating biomarkers of antiangiogenic therapy. No validated biological markers (or biomarkers) currently exist for appropriately selecting patients with cancer for antiangiogenic therapy. Nor are there biomarkers identifying escape pathways that should be targeted after tumors develop resistance to a given antiangiogenic agent. A number of potential systemic, circulating, tissue and imaging biomarkers have emerged from recently completed phase I–III studies. Some of these are measured at baseline (for example VEGF polymorphisms), others are measured during treatment (such as hypertension, MRI-measured Ktrans, circulating angiogenic molecules or collagen IV), and all are mechanistically based. Some of these biomarkers might be pharmacodynamic (for example, increase in circulating VEGF, placental growth factor) while others have potential for predicting clinical benefit or identifying the escape pathways (for example, stromal-cell-derived factor 1α, interleukin-6). Most biomarkers are disease and/or agent specific and all of them need to be validated prospectively. We discuss the current challenges in establishing biomarkers of antiangiogenic therapy, define systemic, circulating, tissue and imaging biomarkers and their advantages and disadvantages, and comment on the future opportunities for validating biomarkers of antiangiogenic therapy.
546 citations
TL;DR: Bvacizumab with chemoradiotherapy appears safe and active and yields promising survival results in locally advanced rectal cancer.
Abstract: Purpose To assess the safety and efficacy of neoadjuvant bevacizumab with standard chemoradiotherapy in locally advanced rectal cancer and explore biomarkers for response. Patients and Methods In a phase I/II study, 32 patients received four cycles of therapy consisting of: bevacizumab infusion (5 or 10 mg/kg) on day 1 of each cycle; fluorouracil infusion (225 mg/m2/24 hours) during cycles 2 to 4; external-beam irradiation (50.4 Gy in 28 fractions over 5.5 weeks); and surgery 7 to 10 weeks after completion of all therapies. We measured molecular, cellular, and physiologic biomarkers before treatment, during bevacizumab monotherapy, and during and after combination therapy. Results Tumors regressed from a mass with mean size of 5 cm (range, 3 to 12 cm) to an ulcer/scar with mean size of 2.4 cm (range, 0.7 to 6.0 cm) in all 32 patients. Histologic examination revealed either no cancer or varying numbers of scattered cancer cells in a bed of fibrosis at the primary site. This treatment resulted in an actuari...
494 citations
TL;DR: Sunitinib shows evidence of modest antitumor activity in advanced HCC with manageable adverse effects and Rapid changes in tumor vascular permeability and circulating inflammatory biomarkers are potential determinants of response and resistance to sunitinIB in HCC.
Abstract: Purpose To assess the safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma (HCC) and explore biomarkers for sunitinib response. Patients and Methods We conducted a multidisciplinary phase II study of sunitinib, an antivascular endothelial growth factor receptor tyrosine kinase inhibitor, in advanced HCC. Patients received sunitinib 37.5 mg/d for 4 weeks followed by 2 weeks of rest per cycle. The primary end point was progression-free survival (PFS). We used functional magnetic resonance imaging to evaluate vascular changes in HCC after sunitinib treatment. Circulating molecular and cellular biomarkers were evaluated before and at six time points after sunitinib treatment. Results Thirty-four patients were enrolled. The objective response rate was 2.9%, and 50% of patients had stable disease. Median PFS was 3.9 months (95% CI, 2.6 to 6.9 months), and overall survival was 9.8 months (95% CI, 7.4 months to not available). Grade 3 or 4 toxicities included leukopenia/neutropenia,...
463 citations
TL;DR: A strong correlation between the peri-spheroid solid stress distribution and spheroid shape is found, a result of the suppression of cell proliferation and induction of apoptotic cell death in regions of high mechanical stress, suggesting how tumors grow in confined locations where the level of solid stress becomes high.
Abstract: Background
Compressive mechanical stress produced during growth in a confining matrix limits the size of tumor spheroids, but little is known about the dynamics of stress accumulation, how the stress affects cancer cell phenotype, or the molecular pathways involved.
Methodology/Principal Findings
We co-embedded single cancer cells with fluorescent micro-beads in agarose gels and, using confocal microscopy, recorded the 3D distribution of micro-beads surrounding growing spheroids. The change in micro-bead density was then converted to strain in the gel, from which we estimated the spatial distribution of compressive stress around the spheroids. We found a strong correlation between the peri-spheroid solid stress distribution and spheroid shape, a result of the suppression of cell proliferation and induction of apoptotic cell death in regions of high mechanical stress. By compressing spheroids consisting of cancer cells overexpressing anti-apoptotic genes, we demonstrate that mechanical stress-induced apoptosis occurs via the mitochondrial pathway.
Conclusions/Significance
Our results provide detailed, quantitative insight into the role of micro-environmental mechanical stress in tumor spheroid growth dynamics, and suggest how tumors grow in confined locations where the level of solid stress becomes high. An important implication is that apoptosis via the mitochondrial pathway, induced by compressive stress, may be involved in tumor dormancy, in which tumor growth is held in check by a balance of apoptosis and proliferation.
402 citations
TL;DR: VEGF blockade with bevacizumab improved hearing in some, but not all, patients with neurofibromatosis type 2 and was associated with a reduction in the volume of most growing vestibular schwannomas.
Abstract: Background Profound hearing loss is a serious complication of neurofibromatosis type 2, a genetic condition associated with bilateral vestibular schwannomas, benign tumors that arise from the eighth cranial nerve. There is no medical treatment for such tumors. Methods We determined the expression pattern of vascular endothelial growth factor (VEGF) and three of its receptors, VEGFR-2, neuropilin-1, and neuropilin-2, in paraffin-embedded samples from 21 vestibular schwannomas associated with neurofibromatosis type 2 and from 22 sporadic schwannomas. Ten consecutive patients with neurofibromatosis type 2 and progressive vestibular schwannomas who were not candidates for standard treatment were treated with bevacizumab, an anti-VEGF monoclonal antibody. An imaging response was defined as a decrease of at least 20% in tumor volume, as compared with baseline. A hearing response was defined as a significant increase in the word-recognition score, as compared with baseline. Results VEGF was expressed in 100% of ...
401 citations
TL;DR: It is shown that evaluation of biomarkers as early as after one day of anti-VEGF therapy with cediranib is predictive of response in patients with recurrent glioblastoma, and the vascular normalization index described here should be validated in randomized clinical trials.
Abstract: Early imaging or blood biomarkers of tumor response are desperately needed to customize antiangiogenic therapy for cancer patients. Anti-vascular endothelial growth factor (VEGF) therapy can "normalize" brain tumor vasculature by decreasing vessel diameter and permeability, and thinning the abnormally thick basement membrane. We hypothesized that the extent of vascular normalization will be predictive of outcome of anti-VEGF therapy in glioblastoma. We used advanced magnetic resonance imaging methods to monitor vascular parameters and treatment response in 31 recurrent glioblastoma patients enrolled in a phase II trial of cediranib, an oral pan-VEGF receptor tyrosine kinase inhibitor. We evaluated the correlation between clinical outcome and magnetic resonance imaging-measured changes in vascular permeability/flow (i.e., K(trans)) and in microvessel volume, and the change of circulating collagen IV levels, all after a single dose of cediranib. Here, we show that evaluation of biomarkers as early as after one day of anti-VEGF therapy with cediranib is predictive of response in patients with recurrent glioblastoma. Changes in K(trans), microvessel volume, and circulating collagen IV correlated with duration of overall survival and/or progression-free survival (P < 0.05). When we combined these three parameters into a "vascular normalization index," we found that it closely associated with overall survival (rho = 0.54; P = 0.004) and progression-free survival (rho = 0.6; P = 0.001). The vascular normalization index described here should be validated in randomized clinical trials.
361 citations
TL;DR: By controlling edema, cediranib significantly increased survival of mice in the face of persistent tumor growth, suggesting anti-VEGF agents may be able to improve survival of patients with glioblastoma, even without inhibiting tumor growth.
Abstract: Purpose Recent clinical trials of antivascular endothelial growth factor (VEGF) agents for glioblastoma showed promising progression-free and overall survival rates. However, available clinical imaging does not separate antitumor effects from antipermeability effects of these agents. Thus although anti-VEGF agents may decrease tumor contrast-enhancement, vascularity, and edema, the mechanisms leading to improved survival in patients remain incompletely understood. Our goal was to determine whether alleviation of edema by anti-VEGF agents alone could increase survival in mice. Methods We treated mice bearing three different orthotopic models of glioblastoma with a VEGF-targeted kinase inhibitor, cediranib. Using intravital microscopy, molecular techniques, and magnetic resonance imaging (MRI), we measured survival, tumor growth, edema, vascular morphology and function, cancer cell apoptosis and proliferation, and circulating angiogenic biomarkers. Results We show by intravital microscopy that cediranib sig...
304 citations
01 Dec 2009
TL;DR: It is suggested that the GI syndrome is caused by the death of GI epithelium cells and that these epithelial cells die by a mechanism that is regulated by p53 but independent of apoptosis.
Abstract: Acute exposure to ionizing radiation can cause lethal damage to the gastrointestinal (GI) tract, a condition called the GI syndrome. Whether the target cells affected by radiation to cause the GI syndrome are derived from the epithelium or endothelium and whether the target cells die by apoptosis or other mechanisms are controversial issues. Studying mouse models, we found that selective deletion of the proapoptotic genes Bak1 and Bax from the GI epithelium or from endothelial cells did not protect mice from developing the GI syndrome after sub-total-body gamma irradiation. In contrast, selective deletion of p53 from the GI epithelium, but not from endothelial cells, sensitized irradiated mice to the GI syndrome. Transgenic mice overexpressing p53 in all tissues were protected from the GI syndrome after irradiation. These results suggest that the GI syndrome is caused by the death of GI epithelial cells and that these epithelial cells die by a mechanism that is regulated by p53 but independent of apoptosis.
192 citations
TL;DR: Anti-VEGF agents are able to decrease vascular permeability and, thus, cerebral edema, by restoring the abnormal tumor vasculature to a more normal state, which minimizes the adverse effects of corticosteroids and could improve clinical outcomes.
Abstract: Most brain tumors oversecrete vascular endothelial growth factor (VEGF), which leads to an abnormally permeable tumor vasculature. This hyperpermeability allows fluid to leak from the intravascular space into the brain parenchyma, which causes vasogenic cerebral edema and increased interstitial fluid pressure. Increased interstitial fluid pressure has an important role in treatment resistance by contributing to tumor hypoxia and preventing adequate tumor penetration of chemotherapy agents. In addition, edema and the corticosteroids needed to control cerebral edema cause significant morbidity and mortality. Agents that block the VEGF pathway are able to decrease vascular permeability and, thus, cerebral edema, by restoring the abnormal tumor vasculature to a more normal state. Decreasing cerebral edema minimizes the adverse effects of corticosteroids and could improve clinical outcomes. Anti-VEGF agents might also be useful in other cancer-related conditions that increase vascular permeability, such as malignant pleural effusions or ascites.
175 citations
TL;DR: A frontal quantitative electroencephalographic (QEEG) biomarker, the Antidepressant Treatment Response (ATR) index, was examined as a predictor of response to escitalopram, and compared ATR with other putative predictors.
Abstract: Patients with Major Depressive Disorder (MDD) may not respond to antidepressants for 8 weeks or longer. A biomarker that predicted treatment effectiveness after only 1 week could be clinically useful. We examined a frontal quantitative electroencephalographic (QEEG) biomarker, the Antidepressant Treatment Response (ATR) index, as a predictor of response to escitalopram, and compared ATR with other putative predictors. Three hundred seventy-five subjects meeting DSM-IV criteria for MDD had a baseline QEEG study. After 1 week of treatment with escitalopram, 10 mg, a second QEEG was performed, and the ATR was calculated. Subjects then were randomly assigned to continue with escitalopram, 10 mg, or change to alternative treatments. Seventy-three evaluable subjects received escitalopram for a total of 49days. Response and remission rates were 52.1% and 38.4%, respectively. The ATR predicted both response and remission with 74% accuracy. Neither serum drug levels nor 5HTTLPR and 5HT2a genetic polymorphisms were significant predictors. Responders had larger decreases in Hamilton Depression Rating Scale (Ham-D(17)) scores at day 7 (P=0.005), but remitters did not. Clinician prediction based upon global impression of improvement at day 7 did not predict outcome. Logistic regression showed that the ATR and early Ham-D(17) changes were additive predictors of response, but the ATR was the only significant predictor of remission. Future studies should replicate these results prior to clinical use.
01 Dec 2009
TL;DR: In this paper, the synthesis of InAs quantum dots with a ZnCdS shell with bright and stable emission in the near-infrared (NIR, 700-900 nm) region for biological imaging applications is presented.
Abstract: We present the synthesis of InAs quantum dots (QDs) with a ZnCdS shell with bright and stable emission in the near-infrared (NIR, 700-900 nm) region for biological imaging applications. We demonstrate how NIR QDs can image tumor vasculature in vivo at significantly deeper penetration depths and with higher contrast than visible emitting CdSe(CdS) QDs. Targeted cellular labeling is also presented and may enable multiplexed and low autofluorescence cellular imaging.
TL;DR: Examination of gene expression profiles of cancer cells and tumor-associated macrophages in tumor biopsies before and 12 days after monotherapy with the anti-VEGF antibody bevacizumab shows that VEGF blockade up-regulates inflammatory pathways and NRP1, which should be evaluated as potential targets for improving anti-veGF therapy.
Abstract: Clinical studies converge on the observation that circulating cytokines are elevated in most cancer patients by anti-vascular endothelial growth factor (VEGF) therapy. However, the source of these molecules and their relevance in tumor escape remain unknown. We examined the gene expression profiles of cancer cells and tumor-associated macrophages in tumor biopsies before and 12 days after monotherapy with the anti-VEGF antibody bevacizumab in patients with rectal carcinoma. Bevacizumab up-regulated stromal cell-derived factor 1alpha (SDF1alpha), its receptor CXCR4, and CXCL6, and down-regulated PlGF, Ang1, and Ang2 in cancer cells. In addition, bevacizumab decreased Ang1 and induced neuropilin 1 (NRP1) expression in tumor-associated macrophages. Higher SDF1alpha plasma levels during bevacizumab treatment significantly associated with distant metastasis at three years. These data show that VEGF blockade up-regulates inflammatory pathways and NRP1, which should be evaluated as potential targets for improving anti-VEGF therapy.
TL;DR: A detailed insight is provided into some of the key factors that affect the efficiency of in situ bioremediation along with a comprehensive account of the integrative approaches used for assessing the ecological sustainability of processes.
Abstract: Application of microbial metabolic potential (bioremediation) is accepted as an environmentally benign and economical measure for decontamination of polluted environments. Bioremediation methods are generally categorized into ex situ and in situ bioremediation. Although in situ bioremediation methods have been in use for two to three decades, they have not yet yielded the expected results. Their limited success has been attributed to reduced ecological sustainability under environmental conditions. An important determinant of sustainability of in situ bioremediation is pollutant bioavailability. Microbial chemotaxis is postulated to improve pollutant bioavailability significantly; consequently, application of chemotactic microorganisms can considerably enhance the performance of in situ degradation. The environmental fate of degradative microorganisms and the ecological consequence of intervention constitute other important descriptors for the efficiency and sustainability of bioremediation processes. Integrative use of culture-dependent, culture-independent methods (e.g. amplified rDNA restriction analysis, terminal restriction fragment length polymorphism, denaturing/thermal gradient gel electrophoresis, phospholipid fatty acid, etc.), computational and statistical analyses has enabled successful monitoring of the above aspects. The present review provides a detailed insight into some of the key factors that affect the efficiency of in situ bioremediation along with a comprehensive account of the integrative approaches used for assessing the ecological sustainability of processes. The review also discusses the possibility of developing suicidal genetically engineered microorganisms for optimized and controlled in situ bioremediation.
Harvard University1, University of California, San Francisco2, University of California, Los Angeles3, Memorial Sloan Kettering Cancer Center4, National Institutes of Health5, University of Wisconsin-Madison6, University of Texas Southwestern Medical Center7, University of Texas MD Anderson Cancer Center8, University of Pittsburgh9
TL;DR: The North American Brain Tumor Consortium conducted a phase II study to evaluate the therapeutic potential of imatinib mesylate (Gleevec), a PDGFR inhibitor, in patients with recurrent meningiomas, with generally well tolerated results.
Abstract: Platelet-derived growth factor (PDGF) and its receptors (PDGFR) are frequently coexpressed in meningiomas, potentially contributing to their pathogenesis. The North American Brain Tumor Consortium conducted a phase II study to evaluate the therapeutic potential of imatinib mesylate (Gleevec), a PDGFR inhibitor, in patients with recurrent meningiomas. Patients were stratified into benign (WHO grade I) meningiomas or atypical (WHO grade II) and malignant (WHO grade III) meningiomas. The primary end point was 6-month progression-free survival (6M-PFS). Patients requiring enzyme-inducing antiepileptic drugs were ineligible. Patients received imatinib at a dose of 600 mg/day for the first 4-week cycle and then gradually increased to 800 mg/day for subsequent cycles, if there were no unacceptable toxicities. Plasma concentrations of imatinib and its active metabolite, {"type":"entrez-protein","attrs":{"text":"CGP74588","term_id":"875877231","term_text":"CGP74588"}}CGP74588, were assessed. Twenty-three heavily pre-treated patients were enrolled into the study (13 benign, 5 atypical, and 5 malignant meningiomas), of whom 22 were eligible. The study was closed prematurely due to slow accrual. Tissue was available only from a minority of patients, but in these specimens there was uniform distribution of PDGFR, the drug target. Imatinib was generally well tolerated. Of 19 patients evaluable for response, 10 progressed at the first scan, and 9 were stable. There were no complete or partial responses. Overall median PFS was 2 months (range, 0.7–34 months); 6M-PFS was 29.4%. For benign meningiomas, median PFS was 3 months (range, 1.1–34 months); 6M-PFS was 45%. For atypical and malignant meningiomas, median PFS was 2 months (range, 0.7–3.7 months); 6M-PFS was 0%. Cycle 1 trough concentrations of imatinib and {"type":"entrez-protein","attrs":{"text":"CGP74588","term_id":"875877231","term_text":"CGP74588"}}CGP74588 were 2,129 ± 1,600 ng/ml and 517 ± 326 ng/ml, respectively. Single-agent imatinib was well tolerated but had no significant activity in recurrent meningiomas. Trough plasma concentrations of imatinib exceeded those associated with imatinib activity in chronic myelogenous leukemia.
TL;DR: It is shown that genetic deletion of eNOS as well as NOS blockade attenuates peritumor lymphatic hyperplasia of VEGF-C-overexpressing T241 fibrosarcomas and decreases the delivery of metastatic tumor cells to the draining lymph nodes, and the correlation between NOS and lymphatic metastasis is explained.
Abstract: Lymphatic metastasis is a critical determinant of cancer prognosis. Recently, several lymphangiogenic molecules such as vascular endothelial growth factor (VEGF)-C and VEGF-D were identified. However, the mechanistic understanding of lymphatic metastasis is still in infancy. Nitric oxide (NO) plays a crucial role in regulating blood vessel growth and function as well as lymphatic vessel function. NO synthase (NOS) expression correlates with lymphatic metastasis. However, causal relationship between NOS and lymphatic metastasis has not been documented. To this end, we first show that both VEGF receptor-2 and VEGF receptor-3 stimulation activate eNOS in lymphatic endothelial cells and that NO donors induce proliferation and/or survival of cultured lymphatic endothelial cells in a dose-dependent manner. We find that an NOS inhibitor, L-NMMA, blocked regeneration of lymphatic vessels. Using intravital microscopy that allows us to visualize the steps of lymphatic metastasis, we show that genetic deletion of eNOS as well as NOS blockade attenuates peritumor lymphatic hyperplasia of VEGF-C-overexpressing T241 fibrosarcomas and decreases the delivery of metastatic tumor cells to the draining lymph nodes. Genetic deletion of eNOS in the host also leads to a decrease in T241 tumor cell dissemination to the lymph nodes and macroscopic lymph node metastasis of B16F10 melanoma. These findings indicate that eNOS mediates VEGF-C-induced lymphangiogenesis and, consequently, plays a critical role in lymphatic metastasis. Our findings explain the correlation between NOS and lymphatic metastasis seen in a number of human tumors and open the door for potential therapies exploiting NO signaling to treat diseases of the lymphatic system.
TL;DR: It is shown that the matrix-modifying hormone relaxin increased tumor-associated fibroblast (TAF) interaction with collagen fibers by stimulating β1-integrin activity, which is necessary for fiber remodeling by matrix metalloproteinases.
Abstract: A combination of multiphoton laser scanning microscopy and second harmonic generation (SHG) imaging is used to track tumor associated fibroblasts and extracellular matrix remodeling in living mice. The SHG signal is used for image registration over several days.
TL;DR: The rationale for antiangiogenic agents in GBM, their potential mechanisms of action, and their clinical development in G BM patients are reviewed.
Abstract: Currently, adult glioblastoma (GBM) patients have poor outcomes with conventional cytotoxic treatments. Because GBMs are highly angiogenic tumors, inhibitors that target tumor vasculature are considered promising therapeutic agents in these patients. Encouraging efficacy and tolerability in preliminary clinical trials suggest that targeting angiogenesis may be an effective therapeutic strategy in GBM patients. However, the survival benefits observed to date in uncontrolled trials of antiangiogenic agents have been modest, and several obstacles have limited their effectiveness. This article reviews the rationale for antiangiogenic agents in GBM, their potential mechanisms of action, and their clinical development in GBM patients. Although challenges remain with this approach, ongoing studies may improve upon the promising initial benefits already observed in GBM patients.
TL;DR: It is suggested that PDGF-C plays an important role in glioma vessel maturation and stabilization, and that it can attenuate the response to anti-VEGF therapy, potentially contributing to escape from vascular normalization.
Abstract: Background: Recent clinical trials of VEGF inhibitors have shown promise in the treatment of recurrent glioblastomas (GBM). However, the survival benefit is usually short-lived as tumors escape anti-VEGF therapies. Here we tested the hypothesis that Platelet Derived Growth Factor-C (PDGF-C), an isoform of the PDGF family, affects GBM progression independent of VEGF pathway and hinders anti-VEGF therapy. Principal Findings: We first showed that PDGF-C is present in human GBMs. Then, we overexpressed or downregulated PDGF-C in a human GBM cell line, U87MG, and grew them in cranial windows in nude mice to assess vessel structure and function using intravital microscopy. PDGF-C overexpressing tumors had smaller vessel diameters and lower vascular permeability compared to the parental or siRNA-transfected tumors. Furthermore, vessels in PDGF-C overexpressing tumors had more extensive coverage with NG2 positive perivascular cells and a thicker collagen IV basement membrane than the controls. Treatment with DC101, an anti-VEGFR-2 antibody, induced decreases in vessel density in the parental tumors, but had no effect on the PDGF-C overexpressing tumors. Conclusion: These results suggest that PDGF-C plays an important role in glioma vessel maturation and stabilization, and that it can attenuate the response to anti-VEGF therapy, potentially contributing to escape from vascular normalization.
TL;DR: The ATR index did not provide a useful prediction of response to combination treatment, but may prove useful in predicting responsiveness to different antidepressant medications.
Abstract: We examined the Antidepressant Treatment Response (ATR) index as a predictor of differential response and remission to escitalopram, bupropion, or a combination of the two medications, in subjects with major depressive disorder (MDD). Three hundred seventy-five subjects had a baseline quantitative electroencephalographic (QEEG) study preceding 1 week of treatment with escitalopram, 10 mg, after which a second QEEG was performed and the ATR index was calculated. Subjects then were randomized to continue escitalopram, switch to bupropion, or receive a combination of the two. Clinical response was assessed using the 17-item Hamilton Depression Rating Scale at 49 days of treatment. Accuracy of ATR in predicting response and remission was calculated. There were no significant differences between response and remission rates in the three treatment groups. A single ATR threshold was useful for predicting differential response to either escitalopram or bupropion monotherapy. Subjects with ATR values above the threshold were more than 2.4 times as likely to respond to escitalopram as those with low ATR values (68% vs. 28%). Subjects with ATR values below the threshold who were switched to bupropion treatment were 1.9 times as likely to respond to bupropion alone as those who remained on escitalopram treatment (53% vs. 28%). The ATR index did not provide a useful prediction of response to combination treatment. The ATR index may prove useful in predicting responsiveness to different antidepressant medications.
TL;DR: Due to the importance of the oxygenases in chemical synthesis of drug intermediates and oxidation of xenobiotic compounds, OxDBase database would be very useful tool in the field of synthetic chemistry as well as bioremediation.
Abstract: Oxygenases belong to the oxidoreductive group of enzymes (E.C. Class 1), which oxidize the substrates by transferring oxygen from molecular oxygen (O2) and utilize FAD/NADH/NADPH as the co-substrate. Oxygenases can further be grouped into two categories i.e. monooxygenases and dioxygenases on the basis of number of oxygen atoms used for oxidation. They play a key role in the metabolism of organic compounds by increasing their reactivity or water solubility or bringing about cleavage of the aromatic ring. We compiled a database of biodegradative oxygenases (OxDBase) which provides a compilation of the oxygenase data as sourced from primary literature in the form of web accessible database. There are two separate search engines for searching into the database i.e. mono and dioxygenases database respectively. Each enzyme entry contains its common name and synonym, reaction in which enzyme is involved, family and subfamily, structure and gene link and literature citation. The entries are also linked to several external database including BRENDA, KEGG, ENZYME and UM-BBD providing wide background information. At present the database contains information of over 235 oxygenases including both dioxygenases and monooxygenases. This database is freely available online at http://www.imtech.res.in/raghava/oxdbase/
. OxDBase is the first database that is dedicated only to oxygenases and provides comprehensive information about them. Due to the importance of the oxygenases in chemical synthesis of drug intermediates and oxidation of xenobiotic compounds, OxDBase database would be very useful tool in the field of synthetic chemistry as well as bioremediation.
TL;DR: Formation of new vessels in fat tissues during DIO is largely due to angiogenesis rather than de novo vasculogenesis, and antiangiogenic treatment by blockade of VEGFR2 but not VEG FR1 may limit adipose tissue expansion.
Abstract: BACKGROUND: We investigated if new vessel formation in fat involves the contribution of local tissue-derived endothelial cells (i.e., angiogenesis) or bone marrow-derived cells (BMDCs, i.e. vasculogenesis) and if antiangiogenic treatment by blockade of vascular endothelial growth factor (VEGF) receptors can prevent diet-induced obesity (DIO).
METHODOLOGY/PRINCIPAL FINDINGS: We performed restorative bone marrow transplantation into wild-type mice using transgenic mice expressing green fluorescent protein (GFP) constitutively (driven by beta-actin promoter) or selectively in endothelial cells (under Tie2 promoter activation) as donors. The presence of donor BMDCs in recipient mice was investigated in fat tissue vessels after DIO using in vivo and ex vivo fluorescence microscopy. We investigated the roles of VEGF receptors 1 and 2 (VEGFR1/VEGFR2) by inducing DIO in mice and treating them with blocking monoclonal antibodies. We found only marginal (less than 1%) incorporation of BMDCs in fat vessels during DIO. When angiogenesis was inhibited by blocking VEGFR2 in mice with DIO, treated mice had significantly lower body weights than control animals. In contrast, blocking VEGFR1 had no discernable effect on the weight gain during DIO.
CONCLUSIONS/SIGNIFICANCE: Formation of new vessels in fat tissues during DIO is largely due to angiogenesis rather than de novo vasculogenesis. Antiangiogenic treatment by blockade of VEGFR2 but not VEGFR1 may limit adipose tissue expansion.
TL;DR: It is demonstrated secreted Gluc assay accurately reflects the amount of viable cancer cells in primary and metastatic tumors, and not only tracks metastatic tumor progression but also serves as a longitudinal biomarker for tumor response to treatments.
Abstract: Background Currently, only few techniques are available for quantifying systemic metastases in preclinical model. Thus techniques that can sensitively detect metastatic colonization and assess treatment response in real-time are urgently needed. To this end, we engineered tumor cells to express a naturally secreted Gaussia luciferase (Gluc), and investigated its use as a circulating biomarker for monitoring viable metastatic or primary tumor growth and their treatment responses. Methodology/principal findings We first developed orthotopic primary and metastatic breast tumors with derivative of MDA-MB-231 cells expressing Gluc. We then correlated tumor burden with Gluc activity in the blood and urine along with bioluminescent imaging (BLI). Second, we utilized blood Gluc assay to monitor treatment response to lapatinib in an experimental model of systemic metastasis. We observed good correlation between the primary tumor volume and Gluc concentration in blood (R(2) = 0.84) and urine (R(2) = 0.55) in the breast tumor model. The correlation deviated as a primary tumor grew due to a reduction in viable tumor fraction. This was also supported by our mathematical models for tumor growth to compare the total and viable tumor burden in our model. In the experimental metastasis model, we found numerous brain metastases as well as systemic metastases including bone and lungs. Importantly, blood Gluc assay revealed early growth of metastatic tumors before BLI could visualize their presence. Using secreted Gluc, we localized systemic metastases by BLI and quantitatively monitored the total viable metastatic tumor burden by blood Gluc assay during the course of treatment with lapatinib, a dual tyrosine kinase inhibitor of EGFR and HER2. Conclusion/significance We demonstrated secreted Gluc assay accurately reflects the amount of viable cancer cells in primary and metastatic tumors. Blood Gluc activity not only tracks metastatic tumor progression but also serves as a longitudinal biomarker for tumor response to treatments.
TL;DR: There are hardly any studies delineating the clinical, aetiological and histological features of melasma in men and the present study was taken up to fill this lacuna.
Abstract: Background Melasma, a facial hypermelanosis, is more common in women. In Indians, men seem to be frequently involved. There are hardly any studies delineating the clinical, aetiological and histological features of melasma in men and the present study was taken up to fill this lacuna.
Materials and methods A total of 200 patients with melasma were screened for only men having melasma. Data including duration, illnesses, sunlight exposure, use of cosmetics, oil or medication, familial pigmentation, nutritional, parasitic infestations, infections, hepatic disorders, occupation were taken followed by general physical, cutaneous and Woods light examination. Laboratory investigations including skin biopsy were performed.
Results Of 200 patients screened, 41 (20.5%) were men. Their ages ranged from 19 to 53 years. Twenty-four (58.5%) of the patients were outdoor workers. Twelve (29.3%) originally belonged to hilly regions. Clinical patterns were malar in 61%, centrofacial in 29.3% and mandibular in 9.7%. The aetiological factors identified were: sun-exposure in 20 (48.8%), mustard oil usage in 18 (43.9%), family history in 16 (37%), chronic illnesses in five (12.2%) and phenytoin in three (7.3%); of these sun-exposure and family history were statistically significant when compared with those for women. Laboratory investigations revealed anaemia in five (12.2%), giardiasis in two (4.9%), increased leuteinizing hormone (LH) and low testosterone in four (9.7%) men. Skin biopsies in 20 (48.8%) patients revealed features of epidermal melasma in 10 (50%) and a mixed type in nine (45%) patients.
Conclusions Melasma is frequently observed in Indian men. The main causative factors among the male patients appeared to be sun-exposure and family history. Melasma in men is definitely less common than in women, but shares the same clinicohistopathological characteristics as in women.
TL;DR: It is shown that interstitial hyaluronan paradoxically improves diffusion and that reducing cellularity enhances diffusive macromolecular transport in solid tumors.
TL;DR: Criteria by which the potential response of a tumor to oncolytic herpes simplex virus therapy can be assessed is suggested and the potential of modifications to the vector delivery method, physicochemical properties of the virus, and tumor extracellular matrix composition to enhance efficacy is revealed.
Abstract: Purpose: Although oncolytic viral vectors show promise for the treatment of various cancers, ineffective initial distribution and propagation throughout the tumor mass often limit the therapeutic response. A mathematical model is developed to describe the spread of herpes simplex virus from the initial injection site. Experimental Design: The tumor is modeled as a sphere of radius R. The model incorporates reversible binding, interstitial diffusion, viral degradation, and internalization and physiologic parameters. Three species are considered as follows: free interstitial virus, virus bound to cell surfaces, and internalized virus. Results: This analysis reveals that both rapid binding and internalization as well as hindered diffusion contain the virus to the initial injection volume, with negligible spread to the surrounding tissue. Unfortunately, increasing the dose to saturate receptors and promote diffusion throughout the tumor is not a viable option: the concentration necessary would likely compromise safety. However, targeted modifications to the virus that decrease the binding affinity have the potential to increase the number of infected cells by 1.5-fold or more. An increase in the effective diffusion coefficient can result in similar gains. Conclusions: This analysis suggests criteria by which the potential response of a tumor to oncolytic herpes simplex virus therapy can be assessed. Furthermore, it reveals the potential of modifications to the vector delivery method, physicochemical properties of the virus, and tumor extracellular matrix composition to enhance efficacy.
TL;DR: It is reported that blockade of VEGFR1 activity does not affect the rate of spontaneous metastasis formation in a clinically relevant and widely used preclinical model, therefore, alternative pathways probably mediate the priming of tissues for metastasis.
Abstract: Molecules such as vascular endothelial growth factor (VEGF) or placental growth factor-critical regulators of tumour angiogenesis-are also thought to mobilize into blood circulation bone marrow-derived cells (BMDCs), which may subsequently be recruited to tumours and facilitate tumour growth and metastasis. A study has suggested that BMDCs form 'metastatic niches' in lungs before arrival of cancer cells, and showed that pharmacological inhibition of VEGF receptor 1 (VEGFR1, also known as Flt1)-cognate receptor for VEGF and placental growth factor-prevented BMDC infiltration in lungs and 'metastatic niche' formation. Here we report that blockade of VEGFR1 activity does not affect the rate of spontaneous metastasis formation in a clinically relevant and widely used preclinical model. Therefore, alternative pathways probably mediate the priming of tissues for metastasis.
TL;DR: Blocking an oxygen sensor in the endothelial cells that line the blood vessels of tumors may reduce tumor and endothelial hypoxia and repress metastasis.
Abstract: Blocking an oxygen sensor in the endothelial cells that line the blood vessels of tumors may reduce tumor and endothelial hypoxia and repress metastasis.
TL;DR: In this article, a physiologically based mathematical model was developed to simulate the regulatory effects of the leptin pathway on murine energy homeostasis and revealed the possibility of multiple steady states for body weight.
TL;DR: It is demonstrated that blockade of VEGFR1 activity neither prevents nor changes the rate of spontaneous metastasis formation after primary tumor removal, and prevention of metastasis will require further identification and exploration of cellular and molecular pathways that mediate the priming of the metastatic soil.
Abstract: The role of vascular endothelial growth factor receptor 1 (VEGFR1/Flt1) in tumor metastasis remains incompletely characterized. Recent reports suggested that blocking VEGFR1 activity or the interaction with its ligands (VEGF and PlGF) has anti-tumor effects. Moreover, several studies showed that VEGFR1 mediates tumor progression to distant metastasis. All these effects may be exerted indirectly by recruitment of bone marrow-derived cells (BMDCs), such as myeloid cells. We investigated the role of VEGFR1 activity in BMDCs during the pre-metastatic phase, i.e., prior to metastatic nodule formation in mice after surgical removal of the primary tumor. Using pharmacologic blockade or genetic deletion of the tyrosine kinase domain of VEGFR1, we demonstrate that VEGFR1 activity is not required for the infiltration of de novo myeloid BMDCs in the pre-metastatic lungs in two tumor models and in two mouse models. Moreover, in line with emerging clinical observations, we show that blockade of VEGFR1 activity neither prevents nor changes the rate of spontaneous metastasis formation after primary tumor removal. Prevention of metastasis will require further identification and exploration of cellular and molecular pathways that mediate the priming of the metastatic soil.