Showing papers by "Rakesh K. Jain published in 2016"
TL;DR: It is concluded that cross-talk between adipocytes, TANs, and PSCs exacerbates desmoplasia and promotes tumor progression in obesity and that clinically available antifibrotic/inflammatory agents can improve the treatment response of PDAC in obese hosts.
Abstract: It remains unclear how obesity worsens treatment outcomes in patients with pancreatic ductal adenocarcinoma (PDAC). In normal pancreas, obesity promotes inflammation and fibrosis. We found in mouse models of PDAC that obesity also promotes desmoplasia associated with accelerated tumor growth and impaired delivery/efficacy of chemotherapeutics through reduced perfusion. Genetic and pharmacological inhibition of angiotensin-II type-1 receptor (AT1) reverses obesity-augmented desmoplasia and tumor growth and improves response to chemotherapy. Augmented activation of pancreatic stellate cells (PSCs) in obesity is induced by tumor-associated neutrophils (TANs) recruited by adipocyte-secreted IL-1s. PSCs further secrete IL-1s, and inactivation of PSCs reduces IL-1s expression and TAN recruitment. Furthermore, depletion of TANs, IL-1s inhibition, or inactivation of PSCs prevents obesity-accelerated tumor growth. In pancreatic cancer patients, we confirmed that obesity is associated with increased desmoplasia and reduced response to chemotherapy. We conclude that crosstalk between adipocytes, TANs, and PSCs exacerbates desmoplasia and promotes tumor progression in obesity.
290 citations
TL;DR: It is shown that dual blockade of angiopoietin-2 and vascular endothelial growth factor delays tumor growth and enhances survival benefits through reprogramming of tumor-associated macrophages toward an antitumor phenotype as well as by pruning immature tumor vessels.
Abstract: Inhibition of the vascular endothelial growth factor (VEGF) pathway has failed to improve overall survival of patients with glioblastoma (GBM). We previously showed that angiopoietin-2 (Ang-2) overexpression compromised the benefit from anti-VEGF therapy in a preclinical GBM model. Here we investigated whether dual Ang-2/VEGF inhibition could overcome resistance to anti-VEGF treatment. We treated mice bearing orthotopic syngeneic (Gl261) GBMs or human (MGG8) GBM xenografts with antibodies inhibiting VEGF (B20), or Ang-2/VEGF (CrossMab, A2V). We examined the effects of treatment on the tumor vasculature, immune cell populations, tumor growth, and survival in both the Gl261 and MGG8 tumor models. We found that in the Gl261 model, which displays a highly abnormal tumor vasculature, A2V decreased vessel density, delayed tumor growth, and prolonged survival compared with B20. In the MGG8 model, which displays a low degree of vessel abnormality, A2V induced no significant changes in the tumor vasculature but still prolonged survival. In both the Gl261 and MGG8 models A2V reprogrammed protumor M2 macrophages toward the antitumor M1 phenotype. Our findings indicate that A2V may prolong survival in mice with GBM by reprogramming the tumor immune microenvironment and delaying tumor growth.
263 citations
TL;DR: Dual inhibition of VEGFR/Ang-2 prolongs survival in preclinical GBM models by reducing tumor burden, improving normalization, and altering TAMs, which may represent a potential therapeutic strategy to overcome the limitations of anti-VEGFR monotherapy in GBM patients.
Abstract: Glioblastomas (GBMs) rapidly become refractory to anti-VEGF therapies. We previously demonstrated that ectopic overexpression of angiopoietin-2 (Ang-2) compromises the benefits of anti-VEGF receptor (VEGFR) treatment in murine GBM models and that circulating Ang-2 levels in GBM patients rebound after an initial decrease following cediranib (a pan-VEGFR tyrosine kinase inhibitor) administration. Here we tested whether dual inhibition of VEGFR/Ang-2 could improve survival in two orthotopic models of GBM, Gl261 and U87. Dual therapy using cediranib and MEDI3617 (an anti–Ang-2–neutralizing antibody) improved survival over each therapy alone by delaying Gl261 growth and increasing U87 necrosis, effectively reducing viable tumor burden. Consistent with their vascular-modulating function, the dual therapies enhanced morphological normalization of vessels. Dual therapy also led to changes in tumor-associated macrophages (TAMs). Inhibition of TAM recruitment using an anti–colony-stimulating factor-1 antibody compromised the survival benefit of dual therapy. Thus, dual inhibition of VEGFR/Ang-2 prolongs survival in preclinical GBM models by reducing tumor burden, improving normalization, and altering TAMs. This approach may represent a potential therapeutic strategy to overcome the limitations of anti-VEGFR monotherapy in GBM patients by integrating the complementary effects of anti-Ang2 treatment on vessels and immune cells.
232 citations
TL;DR: In this paper, a protease-activated fluorescent imaging probe, LUM015, was used to detect cancer in vivo in a mouse model of soft tissue sarcoma (STS) and ex vivo in the first-in-human phase 1 clinical trial.
Abstract: Local recurrence is a common cause of treatment failure for patients with solid tumors. Intraoperative detection of microscopic residual cancer in the tumor bed could be used to decrease the risk of a positive surgical margin, reduce rates of reexcision, and tailor adjuvant therapy. We used a protease-activated fluorescent imaging probe, LUM015, to detect cancer in vivo in a mouse model of soft tissue sarcoma (STS) and ex vivo in a first-in-human phase 1 clinical trial. In mice, intravenous injection of LUM015 labeled tumor cells, and residual fluorescence within the tumor bed predicted local recurrence. In 15 patients with STS or breast cancer, intravenous injection of LUM015 before surgery was well tolerated. Imaging of resected human tissues showed that fluorescence from tumor was significantly higher than fluorescence from normal tissues. LUM015 biodistribution, pharmacokinetic profiles, and metabolism were similar in mouse and human subjects. Tissue concentrations of LUM015 and its metabolites, including fluorescently labeled lysine, demonstrated that LUM015 is selectively distributed to tumors where it is activated by proteases. Experiments in mice with a constitutively active PEGylated fluorescent imaging probe support a model where tumor-selective probe distribution is a determinant of increased fluorescence in cancer. These co-clinical studies suggest that the tumor specificity of protease-activated imaging probes, such as LUM015, is dependent on both biodistribution and enzyme activity. Our first-in-human data support future clinical trials of LUM015 and other protease-sensitive probes.
208 citations
TL;DR: The researchers found that VEGF inhibition increased the stiffness of colorectal cancer liver metastases, making them more difficult to treat with chemotherapy, and suggested that extracellular matrix components such as HA could be a potential therapeutic target for reducing physical barriers to systemic treatments in patients with mCRC who receive anti-VEGF therapy.
Abstract: Antiangiogenic therapy with drugs that block vascular endothelial growth factor (VEGF) signaling to inhibit formation of new blood vessels in tumors is commonly used in colorectal cancer. Unfortunately, the effects of this therapy usually do not last for long, and a study by Rahbari et al . shows why this might be the case. The authors found that VEGF inhibition increased the stiffness of colorectal cancer liver metastases, making them more difficult to treat with chemotherapy. In a mouse model, the researchers were able to overcome this difficulty by using an enzyme to degrade a component of the extracellular matrix in liver metastases, suggesting that the matrix may be a target for future cancer therapies.
162 citations
TL;DR: Two strategies to reengineer the tumor microenvironment-vessel normalization and decompression-that can alleviate hypoxia are summarized and discussed, and how these two strategies alone and in combination with each other-or other therapeutic strategies-may overcome the challenges posed by cancer heterogeneity are discussed.
Abstract: Solid tumors consist of cancer cells and stromal cells, including resident and transiting immune cells-all ensconced in an extracellular matrix (ECM)-nourished by blood vessels and drained by lymphatic vessels. The microenvironment constituents are abnormal and heterogeneous in morphology, phenotype, and physiology. Such irregularities include an inefficient tumor vascular network comprised of leaky and compressed vessels, which impair blood flow and oxygen delivery. Low oxygenation in certain tumor regions-or focal hypoxia-is a mediator of cancer progression, metastasis, immunosuppression, and treatment resistance. Thus, repairing an abnormal and heterogeneous microenvironment-and hypoxia in particular-can significantly improve treatments of solid tumors. Here, we summarize two strategies to reengineer the tumor microenvironment (TME)-vessel normalization and decompression-that can alleviate hypoxia. In addition, we discuss how these two strategies alone and in combination with each other-or other therapeutic strategies-may overcome the challenges posed by cancer heterogeneity.
136 citations
TL;DR: It was found that obesity increased TAM infiltration, tumor growth, and metastasis in pancreatic cancers, without affecting vessel density, and targeting PlGF/VEGFR-1 signaling inhibits obesity-induced acceleration of tumor progression.
Abstract: Purpose: Obesity promotes pancreatic and breast cancer progression via mechanisms that are poorly understood. Although obesity is associated with increased systemic levels of placental growth factor (PlGF), the role of PlGF in obesity-induced tumor progression is not known. PlGF and its receptor VEGFR-1 have been shown to modulate tumor angiogenesis and promote tumor-associated macrophage (TAM) recruitment and activity. Here, we hypothesized that increased activity of PlGF/VEGFR-1 signaling mediates obesity-induced tumor progression by augmenting tumor angiogenesis and TAM recruitment/activity. Experimental Design: We established diet-induced obese mouse models of wild-type C57BL/6, VEGFR-1 tyrosine kinase (TK)-null, or PlGF-null mice, and evaluated the role of PlGF/VEGFR-1 signaling in pancreatic and breast cancer mouse models and in human samples. Results: We found that obesity increased TAM infiltration, tumor growth, and metastasis in pancreatic cancers, without affecting vessel density. Ablation of VEGFR-1 signaling prevented obesity-induced tumor progression and shifted the tumor immune environment toward an antitumor phenotype. Similar findings were observed in a breast cancer model. Obesity was associated with increased systemic PlGF, but not VEGF-A or VEGF-B, in pancreatic and breast cancer patients and in various mouse models of these cancers. Ablation of PlGF phenocopied the effects of VEGFR-1-TK deletion on tumors in obese mice. PlGF/VEGFR-1-TK deletion prevented weight gain in mice fed a high-fat diet, but exacerbated hyperinsulinemia. Addition of metformin not only normalized insulin levels but also enhanced antitumor immunity. Conclusions: Targeting PlGF/VEGFR-1 signaling reprograms the tumor immune microenvironment and inhibits obesity-induced acceleration of tumor progression. Clin Cancer Res; 22(12); 2993–3004. ©2016 AACR.
102 citations
01 Oct 2016
85 citations
TL;DR: Bvacizumab treatment resulted in durable hearing response in 36% of patients with NF2 and confirmed progressive VS-associated hearing loss and imaging and plasma biomarkers showed promising associations with response that should be validated in larger studies.
Abstract: PurposeNeurofibromatosis type 2 (NF2) is a tumor predisposition syndrome characterized by bilateral vestibular schwannomas (VSs) resulting in deafness and brainstem compression. This study evaluated efficacy and biomarkers of bevacizumab activity for NF2-associated progressive and symptomatic VSs.Patients and MethodsBevacizumab 7.5 mg/kg was administered every 3 weeks for 46 weeks, followed by 24 weeks of surveillance after treatment with the drug. The primary end point was hearing response defined by word recognition score (WRS). Secondary end points included toxicity, tolerability, imaging response using volumetric magnetic resonance imaging analysis, durability of response, and imaging and blood biomarkers.ResultsFourteen patients (estimated to yield > 90% power to detect an alternative response rate of 50% at alpha level of 0.05) with NF2, with a median age of 30 years (range, 14 to 79 years) and progressive hearing loss in the target ear (median baseline WRS, 60%; range 13% to 82%), were enrolled. Th...
78 citations
TL;DR: T-DM1 can overcome resistance to trastuzumab therapy in HER2-driven or PI3K-driven breast cancer brain lesions due to the cytotoxicity of the DM1 component.
Abstract: BACKGROUND Central nervous system (CNS) metastases represent a major problem in the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer because of the disappointing efficacy of HER2-targeted therapies against brain lesions. The antibody-drug conjugate ado-trastuzumab emtansine (T-DM1) has shown efficacy in trastuzumab-resistant systemic breast cancer. Here, we tested the hypothesis that T-DM1 could overcome trastuzumab resistance in murine models of brain metastases. METHODS We treated female nude mice bearing BT474 or MDA-MB-361 brain metastases (n = 9-11 per group) or cancer cells grown in organotypic brain slice cultures with trastuzumab or T-DM1 at equivalent or equipotent doses. Using intravital imaging, molecular techniques and histological analysis we determined tumor growth, mouse survival, cancer cell apoptosis and proliferation, tumor drug distribution, and HER2 signaling. Data were analyzed with one-way analysis of variance (ANOVA), Kaplan-Meier analysis, and Coefficient of Determination. All statistical tests were two-sided. RESULTS T-DM1 delayed the growth of HER2-positive breast cancer brain metastases compared with trastuzumab. These findings were consistent between HER2-driven and PI3K-driven tumors. The activity of T-DM1 resulted in a survival benefit (median survival for BT474 tumors: 28 days for trastuzumab vs 112 days for T-DM1, hazard ratio = 6.2, 95% confidence interval = 6.1 to 85.84, P < .001). No difference in drug distribution or HER2-signaling was revealed between the two groups. However, T-DM1 led to a statistically significant increase in tumor cell apoptosis (one-way ANOVA for ApopTag, P < .001), which was associated with mitotic catastrophe. CONCLUSIONS T-DM1 can overcome resistance to trastuzumab therapy in HER2-driven or PI3K-driven breast cancer brain lesions due to the cytotoxicity of the DM1 component. Clinical investigation of T-DM1 for patients with CNS metastases from HER2-positive breast cancer is warranted.
60 citations
TL;DR: How the dysfunctional angiogenesis and inflammation occurring in adipose tissue in obesity may promote tumor progression, resistance to chemotherapy, and targeted therapies such as anti‐angiogenic and immune therapies are discussed.
Abstract: With the current epidemic of obesity, a large number of patients diagnosed with cancer are overweight or obese. Importantly, this excess body weight is associated with tumor progression and poor prognosis. The mechanisms for this worse outcome, however, remain poorly understood. We review here the epidemiological evidence for the association between obesity and cancer, and discuss potential mechanisms focusing on angiogenesis and inflammation. In particular, we will discuss how the dysfunctional angiogenesis and inflammation occurring in adipose tissue in obesity may promote tumor progression, resistance to chemotherapy, and targeted therapies such as anti-angiogenic and immune therapies. Better understanding of how obesity fuels tumor progression and therapy resistance is essential to improve the current standard of care and the clinical outcome of cancer patients. To this end, we will discuss how an anti-diabetic drug such as metformin can overcome these adverse effects of obesity on the progression and treatment resistance of tumors.
TL;DR: Embryonic fibroblasts are highly heterogeneous and exhibit anatomic and developmental variation that has both practical consequences for the interpretation of experimental results and theoretical implications for the nature and organization of metazoan organisms.
Abstract: Analysis of embryonic fibroblasts from GFP reporter mice indicates that the fibroblast cell type harbors a large collection of developmentally and phenotypically heterogeneous subtypes. Some of these cells exhibit multipotency, whereas others do not. Multiparameter flow cytometry analysis shows that a large number of distinct populations of fibroblast-like cells can be found in cultures initiated from different embryonic organs, and cells sorted according to their surface phenotype typically retain their characteristics on continued propagation in culture. Similarly, surface phenotypes of individual cloned fibroblast-like cells exhibit significant variation. The fibroblast cell class appears to contain a very large number of denumerable subtypes.
01 Jan 2016
TL;DR: Experiments in mice with a constitutively active PEGylated fluorescent imaging probe support a model where tumor-selective probe distribution is a determinant of increased fluorescence in cancer, and suggest that the tumor specificity of protease-activated imaging probes, such as LUM015, is dependent on both biodistribution and enzyme activity.
TL;DR: Dual anti-angiogenic therapy has the potential to overcome resistance to anti-VEGF therapy and confer clinical benefits in GBM patients through vascular and immuno-modulatory effects.
Abstract: OBJECTIVE: We aimed to enhance the efficacy of anti-VEGF therapy in glioblastoma (GBM) through additional inhibition of Angiopoietin-2 (Ang-2), a potential mediator of resistance to antiangiogenic therapy using VEGF inhibition. INTRODUCTION: Glioblastoma (GBM) is a uniformly lethal primary brain tumor affecting more than 12.000 patients every year in the US alone. The standard therapy regimen for this highly angiogenic tumor entity comprises maximal safe resection and chemoradiation with temozolomide. The addition of antiangiogenic (anti-VEGF) therapy to the standard of care regimen improved progression-free survival, but failed to improve overall survival of GBM patients. Preclinical and clinical data suggest that resistance to anti-VEGF therapy in GBM is mediated by Ang-2, making this pathway a potential target. EXPERIMENTAL DESIGN: We tested the effect of dual Ang-2/VEGF blockade with A2V on mouse survival using a syngeneic (Gl261) model and a human xenograft (MGG8) model, compared to anti-VEGF antibody therapy (B20). In addition, we used blood-based Gaussian Luciferase (GLUC) assays, immunohistochemistry and flow cytometry to measure changes in tumor growth, microvessel density (MVD), and immune microenvironment, respectively. RESULTS: Gl261 tumors have a highly abnormal tumor vasculature. In this model, treatment with A2V reduced MVD compared to B20. The decrease in MVD was due to a reduction in pericyte-low tumor vessels, while pericyte-high vessels were unaffected. These vascular changes were accompanied by reduced tumor burden and enhanced survival. Interestingly, in the MGG8 tumors, which have a vasculature similar to the normal brain, we detected no change in MVD after A2V treatment. Nevertheless, we found a reduced tumor burden and prolonged animal survival in the MGG8 model. Since vascular normalization may impact immune cell infiltration and function in tumors, we next evaluated these cell populations. We found that A2V therapy reduced pro-tumor M2 polarization of macrophages and microglia and reprogrammed these cells toward the M1 phenotype in both the Gl261 and MGG8 models. Collectively, our data indicate that therapy-induced anti-tumor immunity is mediated by M1-type macrophages but not by T-cell infiltration or function. CONCLUSION: Dual Ang-2/VEGF therapy with A2V reprogrammed macrophages and microglia from pro-tumor M2 toward the anti-tumor M1 phenotype in two GBM models, in addition to normalizing vasculature in tumors with abnormal vessels. These data indicate that dual anti-angiogenic therapy has the potential to overcome resistance to anti-VEGF therapy and confer clinical benefits in GBM patients through vascular and immuno-modulatory effects. Citation Format: Jonas Kloepper, Lars Riedemann, Zohreh Amoozgar, Giorgio Seano, Katharina H. Susek, Veronica Yu, Nisha Dalvie, Robin L. Amelung, Meenal Datta, Jonathan W. Song, Vasileios Askoxylakis, Jennie W. Taylor, Christine Lu-Emerson, Ana Batista, Nathaniel D. Kirkpatrick, Keehoon Jung, Matija Snuderl, Alona Muzikansky, Kay G. Stubenrauch, Oliver Krieter, Hiroaki Wakimoto, Lei Xu, Lance L. Munn, Dan G. Duda, Dai Fukumura, Tracy T. Batchelor, Rakesh K. Jain. Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-347.
TL;DR: MRI using FDA-approved MNPs provides a noninvasive, translatable means of assaying microvascular parameters induced by losartan in pancreatic cancer and PET measurements demonstrated thatLosartan significantly increased the uptake of 18F-5FU.
TL;DR: In this article, a coherent laser beam illuminates the specimen and a high-speed camera acquires the time-varying speckle images, from which the frequency-dependent viscoelastic modulus, g2(t), is deduced.
Abstract: Natural and synthetic hydrogel scaffolds exhibit distinct viscoelastic properties at various length scales and deformation rates. Laser Speckle Rheology (LSR) offers a novel, non-contact optical approach for evaluating the frequency-dependent viscoelastic properties of hydrogels. In LSR, a coherent laser beam illuminates the specimen and a high-speed camera acquires the time-varying speckle images. Cross-correlation analysis of frames returns the speckle intensity autocorrelation function, g2(t), from which the frequency-dependent viscoelastic modulus, G*(ω), is deduced. Here, we establish the capability of LSR for evaluating the viscoelastic properties of hydrogels over a large range of moduli, using conventional mechanical rheometry and atomic force microscopy (AFM)-based indentation as reference-standards. Results demonstrate a strong correlation between |G*(ω)| values measured by LSR and mechanical rheometry (r = 0.95, p 0.08) over a large range (47 Pa – 36 kPa). In addition, |G*(ω)| values measured by LSR correlate well with indentation moduli, E, reported by AFM (r = 0.92, p < 10−7). Further, spatially-resolved moduli measurements in micro-patterned substrates demonstrate that LSR combines the strengths of conventional rheology and micro-indentation in assessing hydrogel viscoelastic properties at multiple frequencies and small length-scales.
TL;DR: A physiologically based mathematical model of oxygen diffusion and consumption is used to calculate oxygen profiles within the granuloma, assuming Michaelis–Menten kinetics and was able to predict the size of hypoxic and necrotic regions in agreement with experimental results from the animal model.
Abstract: Pulmonary granulomas—the hallmark of Mycobacterium tuberculosis (MTB) infection—are dense cellular lesions that often feature regions of hypoxia and necrosis, partially due to limited transport of oxygen. Low oxygen in granulomas can impair the host immune response, while MTB are able to adapt and persist in hypoxic environments. Here, we used a physiologically based mathematical model of oxygen diffusion and consumption to calculate oxygen profiles within the granuloma, assuming Michaelis–Menten kinetics. An approximate analytical solution—using a priori and newly estimated parameters from experimental data in a rabbit model of tuberculosis—was able to predict the size of hypoxic and necrotic regions in agreement with experimental results from the animal model. Such quantitative understanding of transport limitations can inform future tuberculosis therapeutic strategies that may include adjunct host-directed therapies that facilitate oxygen and drug delivery for more effective treatment.
Patent•
14 Mar 2016TL;DR: In this article, a semiconductor layer including a plurality of inhomogeneous regions is provided, each region has one or more attributes that differ from a material forming the semiconductor layers.
Abstract: A semiconductor layer including a plurality of inhomogeneous regions is provided. Each inhomogeneous region has one or more attributes that differ from a material forming the semiconductor layer. The inhomogeneous regions can include one or more regions configured based on radiation having a target wavelength. These regions can include transparent and/or reflective regions. The inhomogeneous regions also can include one or more regions having a higher conductivity than a conductivity of the radiation-based regions, e.g., at least ten percent higher.
TL;DR: Experimental evidence is provided indicating that mast cells contribute to the increase in vascular permeability for albumin in normal mouse skin after irradiation, and exposure to radiation induces vascular hyperpermeability in a dose-dependent manner.
Abstract: Induction of vascular hyperpermeability is one of the early vascular responses to radiation exposure and is considered to contribute to subsequent fibrosis and tissue injuries. However, the mechanism underlying radiation-induced hyperpermeability has not yet been clearly elucidated. Here, we provide experimental evidence indicating that mast cells contribute to the increase in vascular permeability for albumin in normal mouse skin after irradiation. Vascular permeability in the skin of C3H mice increased after 2, 15 and 50 Gy irradiation, peaked at 24 h after irradiation and gradually decreased thereafter to the baseline level within 3-10 days. Both the extent and duration of hyperpermeability were dose dependent. We found significant degranulation of mast cells in the skin after 15 Gy irradiation. To further investigate the role of mast cells in the radiation-induced increase in vascular permeability, we measured vascular permeability in the skin of mast cell-deficient mice (WW(v)) and their wild-type littermates at 24 h after irradiation. Vascular permeability in WW(v) mice did not change, whereas that in wild-type mice significantly increased after irradiation. There were no appreciable changes in the total tissue levels of vascular endothelial growth factor or endothelial nitric oxide synthase after 15 Gy irradiation and there was no detectable expression of inducible nitric oxide synthase. Collectively, these results show that exposure to radiation induces vascular hyperpermeability in a dose-dependent manner and that mast cells contribute to this process.
TL;DR: Despite the broad range of treatment options currently available, nonadherence remains a significant problem in ADHD and evidence is currently lacking, the availability of new formulations may improve adherence.
Abstract: OBJECTIVE To review currently available formulations and emphasize unmet needs in the pharmacologic management of attention-deficit/hyperactivity disorder (ADHD). DATA SOURCES Publications and clinical trials were identified through PubMed and ClinicalTrials.gov, respectively. A Web-based search identified prescribing information for approved agents for treating ADHD, along with relevant guidelines and diagnostic criteria. STUDY SELECTION The following search terms were used: (1) ADHD or attention-deficit/hyperactivity disorder or ADD or attention deficit hyperactivity disorder and/or (2) amphetamine or methylphenidate or atomoxetine or guanfacine or clonidine. Additional searches were performed using product brand names, and clinical trial was applied as a filter. Relevant studies were only included if published in English-language peer-reviewed journals and if involved agents were currently available (or pursuing approval) in the United States. Reviews of literature prior to 2005 and from 2005 to 2008 have been published previously; therefore, the present search focused on studies published from January 2009 through May 2016. In addition, reference lists of review articles and relevant studies were also examined to help identify additional studies. DATA EXTRACTION A total of 578 publications were identified from the PubMed search, from which 426 publications were initially excluded based on review of the title and abstract. Reasons for exclusion included a focus on comorbid disorders, specific subpopulations, endpoints unrelated to improving ADHD symptomatology (eg, executive function, cognition, substance use), or quality of life measures. A more thorough assessment of the remaining citations, including publications and prescribing information, produced the final 219. RESULTS Pharmacotherapy with stimulant and nonstimulant options is the most common approach for treating ADHD in adults and children. Stimulants are mostly formulated as either tablets or capsules; however, the newer generation includes transdermal patches, oral suspensions (liquids), chewable tablets, and orally disintegrating tablets. Nonstimulants are available in oral capsule (atomoxetine) and tablet (guanfacine and clonidine) formulations. CONCLUSIONS Despite the broad range of treatment options currently available, nonadherence remains a significant problem in ADHD. While evidence is currently lacking, the availability of new formulations may improve adherence.
TL;DR: Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels and improves the delivery of nanomedicines in a size-dependent manner.
Abstract: Chauhan VP, Stylianopoulos T, Martin JD, Popovic Z, Chen O, Kamoun WS, Bawendi MG, Fukumura D, Jain RK. 2012. Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner. Nat Nanotechnol 7: 383–388. Chauhan VP, Martin JD, Liu H, Lacorre DA, Jain SR, Kozin SV, Stylianopoulos T, Mousa AS, Han X, Adstamongkonkul P, et al. 2013. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat Commun 4: 2516.
TL;DR: Hi-MELASQOL is a reliable and validated tool to measure the quality of life in Indians with melasma and is highly, positively and significantly correlated.
Abstract: Background: Melasma, which is fairly common in Indians, causes significant emotional and psychological impact. A Hindi instrument would be useful to assess the impact of melasma on the quality of life in Indian patients. Objective: To create a semantic equivalent of the original MELASQOL questionnaire in Hindi and validate it. Methods: A Hindi adaptation of the original MELASQOL (Hi-MELASQOL) was prepared using previously established guidelines. After pre-testing, the Hi-MELASQOL questionnaire was administered to 100 women with melasma visiting the out-patient registration counter of Safdarjung Hospital, Delhi. These women were also administered a Hindi equivalent of the Health Related Quality of Life (HRQOL) questionnaire. Melasma area severity index (MASI) of all the participants was calculated. Results: The mean MASI score was 20.0 ± 7.5 and Hi-MELASQOL score was 37.19 ± 18.15; both were highly, positively and significantly correlated. Reliability analysis showed satisfactory results. Physical health, emotional well-being and social life were the most adversely affected life domains. Limitations: It was a single-center study and the number of patients studied could have been larger. Conclusion: Hi-MELASQOL is a reliable and validated tool to measure the quality of life in Indians with melasma.
Patent•
16 Dec 2016TL;DR: In this paper, the authors provided polymers, pH-sensitive polymers and/or linkers; conjugates comprising polymers or linkers, optionally coupled to one or more agents and targeting moieties; and particles (e.g., nanoparticles comprising the aforesaid polymers/linkers/conjugates).
Abstract: Provided herein are polymers, pH-sensitive polymers and/or linkers; conjugates comprising said polymers and/or linkers, optionally, coupled to one or more agents and/or targeting moieties; and particles (e.g., nanoparticles comprising the aforesaid polymers, linkers and/or conjugates), which can be used to enhance the delivery and/or efficacy of one or more agents in a subject.
TL;DR: A novel mechanism of astrocyte-carcinoma interaction is identified and vulnerabilities therein are exploited to slow brain metastatic growth in pre-clinical models.
Abstract: Astrocytes are emerging as essential regulators of brain metastasis progression. In a current issue of Nature, Chen et al. identify a novel mechanism of astrocyte-carcinoma interaction and exploit vulnerabilities therein to slow brain metastatic growth in pre-clinical models.
TL;DR: Human data is presented demonstrating that adding matrix-depleting anti-hypertensives, safe and inexpensive drugs with decades of use, improve vascular function in glioblastoma patients receiving anti-cancer therapy.
Abstract: Introduction: Impaired tumor perfusion is associated with poor drug delivery, hypoxia and metastatic behavior that effectively make cancers difficult to treat [1]. A main driver of impaired perfusion in permeable and impermeable tumor vessels is solid stress caused by proliferating tumor cells and the extracellular matrix that squeeze vessels shut [2]. Here, we demonstrate improved vascular function in glioblastoma patients who receive hypertension treatments with an anti-cancer cell, matrix-depleting effect as part of anti-angiogenic therapy. Methods: We retrospectively assessed data from 40 patients with newly diagnosed glioblastomas (nGBM) and 30 with recurrent glioblastomas (rGBM) receiving cediranib, an oral pan-VEGFR inhibitor, with- (NCT00662506) and without (NCT00305656) chemoradiation, respectively. After cediranib onset, for nGBM, 12/40 patients received matrix-depleting angiotensin II receptor blockers (Valsartan), β1 receptor antagonists (Atenolol) or angiotensin-converting enzyme inhibitors (Lisinopril), while 8/40 patients received non-depleting calcium antagonists (Norvasc, Amlodipine) [3, 4]. For rGBM, 15/30 patients received Atenolol and 7/30 patients Norvasc. Perfusion and vessel caliber MRI were performed at baseline and repeated weekly (nGBM) or monthly (rGBM) [5, 6]. Tumor values were normalized to healthy tissue to account for patient-level systemic effects and variations in hypertension. Results: In the total tumor bed (enhancing + edematous regions), the matrix-depleting alternatives significantly improved the perfused vessel fraction (% of tumor values >½ the value of healthy tissue) from 81% to 93% in nGBM (Wilcoxon: P Conclusion: In line with theoretical [7] and pre-clinical [3] findings, we here present human data demonstrating that adding matrix-depleting anti-hypertensives, safe and inexpensive drugs with decades of use, improve vascular function in glioblastoma patients receiving anti-cancer therapy. Vascular MRI can help refine matrix-depleting drugs by directly assessing mechanisms of action in vivo. References: 1: Science 2005; 307, 58-62 2: PNAS 2012; 109, 15101-8 3: Nat Commun 2013; 4, 2516 4: Blood Press 2006; 15, 198-206 5: PNAS 2013; 110, 19059-64 6: Nat Med 2013; 19, 1178-83 7: PNAS 2013;110:18632-37 Citation Format: Kyrre E. Emblem, Elizabeth R. Gerstner, Gregory Sorensen, Bruce R. Rosen, Patrick Y. Wen, Tracy T. Batchelor, Rakesh K. Jain. Matrix-depleting anti-hypertensives decompress tumor blood vessels and improve perfusion in patients with glioblastomas receiving anti-angiogenic therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3975.
TL;DR: A combined therapeutic strategy is suggested that reduces co-option in mice and increases resistance to bevacizumab, an anti-vascular endothelial growth factor-A antibody, in patients with liver metastases.
Abstract: A recent study confirms an association between vessel co-option and resistance to bevacizumab, an anti-vascular endothelial growth factor-A (VEGFA) antibody, in patients with liver metastases. The authors suggest a combined therapeutic strategy that reduces co-option in mice.
TL;DR: The primary aim of this study was to evaluate the changes in circulating immune cell populations in patients enrolled in a phase II study of cabozantinib (cabo), an inhibitor of multiple receptor tyrosine kinases.
Abstract: 1093Background: We evaluated the changes in circulating immune cell populations in patients enrolled in a phase II study of cabozantinib (cabo), an inhibitor of multiple receptor tyrosine kinases, ...
TL;DR: The findings show that telmisartan reduces the viability of PDAC cells with a mesenchymal morphology and low expression of PPARγ, inhibits PDAC growth and improves the survival of mice.
Abstract: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer with a 5-year survival rate of less than 5%. PDAC is highly resistant to chemotherapy, which impels search for novel approaches for treatment. Our group has previously shown in PDAC models that the angiotensin II type 1 receptor (AT1R) blocker losartan decreases desmoplasia and solid stress, which enhances blood flow, and improves the delivery and effectiveness of cytotoxic agents (Chauhan et al, Nature Comm 2013). In contrast to losartan, which had no effects on the growth of primary PDAC, we recently found that the AT1R blocker telmisartan significantly reduces the growth of PDAC. In addition to inhibiting AT1R activity telmisartan is also a partial agonist of Peroxisome Proliferator Activated Receptor γ (PPARγ). We determined in a panel of PDAC cell lines the effects of telmisartan on cellular viability. Our findings suggest that the sensitivity to telmisartan treatment correlates with low steady-state expression of PPARγ and a mesenchymal morphology. Furthermore, telmisartan induced a transcriptional profile distinct from the response to the direct PPARγ agonist pioglitazone. In support of our correlative results, the genetic knockdown of PPARγ increased the sensitivity to telmisartan and stimulated epithelial to mesenchymal transition (e.g. decreased expression of E-cadherin, increased expression of the mesenchymal markers Snail and N-cadherin). We also tested the effects of telmisartan in orthotopically implanted and genetically engineered mouse models of PDAC. Telmisartan inhibited the growth of primary tumors, decreased the incidence of metastasis and improved mice survival. In summary, our findings show that telmisartan reduces the viability of PDAC cells with a mesenchymal morphology and low expression of PPARγ, inhibits PDAC growth and improves the survival of mice. Citation Format: Jelena Grahovac, Shiwei Han, Hao Liu, Rakesh Jain, Yves Boucher.{Authors}. The angiotensin receptor blocker telmisartan inhibits the growth of pancreatic ductal adenocarcinoma and improves survival. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B41.
TL;DR: This exciting finding provides another rationale to normalize the tumor vasculature to alleviate hypoxia and its consequences, and may be through epigenetic regulation of gene expression by the ten-eleven translocation (TET) methylcytosine dioxygenases.
Abstract: As solid tumors grow, regions within the tumors often experience a deficit in oxygen, known as hypoxia. Hypoxia results from an imbalance in oxygen supply and demand. There is an increase in oxygen demand as cells proliferate or get recruited to build the tumor biomass, while oxygen supply becomes limited as the blood vessels within the growing tumor are absent and/or become abnormal in their structure and function (1,2). In addition to causing cell death, hypoxia can also promote tumor progression, immunosuppression, and treatment resistance. Indeed, tumor hypoxia is associated with poor patient outcome (3). This somewhat counter-intuitive relationship is, in part, due to the ability of tumors to adapt to and evolve in oxygen- and nutrient-deficient microenvironments. A recent report by Thienpont et al . demonstrated that one such mechanism may be through epigenetic regulation of gene expression by the ten-eleven translocation (TET) methylcytosine dioxygenases (4). This exciting finding provides another rationale to normalize the tumor vasculature to alleviate hypoxia and its consequences.
14 Mar 2016
TL;DR: The isolation and screening of newly isolated potent fungal strain as Aspergillus niger RKJP under solid state fermentation for production of cellulase enzyme consisting of all the three components endoglucanase, cellobiohydrase & glucosidase are highlighted.
Abstract: The present research work highlights the isolation and screening of newly isolated potent fungal strain as Aspergillus niger RKJP under solid state fermentation for production of cellulase enzyme consisting of all the three components endoglucanase, cellobiohydrase & glucosidase. Further the studies were undertaken on the optimization of physiological and nutritional culture conditions in respect of pH , incubation time, temperature and moisture ratio (solid: liquid) for production of higher activity of cellulase enzyme consisting of endoglucanase, cellobiohydrolase & glucosidase in synergistic ratio for complete saccharification of pretreated rice straw to fermentable sugars. Among various carbon & nitrogen sources used, wheat bran and peptone yielded higher cellulase enzyme activity. Supplementation of surfactants such as Tween- 80 with wheat bran further enhanced the production of components endoglucanase (30.14 IU/gds), glucosidase (61.24IU/gds) and cellobiohydrase (6.13IU/gds). The cellulase enzyme thus produced was evaluated for saccharification of pretreated rice straw. The results were highly encouraging while achieving a saccharification efficiency of more than 85%.