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Showing papers by "Rakesh K. Jain published in 2014"


Journal ArticleDOI
TL;DR: In this paper, the authors summarize lessons learned from preclinical and clinical studies over the past decade and propose strategies for improving antiangiogenic therapy outcomes for malignant and nonmalignant diseases.

1,093 citations


Journal ArticleDOI
TL;DR: Shear stresses exerted by flowing blood and interstitial fluid modulate the behavior of cancer and a variety of host cells, and taming these physical forces can improve therapeutic outcomes in many cancers.
Abstract: Tumors generate physical forces during growth and progression. These physical forces are able to compress blood and lymphatic vessels, reducing perfusion rates and creating hypoxia. When exerted directly on cancer cells, they can increase cells' invasive and metastatic potential. Tumor vessels-while nourishing the tumor-are usually leaky and tortuous, which further decreases perfusion. Hypoperfusion and hypoxia contribute to immune evasion, promote malignant progression and metastasis, and reduce the efficacy of a number of therapies, including radiation. In parallel, vessel leakiness together with vessel compression causes a uniformly elevated interstitial fluid pressure that hinders delivery of blood-borne therapeutic agents, lowering the efficacy of chemo- and nanotherapies. In addition, shear stresses exerted by flowing blood and interstitial fluid modulate the behavior of cancer and a variety of host cells. Taming these physical forces can improve therapeutic outcomes in many cancers.

716 citations


Journal ArticleDOI
TL;DR: In this article, a simple approach for co-assembling magnetic nanoparticles with fluorescent quantum dots to form colloidal magneto-fluorescent supernanoparticles was reported, which exhibit a superstructure consisting of a close-packed magnetic nanoparticle core, which is fully surrounded by a shell of fluorescent quantum dot.
Abstract: Magneto-fluorescent particles have been recognized as an emerging class of materials that exhibit great potential in advanced applications. However, synthesizing such magneto-fluorescent nanomaterials that simultaneously exhibit uniform and tunable sizes, high magnetic content loading, maximized fluorophore coverage at the surface and a versatile surface functionality has proven challenging. Here we report a simple approach for co-assembling magnetic nanoparticles with fluorescent quantum dots to form colloidal magneto-fluorescent supernanoparticles. Importantly, these supernanoparticles exhibit a superstructure consisting of a close-packed magnetic nanoparticle 'core', which is fully surrounded by a 'shell' of fluorescent quantum dots. A thin layer of silica coating provides high colloidal stability and biocompatibility, and a versatile surface functionality. We demonstrate that after surface pegylation, these silica-coated magneto-fluorescent supernanoparticles can be magnetically manipulated inside living cells while being optically tracked. Moreover, our silica-coated magneto-fluorescent supernanoparticles can also serve as an in vivo multi-photon and magnetic resonance dual-modal imaging probe.

221 citations


Journal ArticleDOI
TL;DR: Blocking SDF‐1α/CXCR4 or Gr‐1+ myeloid cell infiltration may reduce hypoxia‐mediated HCC desmoplasia and increase the efficacy of sorafenib treatment.

177 citations


Journal ArticleDOI
TL;DR: The consensus of the international panel is that exercise is recommended for older adults with osteoporosis or vertebral fracture, but the recommendations are conditional.
Abstract: Summary A consensus process was conducted to develop exercise recommendations for individuals with osteoporosis or vertebral fractures. A multicomponent exercise program that includes balance and resistance training is recommended.

169 citations


Journal ArticleDOI
TL;DR: In this article, the external quantum efficiency of AlGaN deep ultraviolet (DUV) light-emitting diodes (LEDs) on sapphire substrates is analyzed.
Abstract: We present the analysis of the external quantum efficiency in AlGaN deep ultraviolet (DUV) light-emitting diodes (LEDs) on sapphire substrates and discuss factors affecting the output power of DUV LEDs. Performance of the LED is related to optimization of the device structure design and improvements of the epitaxial material quality.

162 citations


Journal ArticleDOI
TL;DR: Provenzano et al. showed that hyaluronan (HA) can mechanically compress blood vessels in pancreatic ductal adenocarcinoma (PDA) patients, but their proposed mechanism—that HA leads to very high IFP that collapses vessels—is not consistent with the physiology of fluid homeostasis and calls for careful assessment of IFP in PDAs.

146 citations


Journal ArticleDOI
TL;DR: The data suggest that the combination of BCL-2/BCL-XL inhibitors with TORC1/2 inhibitors constitutes a promising targeted therapy strategy to treat these recalcitrant cancers.
Abstract: Colorectal cancers (CRCs) harboring KRAS or BRAF mutations are refractory to current targeted therapies. Using data from a high-throughput drug screen, we have developed a novel therapeutic strategy that combines targeting of the apoptotic machinery using the BCL-2 family inhibitor ABT-263 (navitoclax) in combination with a TORC1/2 inhibitor, AZD8055. This combination leads to efficient apoptosis specifically in KRAS mutant (MT) and BRAF MT but not wild-type (WT) CRC cells. This specific susceptibility results from TORC1/2 inhibition leading to suppression of MCL-1 expression in mutant, but not WT CRCs, leading to abrogation of BIM/MCL-1 complexes. This combination strategy leads to tumor regressions in both KRAS MT colorectal cancer xenograft and genetically-engineered mouse models of CRC, but not in the corresponding KRAS WT CRC models. These data suggest that the combination of BCL-2/XL inhibitors with TORC1/2 inhibitors constitutes a promising targeted therapy strategy to treat these recalcitrant cancers.

125 citations


Journal ArticleDOI
TL;DR: The results advocate potential of SLNs as a novel carrier for topical delivery of ADA in topical therapeutic approaches and open new avenues for drug delivery which better meets the need of anti-acne research.

124 citations


Journal ArticleDOI
TL;DR: It is shown that the angiogenic endothelium is characterized by the presence of functional podosome rosettes, which are precursors of de novo branching points and represent a key feature in the formation of new blood vessels.
Abstract: Seano, Primo and colleagues report that blood vessel branching during tumour angiogenesis is mediated by the formation of podosome rosettes that depends on VEGF-A and integrin α6β1.

101 citations


Journal ArticleDOI
TL;DR: This study met the primary endpoint by showing a rate of 4.1% grade 3 toxicity for neoadjuvant short-course proton-based chemoradiation, and KRAS(G12D) status and high CXCR7 expression and circulating CEA, CA19-9, and HGF levels were associated with poor survival.
Abstract: Purpose To evaluate the safety, efficacy and biomarkers of short-course proton beam radiation and capecitabine, followed by pancreaticoduodenectomy in a phase 1/2 study in pancreatic ductal adenocarcinoma (PDAC) patients Methods and Materials Patients with radiographically resectable, biopsy-proven PDAC were treated with neoadjuvant short-course (2-week) proton-based radiation with capecitabine, followed by surgery and adjuvant gemcitabine The primary objective was to demonstrate a rate of toxicity grade ≥3 of Results The phase 2 dose was established at 5 daily doses of 5 GyE Fifty patients were enrolled, of whom 35 patients were treated in the phase 2 portion There were no grade 4 or 5 toxicities, and only 2 of 35 patients (41%) experienced a grade 3 toxicity event (chest wall pain grade 1, colitis grade 1) Of 48 patients eligible for analysis, 37 underwent pancreaticoduodenectomy Thirty of 37 (81%) had positive nodes Locoregional failure occurred in 6 of 37 resected patients (162%), and distant recurrence occurred in 35 of 48 patients (729%) With median follow-up of 38 months, the median progression-free survival for the entire group was 10 months, and overall survival was 17 months Biomarker studies showed significant associations between worse survival outcomes and the KRAS point mutation change from glycine to aspartic acid at position 12, stromal CXCR7 expression, and circulating biomarkers CEA, CA19-9, and HGF (all, P Conclusions This study met the primary endpoint by showing a rate of 41% grade 3 toxicity for neoadjuvant short-course proton-based chemoradiation Treatment was associated with favorable local control In exploratory analyses, KRAS G12D status and high CXCR7 expression and circulating CEA, CA19-9, and HGF levels were associated with poor survival

Journal ArticleDOI
TL;DR: The sequential enzyme treatment of xylanase followed by laccase resulted in improved pulp properties and reduced AOX levels in bleach effluents, which will help to meet AOX discharge limits and improve pulp properties will be value addition to the paper.

Journal ArticleDOI
TL;DR: The field of vessel-calibre MRI is reviewed and the emerging evidence supporting the use of this technique to monitor response to anticancer therapy is summarized, including the potential use in clinical imaging trials and relevant avenues for future research.
Abstract: Our understanding of the importance of blood vessels and angiogenesis in cancer has increased considerably over the past decades, and the assessment of tumour vessel calibre and structure has become increasingly important for in vivo monitoring of therapeutic response. The preferred method for in vivo imaging of most solid cancers is MRI, and the concept of vessel-calibre MRI has evolved since its initial inception in the early 1990s. Almost a quarter of a century later, unlike traditional contrast-enhanced MRI techniques, vessel-calibre MRI remains widely inaccessible to the general clinical community. The narrow availability of the technique is, in part, attributable to limited awareness and a lack of imaging standardization. Thus, the role of vessel-calibre MRI in early phase clinical trials remains to be determined. By contrast, regulatory approvals of antiangiogenic agents that are not directly cytotoxic have created an urgent need for clinical trials incorporating advanced imaging analyses, going beyond traditional assessments of tumour volume. To this end, we review the field of vessel-calibre MRI and summarize the emerging evidence supporting the use of this technique to monitor response to anticancer therapy. We also discuss the potential use of this biomarker assessment in clinical imaging trials and highlight relevant avenues for future research.

Journal ArticleDOI
TL;DR: In this article, a quantum dot and an analyte-responsive dye are used to measure pH, oxygen, and glucose in the tumor microenvironment by using multiphoton imaging.
Abstract: Acidity, hypoxia, and glucose levels characterize the tumor microenvironment rendering pH, pO2, and pGlucose, respectively, important indicators of tumor health. To this end, understanding how these parameters change can be a powerful tool for the development of novel and effective therapeutics. We have designed optical chemosensors that feature a quantum dot and an analyte-responsive dye. These noninvasive chemosensors permit pH, oxygen, and glucose to be monitored dynamically within the tumor microenvironment by using multiphoton imaging.

Journal ArticleDOI
TL;DR: It is reported that a simple PCR-based assay interrogating somatic variation in hypermutable polyguanine (poly-G) repeats can provide a rapid and reliable assessment of mitotic history and clonal architecture in human cancer.
Abstract: Intratumor genetic heterogeneity reflects the evolutionary history of a cancer and is thought to influence treatment outcomes. Here we report that a simple PCR-based assay interrogating somatic variation in hypermutable polyguanine (poly-G) repeats can provide a rapid and reliable assessment of mitotic history and clonal architecture in human cancer. We use poly-G repeat genotyping to study the evolution of colon carcinoma. In a cohort of 22 patients, we detect poly-G variants in 91% of tumors. Patient age is positively correlated with somatic mutation frequency, suggesting that some poly-G variants accumulate before the onset of carcinogenesis during normal division in colonic stem cells. Poorly differentiated tumors have fewer mutations than well-differentiated tumors, possibly indicating a shorter mitotic history of the founder cell in these cancers. We generate poly-G mutation profiles of spatially separated samples from primary carcinomas and matched metastases to build well-supported phylogenetic trees that illuminate individual patients’ path of metastatic progression. Our results show varying degrees of intratumor heterogeneity among patients. Finally, we show that poly-G mutations can be found in other cancers than colon carcinoma. Our approach can generate reliable maps of intratumor heterogeneity in large numbers of patients with minimal time and cost expenditure.

Journal ArticleDOI
TL;DR: The research priorities identified as part of the Too Fit To Fracture initiative can be used to inform the development of multicentre collaborations to evaluate and implement strategies for engaging individuals with osteoporosis in a safe and effective exercise.
Abstract: Summary An international consensus process identified the following research priorities in osteoporosis and exercise: study of exercise in high-risk cohorts, evaluation of multimodal interventions, research examining translation into practice and a goal to examine fracture outcomes.

Journal ArticleDOI
TL;DR: The article focuses on research led by the author on how the matrix structure of cancerous tumors squeezes blood vessels, preventing the effectiveness of drug treatments, and the use of angiotensin-blocking drugs to counteract this as of February 2014.
Abstract: The article focuses on research led by the author on how the matrix structure of cancerous tumors squeezes blood vessels, preventing the effectiveness of drug treatments, and the use of angiotensin-blocking drugs to counteract this as of February 2014. Background information on the research is presented, the potential of blood pressure drug losartan in depleting the matrix is explained, and further research needed is outlined.

Journal ArticleDOI
TL;DR: In this paper, six clinicians provide an overview of the serotonergic antidepressant vortioxetine, which was recently approved for the treatment of major depressive disorder in adults, and discuss the pharmacologic profile and receptor-mediated effects of VOR in relation to potential outcomes.
Abstract: Six clinicians provide an overview of the serotonergic antidepressant vortioxetine, which was recently approved for the treatment of major depressive disorder in adults. They discuss the pharmacologic profile and receptor-mediated effects of vortioxetine in relation to potential outcomes. Additionally, they summarize the clinical trials, which demonstrate vortioxetine's efficacy, and discuss findings related to safety and tolerability that have high relevance to patient compliance.

Journal ArticleDOI
TL;DR: To understand the mechanistic model of symptom development and the role of programmed cell death (PCD) during infection, the levels of biochemical intermediates and stress responsive micro RNAs (miRNAs) with their target transcripts in Vigna unguiculata are compared.

Journal ArticleDOI
TL;DR: In vitro studies suggest that amino acid N(182) of the conserved FRNK box may regulate RNA silencing mechanisms, and is required for maintenance of the subcellular localization of the protein for its multi-functionality.
Abstract: The multifunctional potyviral helper-component protease (HcPro) contains variable regions with some functionally conserved domains, such as the FRNK box. Natural variants occur at the FRNK box, a conserved central domain, known for its role in RNA binding and RNAi suppression activities, although no dominant natural variants for the N182 residue are known to occur. Here, a mutant at HcProN182L was developed to investigate its role in natural populations. Using in vitro studies, we found an increase in the small RNA (sRNA) binding potential of HcProN182L without affecting its protein–protein interaction properties, suggesting that the presence of N182 is critical to maintain threshold levels of sRNAs, but does not interfere in the self-interaction of HcPro. Furthermore, we found that expression of HcProN182L in Nicotiana benthamiana affected plant growth. Transient expression of HcProN182L induced reporter gene expression in 16c GFP transgenic plants more than HcPro did, suggesting that replacement of asparagine in the FRNK box favours RNA silencing suppression. HcPro was found to be distributed in the nucleus and cytoplasm, whereas HcProN182L was observed only in cytoplasmic inclusion bodies in N. benthamiana leaves, when fused to a GFP tag and expressed by agro-infiltration, suggesting mutation favours oligomerization of HcPro. These findings suggest that amino acid N182 of the conserved FRNK box may regulate RNA silencing mechanisms, and is required for maintenance of the subcellular localization of the protein for its multi-functionality. Hence, the N182 residue of the FRNK box seems to be indispensable for potyvirus infection during evolution.


Journal ArticleDOI
TL;DR: Two models of intravital FRET/cGMP imaging in the vasculature of cGMP sensor mice are described: epifluorescence-based ratio imaging in resistance-type vessels of the cremaster muscle and ratio imaging by multiphoton microscopy within the walls of subcutaneous blood vessels accessed through a dorsal skinfold chamber.
Abstract: Cyclic guanosine monophosphate (cGMP) is an important signaling molecule and drug target in the cardiovascular system. It is well known that stimulation of the vascular nitric oxide (NO)-cGMP pathway results in vasodilation. However, the spatiotemporal dynamics of cGMP signals themselves and the cGMP concentrations within specific cardiovascular cell types in health, disease, and during pharmacotherapy with cGMP-elevating drugs are largely unknown. To facilitate the analysis of cGMP signaling in vivo, we have generated transgenic mice that express fluorescence resonance energy transfer (FRET)-based cGMP sensor proteins. Here, we describe two models of intravital FRET/cGMP imaging in the vasculature of cGMP sensor mice: (1) epifluorescence-based ratio imaging in resistance-type vessels of the cremaster muscle and (2) ratio imaging by multiphoton microscopy within the walls of subcutaneous blood vessels accessed through a dorsal skinfold chamber. Both methods allow simultaneous monitoring of NO-induced cGMP transients and vasodilation in living mice. Detailed protocols of all steps necessary to perform and evaluate intravital imaging experiments of the vasculature of anesthetized mice including surgery, imaging, and data evaluation are provided. An image segmentation approach is described to estimate FRET/cGMP changes within moving structures such as the vessel wall during vasodilation. The methods presented herein should be useful to visualize cGMP or other biochemical signals that are detectable with FRET-based biosensors, such as cyclic adenosine monophosphate or Ca2+, and to correlate them with respective vascular responses. With further refinement and combination of transgenic mouse models and intravital imaging technologies, we envision an exciting future, in which we are able to ‘watch’ biochemistry, (patho )physiology, and pharmacotherapy in the context of a living mammalian organism.


Patent
03 Sep 2014
TL;DR: In this article, an improved heterostructure for an optoelectronic device is provided, which includes an active region, an electron blocking layer, and a p-type contact layer.
Abstract: An improved heterostructure for an optoelectronic device is provided. The heterostructure includes an active region, an electron blocking layer, and a p-type contact layer. The p-type contact layer and electron blocking layer can be doped with a p-type dopant. The dopant concentration for the electron blocking layer can be at most ten percent the dopant concentration of the p-type contact layer. A method of designing such a heterostructure is also described.

Proceedings ArticleDOI
06 Nov 2014
TL;DR: The feasibility of the technology was demonstrated by fabrication and testing inverter and differential amplifier ICs using AlInN/GaN heterostructures, and the developed ICs show stable performance with unit-gain bandwidth above 1 MHz and internal response time 45 ns*.
Abstract: High-temperature technology platform has been developed based on AlInN/GaN heterostructures. High electron concentration in 2DEG channel of AlInN/GaN devices is remarkably stable over a broad temperature range, enabling device operation above 500 °C. The developed IC technology is based on three key elements: (1) exceptional quality AlInN/GaN heterostructure with very high carrier concentration and mobility that enables IC fast operation in a broad temperature range; (2) heterostructure field effect transistor approach that provides fully planar IC structure which is easy to scale and to combine with the other high temperature electronic components; (3) fabrication advancements including novel metallization scheme and high-k passivation/gate dielectrics, specifically developed for high temperature operation. The feasibility of the technology was demonstrated by fabrication and testing inverter and differential amplifier ICs using AlInN/GaN heterostructures. At temperature exceeding 500°C, the developed ICs show stable performance with unit-gain bandwidth above 1 MHz and internal response time 45 ns*.

Patent
23 Sep 2014
TL;DR: In this paper, a heterostructures for use in optoelectronic devices are described, where one or more parameters of the heterostructure can be configured to improve the reliability of the corresponding optolectronic device.
Abstract: Heterostructures for use in optoelectronic devices are described. One or more parameters of the heterostructure can be configured to improve the reliability of the corresponding optoelectronic device. The materials used to create the active structure of the device can be considered in configuring various parameters the n-type and/or p-type sides of the heterostructure.

Journal ArticleDOI
TL;DR: In this article, near-field photoluminescence (PL) spectroscopy was applied to study spatial variations of emission spectra of AlxGa1−xN epilayers with 0.6≤x≤0.7.
Abstract: Scanning near-field photoluminescence (PL) spectroscopy was applied to study spatial variations of emission spectra of AlxGa1−xN epilayers with 0.6≤x≤0.7. PL spectra were found to be spatially uniform with peak wavelength standard deviations of only ∼2 meV and ratios between peak intensity standard deviations and average peak intensity values of 0.06. The observed absence of correlation between the PL peak wavelength and intensity shows that spatial distribution of nonradiative recombination centers is not related to band potential fluctuations. Our results demonstrate that the homogeneous broadening and the random cation distribution primarily determine PL linewidths for layers grown under optimized conditions.

Journal ArticleDOI
TL;DR: Whether the addition of a vascular endothelial growth factor (VEGF) signaling inhibitor (cediranib) to conventional CRT had an impact on the frequency of PsP is sought, by comparing two groups of patients with newly diagnosed glioblastoma before, during, and after CRT.
Abstract: Background. Chemoradiation (CRT) can significantly modify the radiographic appearance of malignant gliomas, especially within the immediate post-CRT period. Pseudoprogression (PsP) is an increasingly recognized phenomenon in this setting, and is thought to be secondary to increased permeability as a byproduct of the complex process of radiation-induced tissue injury, possibly enhanced by temozolomide. We sought to determine whether the addition of a vascular endothelial growth factor (VEGF) signaling inhibitor (cediranib) to conventional CRT had an impact on the frequency of PsP, by comparing two groups of patients with newly diagnosed glioblastoma before, during, and after CRT.

Journal ArticleDOI
TL;DR: Early and sustained improvement of depressive symptoms was retrospectively observed in patients treated with vilazodone; early findings may be related to overall treatment outcomes.
Abstract: Objective:To retrospectively examine the timing of depressive symptom improvement in patients treated with vilazodone, a selective serotonin reuptake inhibitor (SSRI) and 5-HT1A partial agonist.Research design and methods:Post hoc analyses were conducted on pooled data from two phase III, multicenter, 8 week, double-blind, randomized, controlled trials (RCTs) of vilazodone 40 mg/day or placebo in adult patients with major depressive disorder (MDD).Clinical trial registration:Randomized controlled trial 1: ClinicalTrials.gov identifier: NCT00285376, http://ClinicalTrials.gov/ct2/show/NCT00285376; randomized controlled trial 2: ClinicalTrials.gov identifier: NCT00683592, http://ClinicalTrials.gov/ct2/show/NCT00683592.Main outcome measures:Montgomery–Asberg Depression Rating Scale (MADRS) total score least squares (LS) mean change from baseline to Week 8; MADRS single items LS mean change from baseline; MADRS responder analyses: response = ≥50% reduction in baseline score; cumulative response = propo...

Patent
21 Oct 2014
TL;DR: In this article, a heterostructure for use in an electronic or optoelectronic device is provided, which includes one or more composite semiconductor layers, at least one of which can be formed by a group of columnar structures (e.g., nanowires).
Abstract: A heterostructure for use in an electronic or optoelectronic device is provided. The heterostructure includes one or more composite semiconductor layers. The composite semiconductor layer can include sub-layers of varying morphology, at least one of which can be formed by a group of columnar structures (e.g., nanowires). Another sub-layer in the composite semiconductor layer can be porous, continuous, or partially continuous.