Showing papers by "Rakesh K. Jain published in 2015"

Role of vascular density and normalization in response to neoadjuvant bevacizumab and chemotherapy in breast cancer patients

Abstract: Preoperative bevacizumab and chemotherapy may benefit a subset of breast cancer (BC) patients. To explore potential mechanisms of this benefit, we conducted a phase II study of neoadjuvant bevacizumab (single dose) followed by combined bevacizumab and adriamycin/cyclophosphamide/paclitaxel chemotherapy in HER2-negative BC. The regimen was well-tolerated and showed a higher rate of pathologic complete response (pCR) in triple-negative (TN)BC (11/21 patients or 52%, [95% confidence interval (CI): 30,74]) than in hormone receptor-positive (HR)BC [5/78 patients or 6% (95%CI: 2,14)]. Within the HRBCs, basal-like subtype was significantly associated with pCR (P = 0.007; Fisher exact test). We assessed interstitial fluid pressure (IFP) and tissue biopsies before and after bevacizumab monotherapy and circulating plasma biomarkers at baseline and before and after combination therapy. Bevacizumab alone lowered IFP, but to a smaller extent than previously observed in other tumor types. Pathologic response to therapy correlated with sVEGFR1 postbevacizumab alone in TNBC (Spearman correlation 0.610, P = 0.0033) and pretreatment microvascular density (MVD) in all patients (Spearman correlation 0.465, P = 0.0005). Moreover, increased pericyte-covered MVD, a marker of extent of vascular normalization, after bevacizumab monotherapy was associated with improved pathologic response to treatment, especially in patients with a high pretreatment MVD. These data suggest that bevacizumab prunes vessels while normalizing those remaining, and thus is beneficial only when sufficient numbers of vessels are initially present. This study implicates pretreatment MVD as a potential predictive biomarker of response to bevacizumab in BC and suggests that new therapies are needed to normalize vessels without pruning.

Anti-vascular endothelial growth factor treatment normalizes tuberculosis granuloma vasculature and improves small molecule delivery

Abstract: Tuberculosis (TB) causes almost 2 million deaths annually, and an increasing number of patients are resistant to existing therapies. Patients who have TB require lengthy chemotherapy, possibly because of poor penetration of antibiotics into granulomas where the bacilli reside. Granulomas are morphologically similar to solid cancerous tumors in that they contain hypoxic microenvironments and can be highly fibrotic. Here, we show that TB-infected rabbits have impaired small molecule distribution into these disease sites due to a functionally abnormal vasculature, with a low-molecular-weight tracer accumulating only in peripheral regions of granulomatous lesions. Granuloma-associated vessels are morphologically and spatially heterogeneous, with poor vessel pericyte coverage in both human and experimental rabbit TB granulomas. Moreover, we found enhanced VEGF expression in both species. In tumors, antiangiogenic, specifically anti-VEGF, treatments can “normalize” their vasculature, reducing hypoxia and creating a window of opportunity for concurrent chemotherapy; thus, we investigated vessel normalization in rabbit TB granulomas. Treatment of TB-infected rabbits with the anti-VEGF antibody bevacizumab significantly decreased the total number of vessels while normalizing those vessels that remained. As a result, hypoxic fractions of these granulomas were reduced and small molecule tracer delivery was increased. These findings demonstrate that bevacizumab treatment promotes vascular normalization, improves small molecule delivery, and decreases hypoxia in TB granulomas, thereby providing a potential avenue to improve delivery and efficacy of current treatment regimens.

Lessons From Anti–Vascular Endothelial Growth Factor and Anti–Vascular Endothelial Growth Factor Receptor Trials in Patients With Glioblastoma

Abstract: Treatment of glioblastoma (GBM), the most common primary malignant brain tumor in adults, remains a significant unmet need in oncology Historically, cytotoxic treatments provided little durable benefit, and tumors recurred within several months This has spurred a substantial research effort to establish more effective therapies for both newly diagnosed and recurrent GBM In this context, antiangiogenic therapy emerged as a promising treatment strategy because GBMs are highly vascular tumors In particular, GBMs overexpress vascular endothelial growth factor (VEGF), a proangiogenic cytokine Indeed, many studies have demonstrated promising radiographic response rates, delayed tumor progression, and a relatively safe profile for anti-VEGF agents However, randomized phase III trials conducted to date have failed to show an overall survival benefit for antiangiogenic agents alone or in combination with chemoradiotherapy These results indicate that antiangiogenic agents may not be beneficial in unselected

Using tumour phylogenetics to identify the roots of metastasis in humans

Abstract: The routes and timing of metastatic dissemination during cancer progression remain shrouded in mystery. However, phylogenetic studies are beginning to shed new light on this process and various models have been proposed. In this Review, Kamila Naxerova and Rakesh Jain discuss the hypothesized trajectories of metastasis, and examine the extent to which the current phylogenetic evidence support these models. In addition, the experimental techniques of lineage tracing, their strengths and weaknesses, and future directions for studies using such methods are discussed.

Metformin Reduces Desmoplasia in Pancreatic Cancer by Reprogramming Stellate Cells and Tumor-Associated Macrophages.

Abstract: Background Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic tumor with a dismal prognosis for most patients. Fibrosis and inflammation are hallmarks of tumor desmoplasia. We have previously demonstrated that preventing the activation of pancreatic stellate cells (PSCs) and alleviating desmoplasia are beneficial strategies in treating PDAC. Metformin is a widely used glucose-lowering drug. It is also frequently prescribed to diabetic pancreatic cancer patients and has been shown to associate with a better outcome. However, the underlying mechanisms of this benefit remain unclear. Metformin has been found to modulate the activity of stellate cells in other disease settings. In this study, we examine the effect of metformin on PSC activity, fibrosis and inflammation in PDACs. Methods/Results In overweight, diabetic PDAC patients and pre-clinical mouse models, treatment with metformin reduced levels of tumor extracellular matrix (ECM) components, in particular hyaluronan (HA). In vitro, we found that metformin reduced TGF-s signaling and the production of HA and collagen-I in cultured PSCs. Furthermore, we found that metformin alleviates tumor inflammation by reducing the expression of inflammatory cytokines including IL-1β as well as infiltration and M2 polarization of tumor-associated macrophages (TAMs) in vitro and in vivo. These effects on macrophages in vitro appear to be associated with a modulation of the AMPK/STAT3 pathway by metformin. Finally, we found in our preclinical models that the alleviation of desmoplasia by metformin was associated with a reduction in ECM remodeling, epithelial-to-mesenchymal transition (EMT) and ultimately systemic metastasis. Conclusion Metformin alleviates the fibro-inflammatory microenvironment in obese/diabetic individuals with pancreatic cancer by reprogramming PSCs and TAMs, which correlates with reduced disease progression. Metformin should be tested/explored as part of the treatment strategy in overweight diabetic PDAC patients.

Improved tumor vascularization after anti-VEGF therapy with carboplatin and nab-paclitaxel associates with survival in lung cancer

Abstract: Addition of anti-VEGF antibody therapy to standard chemotherapies has improved survival and is an accepted standard of care for advanced non–small cell lung cancer (NSCLC). However, the mechanisms by which anti-VEGF therapy increases survival remain unclear. We evaluated dynamic CT-based vascular parameters and plasma cytokines after bevacizumab alone and after bevacizumab plus chemotherapy with carboplatin and nab-paclitaxel in advanced NSCLC patients to explore potential biomarkers of treatment response and resistance to this regimen. Thirty-six patients were enrolled in this study. The primary end point was 6-mo progression-free survival rate, which was 74% (95% CI: 57, 97). This regimen has a promising overall response rate of 36% and median time to progression of 8.5 (6.0, 38.7) mo and overall survival of 12.2 (9.6, 44.1) mo. We found that anti-VEGF therapy led to a sustained increase in plasma PlGF, a potential pharmacodynamic marker. We also found that higher levels of soluble VEGFR1 measured before starting bevacizumab with chemotherapy were associated with worse survival, supporting its potential role as biomarker of treatment resistance. Our imaging biomarker studies indicate that bevacizumab-based treatment—while reducing blood flow, volume, and permeability in the overall population—may be associated with improved survival in patients with improved tumor vasculature and blood perfusion after treatment. This hypothesis-generating study supports the notion that excessively decreasing vascular permeability and pruning/rarefaction after bevacizumab therapy may negatively impact the outcome of combination therapy in NSCLC patients. This hypothesis warrants further dose-titration studies of bevacizumab to examine the dose effect on tumor vasculature and treatment efficacy.

Quantum dot/antibody conjugates for in vivo cytometric imaging in mice

Abstract: Multiplexed, phenotypic, intravital cytometric imaging requires novel fluorophore conjugates that have an appropriate size for long circulation and diffusion and show virtually no nonspecific binding to cells/serum while binding to cells of interest with high specificity. In addition, these conjugates must be stable and maintain a high quantum yield in the in vivo environments. Here, we show that this can be achieved using compact (∼15 nm in hydrodynamic diameter) and biocompatible quantum dot (QD) -Ab conjugates. We developed these conjugates by coupling whole mAbs to QDs coated with norbornene-displaying polyimidazole ligands using tetrazine–norbornene cycloaddition. Our QD immunoconstructs were used for in vivo single-cell labeling in bone marrow. The intravital imaging studies using a chronic calvarial bone window showed that our QD-Ab conjugates diffuse into the entire bone marrow and efficiently label single cells belonging to rare populations of hematopoietic stem and progenitor cells (Sca1+c-Kit+ cells). This in vivo cytometric technique may be useful in a wide range of structural and functional imaging to study the interactions between cells and between a cell and its environment in intact and diseased tissues.

Micelle-Encapsulated Quantum Dot-Porphyrin Assemblies as in Vivo Two-Photon Oxygen Sensors.

Abstract: Micelles have been employed to encapsulate the supramolecular assembly of quantum dots with palladium(II) porphyrins for the quantification of O2 levels in aqueous media and in vivo. Forster resonance energy transfer from the quantum dot (QD) to the palladium porphyrin provides a means for signal transduction under both one- and two-photon excitation. The palladium porphyrins are sensitive to O2 concentrations in the range of 0–160 Torr. The micelle-encapsulated QD-porphyrin assemblies have been employed for in vivo multiphoton imaging and lifetime-based oxygen measurements in mice with chronic dorsal skinfold chambers or cranial windows. Our results establish the utility of the QD-micelle approach for in vivo biological sensing applications.

Blockade of MMP14 Activity in Murine Breast Carcinomas: Implications for Macrophages, Vessels, and Radiotherapy

Abstract: Matrix metalloproteinases (MMPs) facilitate cancer progression (1–3). However, broad-spectrum MMP inhibitors failed in part because MMPs mediate both pro- and anticancer effects (4–7) and because off-target, dose-limiting toxicity impeded efficacy (7). To counter these deficiencies, agents targeting specific MMPs have been developed. For breast cancer (BC), MMP14 (membrane type 1-MMP; MT1-MMP) is an especially attractive target (2,8). Genetic knockdown of MMP14 in BC cells impedes their migration and metastases but does not affect their in vitro viability or primary tumor growth (3,8). In contrast, antibody inhibition—which blocks both cancer and stromal MMP14 activity—slows primary tumor growth (9,10). Indeed, a considerable number of reactive stromal cells also express MMP14 (2), illustrating the potential importance of stromal MMP14. MMP14 facilitates angiogenesis (11–13), and MMP14 blockade can inhibit tumor angiogenesis (9,10). Various antiangiogenic agents, however, can also transiently normalize the tumor vasculature, improving tumor perfusion and oxygenation, leading to enhanced efficacy of chemo- and/or radiation-therapy (14–16). In preclinical models, blockade of MMP14 could enhance the response to cytotoxic therapies (9,10). These findings prompted us to determine a potential improvement in tumor vascular function by MMP14 blockade. The antiangiogenic effect of MMP14 inhibition is thought to result from reduced activation of MMP2 by MMP14 (9). However, other MMP14 targets have not been studied, including transforming growth factor β (TGFβ), a mediator of vascular response and a potent immunosuppressor. TGFβ is associated with poor clinical outcome in BC (17). TGFβ has proangiogenic activities and mediates vessel stabilization (18–20). TGFβ inhibitors increase antitumor immunity associated with increasing interferon (IFN)-γ and granzyme B production from natural killer (NK) cells and cytotoxic CD8+ T cells, reducing T regulatory cells, and shifting macrophages toward an inducible nitric oxide synthase (iNOS)–expressing antitumor M1-like phenotype and away from tumor-supportive M2-type (21–27). In this study we investigated if DX-2400 (9), a highly selective MMP14 inhibitory antibody, could decrease TGFβ levels and alter the macrophage phenotype in tumors. We also aimed to determine if DX-2400 could improve tumor vessel function and thus provide additional benefits when combined with radiation therapy.

Investigation of the Lack of Angiogenesis in the Formation of Lymph Node Metastases

Abstract: Background To date, antiangiogenic therapy has failed to improve overall survival in cancer patients when used in the adjuvant setting (local-regional disease with no detectable systemic metastasis). The presence of lymph node metastases worsens prognosis, however their reliance on angiogenesis for growth has not been reported. Methods Here, we introduce a novel chronic lymph node window (CLNW) model to facilitate new discoveries in the growth and spread of lymph node metastases. We use the CLNW in multiple models of spontaneous lymphatic metastases in mice to study the vasculature of metastatic lymph nodes (n = 9-12). We further test our results in patient samples (n = 20 colon cancer patients; n = 20 head and neck cancer patients). Finally, we test the ability of antiangiogenic therapy to inhibit metastatic growth in the CLNW. All statistical tests were two-sided. Results Using the CLNW, we reveal the surprising lack of sprouting angiogenesis during metastatic growth, despite the presence of hypoxia in some lesions. Treatment with two different antiangiogenic therapies showed no effect on the growth or vascular density of lymph node metastases (day 10: untreated mean = 1.2%, 95% confidence interval [CI] = 0.7% to 1.7%; control mean = 0.7%, 95% CI = 0.1% to 1.3%; DC101 mean = 0.4%, 95% CI = 0.0% to 3.3%; sunitinib mean = 0.5%, 95% CI = 0.0% to 1.0%, analysis of variance P = .34). We confirmed these findings in clinical specimens, including the lack of reduction in blood vessel density in lymph node metastases in patients treated with bevacizumab (no bevacizumab group mean = 257 vessels/mm(2), 95% CI = 149 to 365 vessels/mm(2); bevacizumab group mean = 327 vessels/mm(2), 95% CI = 140 to 514 vessels/mm(2), P = .78). Conclusion We provide preclinical and clinical evidence that sprouting angiogenesis does not occur during the growth of lymph node metastases, and thus reveals a new mechanism of treatment resistance to antiangiogenic therapy in adjuvant settings. The targets of clinically approved angiogenesis inhibitors are not active during early cancer progression in the lymph node, suggesting that inhibitors of sprouting angiogenesis as a class will not be effective in treating lymph node metastases.

Too Fit To Fracture: outcomes of a Delphi consensus process on physical activity and exercise recommendations for adults with osteoporosis with or without vertebral fractures

Abstract: Summary An international consensus process resulted in exercise and physical activity recommendations for individuals with osteoporosis. Emphasis was placed on strength, balance, and postural alignment. Rather than providing generic restrictions, activity should be encouraged while considering impairments, fracture risk, activity history, and preference, and guidance on spine sparing techniques should be provided.

An orthotopic mouse model of hepatocellular carcinoma with underlying liver cirrhosis

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

A Multicenter, Phase II, Randomized, Noncomparative Clinical Trial of Radiation and Temozolomide with or without Vandetanib in Newly Diagnosed Glioblastoma Patients

Abstract: Purpose: Vandetanib, a tyrosine kinase inhibitor of KDR (VEGFR2), EGFR, and RET, may enhance sensitivity to chemotherapy and radiation. We conducted a randomized, non-comparative, phase II study of radiation (RT) and temozolomide (TMZ) with or without vandetanib in patients with newly diagnosed glioblastoma (GBM). Experimental Design: We planned to randomize a total of 114 newly diagnosed GBM patients in a ratio of 2:1 to standard RT and TMZ with (76 patients) or without (38 patients) vandetanib 100 mg daily. Patients with age ≥ 18, Karnofsky performance status (KPS) ≥ 60, and not on enzyme-inducing antiepileptics were eligible. Primary endpoint was median overall survival (OS) from the date of randomization. Secondary endpoints included median progression-free survival (PFS), 12-month PFS, and safety. Correlative studies included pharmacokinetics as well as tissue and serum biomarker analysis. Results: The study was terminated early for futility based on the results of an interim analysis. We enrolled 106 pts (36 in the RT/TMZ arm, 70 in the vandetanib/RT/TMZ arm). Median OS was 15.9 months [95% CI, 11.0 months, 22.5 months] in the RT/TMZ arm and 16.6 months [95% CI, 14.9 months, 20.1 months] in the vandetanib/RT/TMZ (log-rank p=0.75). Conclusions: The addition of vandetanib at a dose of 100 mg daily to standard chemoradiation in patients with newly diagnosed GBM or GS was associated with potential pharmacodynamic biomarker changes and was reasonably well tolerated. However, the regimen did not significantly prolong overall survival compared to the parallel control arm, leading to early termination of the study.

Towards Optimal Design of Cancer Nanomedicines: Multi-stage Nanoparticles for the Treatment of Solid Tumors.

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

Endothelial podosome rosettes regulate vascular branching in tumour angiogenesis

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.

A phase I study of cediranib in combination with cilengitide in patients with recurrent glioblastoma

Abstract: Background Despite being a highly vascularized tumor, glioblastoma response to anti-vascular endothelial growth factor (VEGF) therapy is transient, possibly because of tumor co-option of preexisting blood vessels and infiltration into surrounding brain. Integrins, which are upregulated after VEGF inhibition, may play a critical role in this resistance mechanism. We designed a study of cediranib, a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor, combined with cilengitide, an integrin inhibitor. Methods This phase I study was conducted through the Adult Brain Tumor Consortium in patients with recurrent glioblastoma. Once the maximum tolerated dose was determined, 40 patients enrolled in a dose expansion cohort with 20 being exposed to anti-VEGF therapy and 20 being naive. The primary endpoint was safety. Secondary endpoints included overall survival, proportion of participants alive and progression free at 6 months, radiographic response, and exploratory analyses of physiological imaging and blood biomarkers. Results Forty-five patients enrolled, and no dose toxicities were observed at a dose of cediranib 30 mg daily and cilengitide 2000 mg twice weekly. Complete response was seen in 2 participants, partial response in 2, stable disease in 13, and progression in 21; 7 participants were not evaluable. Median overall survival was 6.5 months, median progression-free survival was 1.9 months, and progression-free survival at 6 months was 4.4%. Plasma-soluble VEGFR2 decreased with treatment and placental growth factor, carbonic anhydrase IX, and SDF1α, and cerebral blood flow increased. Conclusions The combination of cediranib with cilengitide was well tolerated and associated with changes in pharmacodynamic blood and imaging biomarkers. However, the survival and response rates do not warrant further development of this combination.

Anti-VEGF treatment improves neurological function and augments radiation response in NF2 schwannoma model.

Abstract: Hearing loss is the main limitation of radiation therapy for vestibular schwannoma (VS), and identifying treatment options that minimize hearing loss are urgently needed. Treatment with bevacizumab is associated with tumor control and hearing improvement in neurofibromatosis type 2 (NF2) patients; however, its effect is not durable and its mechanism of action on nerve function is unknown. We modeled the effect anti-VEGF therapy on neurological function in the sciatic nerve model and found that it improves neurological function by alleviating tumor edema, which may further improve results by decreasing muscle atrophy and increasing nerve regeneration. Using a cranial window model, we showed that anti-VEGF treatment may achieve these effects via normalizing the tumor vasculature, improving vessel perfusion, and delivery of oxygenation. It is known that oxygen is a potent radiosensitizer; therefore, we further demonstrated that combining anti-VEGF with radiation therapy can achieve a better tumor control and help lower the radiation dose and, thus, minimize radiation-related neurological toxicity. Our results provide compelling rationale for testing combined therapy in human VS.

Glioma Angiogenesis and Perfusion Imaging: Understanding the Relationship between Tumor Blood Volume and Leakiness with Increasing Glioma Grade

Abstract: BACKGROUND AND PURPOSE: The purpose of this study was to investigate imaging correlates to the changes occurring during angiogenesis in gliomas. This was accomplished through in vivo assessment of vascular parameters (relative CBV and permeability surface-area product) and their changing relationship with increasing glioma grade. MATERIALS AND METHODS: Seventy-six patients with gliomas underwent preoperative perfusion CT and assessment of relative CBV and permeability surface-area product. Regression analyses were performed to assess the rate of change between relative CBV and permeability surface-area product and to test whether these differed for distinct glioma grades. The ratio of relative CBV to permeability surface-area product was also computed and compared among glioma grades by using analysis of variance methods. RESULTS: The rate of change in relative CBV with respect to permeability surface-area product was highest for grade II gliomas followed by grade III and then grade IV (1.64 versus 0.91 versus 0.27, respectively). The difference in the rate of change was significant between grade III and IV (P = .003) and showed a trend for grades II and IV (P = .098). Relative CBV/permeability surface-area product ratios were the highest for grade II and lowest for grade IV. The pair-wise difference among all 3 groups was significant (P CONCLUSIONS: There is an increase in relative CBV more than permeability surface-area product in lower grade gliomas, whereas in grade III and especially grade IV gliomas, permeability surface-area product increases much more than relative CBV. The rate of change of relative CBV with respect to permeability surface-area product and relative CBV/permeability surface-area product ratio can serve as an imaging correlate to changes occurring at the tumor microvasculature level.

Vascular diseases await translation of blood vessels engineered from stem cells

Abstract: The discovery of human induced pluripotent stem cells (hiPSCs) might pave the way toward a long-sought solution for obtaining sufficient numbers of autologous cells for tissue engineering. Several methods exist for generating endothelial cells or perivascular cells from hiPSCs in vitro for use in the building of vascular tissue. We discuss current developments in the generation of vascular progenitor cells from hiPSCs and the assessment of their functional capacity in vivo, opportunities and challenges for the clinical translation of engineered vascular tissue, and modeling of vascular diseases using hiPSC-derived vascular progenitor cells.

Energy audit of residential buildings to gain energy efficiency credits for LEED certification

Abstract: Energy audit is a primary study that identifies energy use among various services and provides opportunities for energy conservation. Energy auditing is an integral part of energy conservation and energy management is also part of conservation. It is an initial study in establishing an energy management programme. This paper reviews the initial attempts to understand the energy consumption patterns in a residential building and to reduce the energy consumptions. A case study is included to investigate the reduction in energy consumption per unit in order to make building energy efficient. A feasibility study is done to check the increase in construction cost to gain energy efficiency credits for LEED certification. Payback calculations are done to understand the Investments required and hence feasibility is confirmed.

Novel AlInN/GaN integrated circuits operating up to 500 °C

Abstract: 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 enables IC fast operation in a broad temperature range; (2) heterostructure field effect transistor approach t 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 enable high temperature operation. The feasibility of the developed technology was confirmed by fabrication and testing of the high temperature inverter and differential amplifier ICs using AlInN/GaN heterostructures. The developed ICs showed stable performance with unit-gain bandwidth above 1 MHz and internal response time 45 ns at temperatures as high as 500 °C.

Semiconductor heterostructure with stress management

Abstract: A heterostructure for use in fabricating an optoelectronic device is provided. The heterostructure includes a layer, such as an n-type contact or cladding layer, that includes thin sub-layers inserted therein. The thin sub-layers can be spaced throughout the layer and separated by intervening sub-layers fabricated of the material for the layer. The thin sub-layers can have a distinct composition from the intervening sub-layers, which alters stresses present during growth of the heterostructure.

Targeting the Tumor Microenvironment to Enhance Pediatric Brain Cancer Treatment.

Abstract: Strategies targeting the microenvironment of pediatric brain cancers have the potential to improve the efficacy of standard and genome-based molecular therapeutics. These strategies also have the potential of helping resolve many of the challenges associated with developing new drugs and running clinical trials for relatively small pediatric brain tumor population. Disrupting vital paracrine and physical interactions between cancer cells and surrounding stroma, targeting and normalizing the abnormal tumor vasculature, and/or inducing antitumor immunity represent some of the most promising approaches. A comprehensive characterization of the pediatric brain tumor microenvironment's composition and function and its modulation by chemoradiation and molecularly targeted therapies is warranted to develop and effectively implement these approaches.