Co-targeting HGF/cMET Signaling with MEK Inhibitors in Metastatic Uveal Melanoma.

Patients with metastatic uveal melanoma usually die within 1 year of diagnosis, emphasizing an urgent need to develop new treatment strategies. The liver is the most common site of metastasis. Mitogen-activated protein kinase kinase (MEK) inhibitors improve survival in V600 BRAF-mutated cutaneous melanoma patients but have limited efficacy in patients with uveal melanoma. Our previous work showed that hepatocyte growth factor (HGF) signaling elicits resistance to MEK inhibitors in metastatic uveal melanoma. In this study, we demonstrate that expression of two BH3-only family proteins, Bim-EL and Bmf, contributes to HGF-mediated resistance to MEK inhibitors. Targeting HGF/cMET signaling with LY2875358, a neutralizing and internalizing anti-cMET bivalent antibody, and LY2801653, a dual cMET/RON inhibitor, overcomes resistance to trametinib provided by exogenous HGF and by conditioned medium from primary hepatic stellate cells. We further determined that activation of PI3Kα/γ/δ isoforms mediates the resistance to MEK inhibitors by HGF. Combination of LY2801653 with trametinib decreases AKT phosphorylation and promotes proapoptotic PARP cleavage in metastatic uveal melanoma explants. Together, our data support the notion that selectively blocking cMET signaling or PI3K isoforms in metastatic uveal melanoma may break the intrinsic resistance to MEK inhibitors provided by factors from stromal cells in the liver

A Case of Novel Coronavirus Disease 19 in a Chronic Hemodialysis Patient Presenting with Gastroenteritis and Developing Severe Pulmonary Disease.

Novel coronavirus disease 2019 (COVID-19) is a highly infectious, rapidly spreading viral disease with an alarming case fatality rate up to 5%. The risk factors for severe presentations are concentrated in patients with chronic kidney disease, particularly patients with end-stage renal disease (ESRD) who are dialysis dependent. We report the first US case of a 56-year-old nondiabetic male with ESRD secondary to IgA nephropathy undergoing thrice-weekly maintenance hemodialysis for 3 years, who developed COVID-19 infection. He has hypertension controlled with angiotensin receptor blocker losartan 100 mg/day and coronary artery disease status-post stent placement. During the first 5 days of his febrile disease, he presented to an urgent care, 3 emergency rooms, 1 cardiology clinic, and 2 dialysis centers in California and Utah. During this interval, he reported nausea, vomiting, diarrhea, and low-grade fevers but was not suspected of COVID-19 infection until he developed respiratory symptoms and was admitted to the hospital. Imaging studies upon admission were consistent with bilateral interstitial pneumonia. He was placed in droplet-eye precautions while awaiting COVID-19 test results. Within the first 24 h, he deteriorated quickly and developed acute respiratory distress syndrome (ARDS), requiring intubation and increasing respiratory support. Losartan was withheld due to hypotension and septic shock. COVID-19 was reported positive on hospital day 3. He remained in critical condition being treated with hydroxychloroquine and tocilizumab in addition to the standard medical management for septic shock and ARDS. Our case is unique in its atypical initial presentation and highlights the importance of early testing

Effects Of Race, Socioeconomic Factors On Emergency Management Of Threatened And Early Pregnancy Loss

Our study aims to determine the effects of race, insurance, and hospital characteristics on the management of threatened abortion and early pregnancy loss. In this retrospective cohort study using the National Hospital Ambulatory Medical Care Survey, patient record files from 2002-2010 with diagnoses of threatened abortion, hemorrhage in pregnancy, or incomplete, inevitable, or unspecified spontaneous abortion were examined using logistic regression. Primary outcomes were rates of admission and active management, defined as surgical termination or use of abortifacients misoprostol or Cytotec. Covariates included race/ethnicity, age, insurance, and hospital location, ownership, and metropolitan status. Of 5,882,623 ED visits for threatened abortion and early pregnancy loss, 15% were admitted and 1.3% were actively managed. Compared to white women, black women were 0.83 times as likely to be admitted (95% CI 0.83-0.84), but 4.37 times as likely be actively managed (95% CI 4.25-4.50). Admission was more likely for “Other” women (Asian, Native Hawaiian, Native Alaskan, Native American, mixed race; OR 2.14, 95% CI 2.11-2.17), Medicaid/SCHIP (OR 1.24, 95% CI 1.22-1.25) and Self-pay (OR 1.04, 95% 1.03-1.05) compared to reference groups of white and privately insured women. Historically-marginalized groups, including uninsured, black, and “Other” women, were more likely to be actively managed. Exceptions were Latina (OR 0.84, 95% CI 0.80-0.89) and Medicaid/SCHIP-insured women (OR 0.13, 95% CI 0.12-0.15). Nonwhite women were less likely to be treated for pain, especially Latinas (OR 0.29, 95% CI 0.28-0.29). The etiology of these disparities is complex, but providers may seek to better understand their own preconceptions of patient risk, and to strengthen social support, communication, and shared decision-making

Statistical Analysis, Data Visualization, and Business Intelligence Tools for Electronic Resources in Academic Libraries

Analytics, business intelligence, and data visualization have an increasingly important space in the changing assessment landscape of academic libraries. Today, most academic libraries are spending a significant amount of their total expenditure budget on electronic resources. While they are high-value assets for modern libraries, the expensive annual subscription cost and continuing price increases of e-resources also make them a substantial budgeting burden. It is therefore essential to have a clear statistical view of the trends and patterns in price changes for e-resources and vendors. This paper focuses on three major topics vital for developing such a view: first, the e-resources landscape and the need for evidence-based decision-making, analysis, and reporting; second, the methodology applied in a statistical analysis and data visualization research project, as well as business trends and patterns in the field of libraries’ e-resources; and third, business intelligence tools available for this type of analysis, including low-cost options such as Excel and Redlink, and premium options such as Tableau

The Role of Astrocyte-Secreted Thrombospondin-1 in the Fragile X Mouse Model

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and autism spectrum disorders. The disorder is typically caused by decreased or absent levels of the fragile X mental retardation protein (FMRP) due to a loss-of-function mutation in the fragile X mental retardation 1 (FMR1) gene. Astrocytes are key participants in various aspects of brain development and function, many of which are executed via secreted proteins. Specifically, the astrocyte-secreted matricellular protein thrombospondin-1 (TSP-1) has been highly implicated in the regulation of neuronal synaptogenesis. Previously, we have shown that astrocytes can prevent the abnormal dendrite morphology and dysregulated synapses that characterize FXS. While we have identified that astrocytes affect synapse development in vitro, the role of secreted factors has not been elucidated. Utilizing a Fragile X mouse model and a neuron-astrocyte, non-contact co-culture system, we investigated the contributions of soluble TSP-1 in spine and synapse development. We found that TSP-1 protein levels were reduced in Fmr1 knockout (KO) cultured astrocytes and astrocyte-conditioned media (ACM). TSP-1 levels were also downregulated in the cortex and hippocampus of Fragile X mice in contrast to their wildtype (WT) counterparts. Additionally, Fmr1 KO hippocampal neurons exhibited significant deficits in dendritic spine morphology and excitatory synapse formation following long-term culture. However, all spine and synaptic abnormalities were prevented in the presence of either ACM or a feeder layer derived from WT astrocytes, or following the application of exogenous TSP-1, thereby suggesting a role for soluble glial factors in the formation and maturation of spines and synapses. These findings presented here provide strong evidence for astroglia-derived TSP-1 as a strong promoter of neuronal development in FXS. Therefore, defects in astrocyte function and secreted molecules during early development may contribute to the abnormal neurobiology in FXS.DissertationDoctor of Philosophy (PhD

Structural optimisation of discontinuous carbon fibre composites

There has been a growing interest in using discontinuous carbon fibre composites for semi-structural applications within the automotive industry. The main advantages of discontinuous fibres are low material costs, low wastage and low touch labour compared with processes using carbon fibre textiles. Directed Carbon Fibre Preforming (DCFP) is an automated process for producing complex 3D preforms for liquid moulding. DCFP offers the potential for producing highly optimised structures, with local control over tow size, fibre length and volume fraction within the component. The execution of this is challenging however, as confidence in the current library of material properties is low and existing structural optimisation packages only consider a very limited number of design variables, which are restricted to more conventional composite materials. This thesis aims to establish a structural design tool to exploit the design freedom offered by the DCFP process. A large number of parameters associated with the fibre architecture can be controlled to meet a range of design criterions such as performance, weight and cost. The optimisation tool is capable of generating locally varied fibre areal mass and thickness maps that are suitable for manufacture by the robot controlled process. The developed model adopts a multi-scaled finite element approach. Meso-scale simulations are performed to establish size effects in discontinuous fibre composites, to quantify the level of stochastic variability and to determine the representative volume element for a given fibre architecture. A DCFP material database is generated to facilitate macro-scale modelling at the component level. The macro-scale model iteratively redistributes material in order to minimise the total strain energy of the model under prescribed loading conditions. The optimised model is segmented into areas of uniform areal mass, where the zone geometries are tailored to achieve representative material properties according to the meso-scale results, whilst ensuring the design is fit for manufacture. An automotive spare wheel well has been chosen as a demonstrator component, enabling two DCFP architectures to be compared against a continuous glass/carbon fibre NCF design. The first case offers a high performance (high specific stiffness) solution and the second offers a low cost option using high filament count tows. Following optimisation, results suggest that a 3K 25mm fibre length DCFP option can achieve a specific stiffness 52% higher than the glass/carbon baseline design, but for 1.33 times higher material cost. Alternatively, the specific stiffness of a 24K 50mm fibre length DCFP is marginally lower than the first option, but still out-performs the baseline for just 67% of the material cost. The structural optimisation method demonstrates that discontinuous fibre composites can compete against continuous fibre counterparts for semi-structural applications

The design of intelligent cookware

Thesis (M. Eng.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2003.Includes bibliographical references (p. 81-82).This thesis investigates the opportunity of teaching people how to cook by analyzing the ingredients' chemical content as they are using them, and the consequent creation of a specific class of context-aware cookware that aids its users. An inquisition on the chemical content of different food and the appropriate electronics for measuring it was done. An instrument, with embedded sensors and intelligence and in the form of a spatula, was created base on the result of the research, and tested to be able to measure salinity, acidity, temperature, and consistency. This tool was used to demonstrate that several ingredients could be measured easily, and recipes as varied as pickles and pancakes could be improved. The work demonstrates the possibility of having intelligence in the kitchen, and examines the pedagogical value of intelligent tools when they are capable of collaborating with and guiding its user. The research also inquires into the field of ubiquitous computing, in which sensors are placed in ordinary objects, and to assess its impact in a domestic environment.by Mansim Connie Cheng.M.Eng

Structural optimisation of discontinuous carbon fibre composites

There has been a growing interest in using discontinuous carbon fibre composites for semi-structural applications within the automotive industry. The main advantages of discontinuous fibres are low material costs, low wastage and low touch labour compared with processes using carbon fibre textiles. Directed Carbon Fibre Preforming (DCFP) is an automated process for producing complex 3D preforms for liquid moulding. DCFP offers the potential for producing highly optimised structures, with local control over tow size, fibre length and volume fraction within the component. The execution of this is challenging however, as confidence in the current library of material properties is low and existing structural optimisation packages only consider a very limited number of design variables, which are restricted to more conventional composite materials. This thesis aims to establish a structural design tool to exploit the design freedom offered by the DCFP process. A large number of parameters associated with the fibre architecture can be controlled to meet a range of design criterions such as performance, weight and cost. The optimisation tool is capable of generating locally varied fibre areal mass and thickness maps that are suitable for manufacture by the robot controlled process. The developed model adopts a multi-scaled finite element approach. Meso-scale simulations are performed to establish size effects in discontinuous fibre composites, to quantify the level of stochastic variability and to determine the representative volume element for a given fibre architecture. A DCFP material database is generated to facilitate macro-scale modelling at the component level. The macro-scale model iteratively redistributes material in order to minimise the total strain energy of the model under prescribed loading conditions. The optimised model is segmented into areas of uniform areal mass, where the zone geometries are tailored to achieve representative material properties according to the meso-scale results, whilst ensuring the design is fit for manufacture. An automotive spare wheel well has been chosen as a demonstrator component, enabling two DCFP architectures to be compared against a continuous glass/carbon fibre NCF design. The first case offers a high performance (high specific stiffness) solution and the second offers a low cost option using high filament count tows. Following optimisation, results suggest that a 3K 25mm fibre length DCFP option can achieve a specific stiffness 52% higher than the glass/carbon baseline design, but for 1.33 times higher material cost. Alternatively, the specific stiffness of a 24K 50mm fibre length DCFP is marginally lower than the first option, but still out-performs the baseline for just 67% of the material cost. The structural optimisation method demonstrates that discontinuous fibre composites can compete against continuous fibre counterparts for semi-structural applications

A functional Notch–survivin gene signature in basal breast cancer

INTRODUCTION: Basal-type, or triple-negative, breast cancer (lacking estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 expression) is a high-risk disease for which no molecular therapies are currently available. We studied genetic signatures of basal breast cancer potentially suitable for therapeutic intervention. METHODS: We analyzed protein expression of the Notch-1 intracellular domain and survivin by immunohistochemistry in a series of basal breast cancer patients. A hierarchical clustering and overall survival analysis was carried out on a microarray mRNA database of 232 breast cancer patients. Fifteen published mRNA datasets containing estrogen receptor-negative or estrogen receptor-positive samples were subjected to meta-analysis for co-segregated gene expression. Experiments of plasmid transfection and gene silencing were carried out in estrogen receptor-negative MDA-MB-231 breast cancer cells. RESULTS: The developmental signaling regulator Notch-1 was highly expressed in breast cancer, compared with normal tissue, and was segregated with basal disease. Higher Notch-1 levels correlated with progressively abbreviated overall survival, and with increased expression of survivin, a tumor-associated cell death and mitotic regulator implicated in stem cell viability. Analysis of Pearson\u27s correlation coefficient indicated that Notch-1 and survivin co-segregated in basal breast cancer. Notch-1 stimulation in MDA-MB-231 cells increased survivin expression, whereas silencing Notch reduced survivin levels. CONCLUSIONS: A Notch-1-survivin functional gene signature is a hallmark of basal breast cancer, and may contribute to disease pathogenesis. Antagonists of Notch and survivin currently in the clinic may be tested as novel molecular therapy for these recurrence-prone patients