Progressive Commemoration: Public Statues of Historical Women in Urban American Cities

Women who made notable accomplishments are underrepresented in commemoration. Some American cities have brought women to the forefront of becoming visible through commemoration in statues. This thesis compares the commemoration of historical women in four different American cities. Stakeholders hold the key to implementing and changing public policy to increase the visibility of women and people of color in public monuments. Cities which lack representation of women and people of color may learn from and follow the efforts of a leading city to achieve lasting and effective change in representing those who historically been underrepresented

Prediction of nitric oxide concentrations during inflammation and carcinogenesis

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2010.Cataloged from PDF version of thesis.Includes bibliographical references (p. 183-204).Nitric oxide is a biological messenger which is synthesized enzymatically throughout the body and which has numerous physiological functions, including roles in blood pressure control, regulation of clotting, and neurotransmission. It is produced also by macrophages as part of the non-specific immune response, and has been shown to be toxic to invasive microorganisms. However, sustained overproduction of NO, as observed with chronic inflammation or infection, may damage the host tissue and has been linked to increased risk for cancer. Nitric oxide may facilitate tumorigenesis or metastasis by influencing tumor-cell proliferation, angiogenesis, or lymphangiogenesis. However, the concentrations of NO in inflamed tissues or during carcinogenesis are largely unknown. The objective of the research in this thesis was to predict NO concentrations in an inflamed colon and a cutaneous metastatic melanoma, two areas where NO has been implicated in the development or progression of disease. Nitric oxide production in the colon has been linked to inflammatory bowel disease (IBD) and increased risk for colon cancer. However, measurements of NO concentration in the inflamed colon have not been available and it is not known what levels of NO are pathophysiological. A computational model, based on anatomical length scales and rates of NO production measured in cell cultures, was developed to predict spatially varying NO concentrations within a colonic crypt under inflammatory conditions. A variety of scenarios were considered, including different spatial distributions of macrophages and a range of possible macrophage and epithelial synthesis rates for NO.(cont.) The results were used to predict the range of NO concentrations (<0.3 tM) and cumulative NO dose (560 [mu]M * min) experienced by a given epithelial cell migrating from the base to the top of the crypt. This first set of predictions was based on literature data on the cellular synthesis and consumption of NO. Knowledge of the rates at which macrophages and epithelial cells synthesize NO is critical for predicting the concentrations of NO and other reactive nitrogen species in colonic crypts during inflammation, and elucidating the linkage between inflammatory bowel disease, NO, and cancer. Macrophage-like RAW264.7 cells, primary bone marrow-derived macrophages (BMDM), and HCT116 colonic epithelial cells were subjected to simulated inflammatory conditions, and rates of formation and consumption were determined for NO, O2, and 02-. Production rates of NO were determined in either of two ways: continuous monitoring of NO concentrations in a closed chamber, with corrections for autoxidation; or NO2- accumulation measurements in an open system, with corrections for diffusional losses of NO. The results obtained using the two methods were in excellent agreement. Rates of NO synthesis (2.3 + 0.6 pmol s-1 106 cells-), NO consumption (1.3 ± 0.3 s-1), and 02 consumption (58.8 ± 17 pmol/s/10 6 cells) for activated BMDM were indistinguishable from those of activated RAW264.7 cells. NO production rates calculated from NO2- accumulation data for HCT1 16 cells infected with Helicobacter cinaedi (3.9 ± 0.1 pmol/s/106 cells) were somewhat greater than those of RAW264.7 macrophages infected under similar conditions (2.6 ± 0.1 pmol/s/106 cells).(cont.) Thus, RAW264.7 cells have nearly identical NO kinetics to primary macrophages, and stimulated epithelial cells are capable of synthesizing NO at rates comparable to macrophages. Using this new cellular data to refine the predictions of the colon model, simulations of NO diffusion and reaction in a crypt during inflammation gave maximum NO concentrations of about 0.2 [mu]M. The presence of iNOS and nitrotyrosine in human metastatic melanoma tumors suggest that NO plays a role in the pathophysiology of metastatic melanomas. However, the concentrations of NO that melanoma cells are exposed to in vivo remains unknown. Cellular rates of NO synthesis and consumption were experimentally determined and used in a reactiondiffusion model to predict NO concentrations in a cutaneous melanoma. NO synthesis by A375 melanoma cells was undetectable using Griess assays. The rate constant for intracellular NO consumption by A375 cells (7.1 ± 1.1 s-1), was determined by monitoring NO concentrations in a closed chamber with corrections for autoxidation and consumption from media-generated 02-. Incorporating NO kinetic data from A375 cells and macrophages into a reaction-diffusion model, NO was found to be localized to the periphery of the melanoma; roughly 90% of the NO synthesized by macrophages is consumed within 30 [mu]m of the tumor edge. Several additional scenarios were modeled, including the effects of varying the volume fraction of macrophages surrounding a melanoma tumor and intratumoral NO synthesis by melanoma cells. As such, a range of NO concentrations were predicted (< 0.2 VM) for the edge of the tumor.(cont.) Our model may offer some insight into the role NO plays in the metastasis of cutaneous melanomas, which occurs primarily through lymphatic spread. At the melanoma edge, NO may inhibit melanoma cell apoptosis, contributing to abnormal tumor growth and invasion of local lymph vessels or NO may act as a lymphangiogenic factor. The colonic crypt model and the cutaneous melanoma model developed in this work provide the first NO concentration predictions for tissues during inflammation. Despite the different geometries and different cell types involved, the maximum values estimated in both cases were - 0.2 [mu]M. The results from this work can be used for predicting intracellular levels of other reactive nitrogen species, and should help guide further studies to understand the mechanisms by which NO contributes to carcinogenesis in IBD and in cutaneous melanomas.by Melanie Pei-Heng Chin.Ph.D

Risk factors for heart failure in patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone methyl

Background: A phase 3 randomized clinical trial was designed to test whether bardoxolone methyl, a nuclear factor erythroid-2–related factor 2 (Nrf2) activator, slows progression to end-stage renal disease in patients with stage 4 chronic kidney disease and type 2 diabetes mellitus. The trial was terminated because of an increase in heart failure in the bardoxolone methyl group; many of the events were clinically associated with fluid retention.&lt;p&gt;&lt;/p&gt; Methods and Results: We randomized 2,185 patients with type 2 diabetes mellitus (T2DM) and stage 4 chronic kidney disease (CKD) (estimated glomerular filtration rate 15 to &lt;30 mL min−1 1.73 m−2) to once-daily bardoxolone methyl (20 mg) or placebo. We used classification and regression tree analysis to identify baseline factors predictive of heart failure or fluid overload events. Elevated baseline B-type natriuretic peptide and previous hospitalization for heart failure were identified as predictors of heart failure events; bardoxolone methyl increased the risk of heart failure by 60% in patients with these risk factors. For patients without these baseline characteristics, the risk for heart failure events among bardoxolone methyl– and placebo-treated patients was similar (2%). The same risk factors were also identified as predictors of fluid overload and appeared to be related to other serious adverse events.&lt;p&gt;&lt;/p&gt; Conclusions: Bardoxolone methyl contributed to events related to heart failure and/or fluid overload in a subpopulation of susceptible patients with an increased risk for heart failure at baseline. Careful selection of participants and vigilant monitoring of the study drug will be required in any future trials of bardoxolone methyl to mitigate the risk of heart failure and other serious adverse events.&lt;p&gt;&lt;/p&gt

Predialysis chronic kidney disease: Evaluation of quality of life in clinic patients receiving comprehensive anemia care

Anemia is common in chronic kidney disease (CKD), and suboptimal management of anemia can lead to serious health complications and poor quality of life

From Plate to Prevention: A Dietary Nutrient-aided Platform for Health Promotion in Singapore

Singapore has been striving to improve the provision of healthcare services to her people. In this course, the government has taken note of the deficiency in regulating and supervising people's nutrient intake, which is identified as a contributing factor to the development of chronic diseases. Consequently, this issue has garnered significant attention. In this paper, we share our experience in addressing this issue and attaining medical-grade nutrient intake information to benefit Singaporeans in different aspects. To this end, we develop the FoodSG platform to incubate diverse healthcare-oriented applications as a service in Singapore, taking into account their shared requirements. We further identify the profound meaning of localized food datasets and systematically clean and curate a localized Singaporean food dataset FoodSG-233. To overcome the hurdle in recognition performance brought by Singaporean multifarious food dishes, we propose to integrate supervised contrastive learning into our food recognition model FoodSG-SCL for the intrinsic capability to mine hard positive/negative samples and therefore boost the accuracy. Through a comprehensive evaluation, we present performance results of the proposed model and insights on food-related healthcare applications. The FoodSG-233 dataset has been released in https://foodlg.comp.nus.edu.sg/

Bardoxolone Methyl Improves Kidney Function in Patients with Chronic Kidney Disease Stage 4 and Type 2 Diabetes:Post-Hoc Analyses from Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes Study

Background: Increases in measured inulin clearance, measured creatinine clearance, and estimated glomerular filtration rate (eGFR) have been observed with bardoxolone methyl in 7 studies enrolling approximately 2,600 patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). The largest of these studies was Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes (BEACON), a multinational, randomized, double-blind, placebo-controlled phase 3 trial which enrolled patients with T2D and CKD stage 4. The BEACON trial was terminated after preliminary analyses showed that patients randomized to bardoxolone methyl experienced significantly higher rates of heart failure events. We performed post-hoc analyses to characterize changes in kidney func-tion induced by bardoxolone methyl. Methods: Patients in -BEACON (n = 2,185) were randomized 1: 1 to receive oncedaily bardoxolone methyl (20 mg) or placebo. We compared the effects of bardoxolone methyl and placebo on a post-hoc composite renal endpoint consisting of = 30% decline from baseline in eGFR, eGFR <15 mL/min/1.73 m2, and end-stage renal disease (ESRD) events (provision of dialysis or kidney transplantation). Results: Consistent with prior studies, patients randomized to bardoxolone methyl experienced mean increases in eGFR that were sustained through study week 48. Moreover, increases in eGFR from baseline were sustained 4 weeks after cessation of treatment. Patients randomized to bardoxolone methyl were significantly less likely to experience the composite renal endpoint (hazards ratio 0.48 [95% CI 0.36-0.64]; p <0.0001). Conclusions: Bardoxolone methyl preserves kidney function and may delay the onset of ESRD in patients with T2D and stage 4 CKD. (C) 2018 The Author(s) Published by S. Karger AG, Base

Plasmodium knowlesi in Human, Indonesian Borneo

Plasmodium knowlesi is now established as the fifth Plasmodium species to cause malaria in humans. We describe a case of P. knowlesi infection acquired in Indonesian Borneo that was imported into Australia. Clinicians need to consider this diagnosis in a patient who has acquired malaria in forest areas of Southeast Asia

DMAPT inhibits NF-κB activity and increases sensitivity of prostate cancer cells to X-rays in vitro and in tumor xenografts in vivo

Constitutive activation of the pro-survival transcription factor NF-κB has been associated with resistance to both chemotherapy and radiation therapy in many human cancers, including prostate cancer. Our lab and others have demonstrated that the natural product parthenolide can inhibit NF-κB activity and sensitize PC-3 prostate cancers cells to X-rays in vitro; however, parthenolide has poor bioavailability in vivo and therefore has little clinical utility in this regard. We show here that treatment of PC-3 and DU145 human prostate cancer cells with dimethylaminoparthenolide (DMAPT), a parthenolide derivative with increased bioavailability, inhibits constitutive and radiation-induced NF-κB binding activity and slows prostate cancer cell growth. We also show that DMAPT increases single and fractionated X-ray-induced killing of prostate cancer cells through inhibition of DNA double strand break repair and also that DMAPT-induced radiosensitization is, at least partially, dependent upon the alteration of intracellular thiol reduction-oxidation chemistry. Finally, we demonstrate that the treatment of PC-3 prostate tumor xenografts with oral DMAPT in addition to radiation therapy significantly decreases tumor growth and results in significantly smaller tumor volumes compared to xenografts treated with either DMAPT or radiation therapy alone, suggesting that DMAPT might have a potential clinical role as a radiosensitizing agent in the treatment of prostate cancer

Novel cyclic di-GMP effectors of the YajQ protein family control bacterial virulence

Bis-(3 ',5 ') cyclic di-guanylate (cyclic di-GMP) is a key bacterial second messenger that is implicated in the regulation of many critical processes that include motility, biofilm formation and virulence. Cyclic di-GMP influences diverse functions through interaction with a range of effectors. Our knowledge of these effectors and their different regulatory actions is far from complete, however. Here we have used an affinity pull-down assay using cyclic di-GMP-coupled magnetic beads to identify cyclic di-GMP binding proteins in the plant pathogen Xanthomonas campestris pv. campestris (Xcc). This analysis identified XC_3703, a protein of the YajQ family, as a potential cyclic di-GMP receptor. Isothermal titration calorimetry showed that the purified XC_3703 protein bound cyclic di-GMP with a high affinity (K-d similar to 2 mu M). Mutation of XC_3703 led to reduced virulence of Xcc to plants and alteration in biofilm formation. Yeast two-hybrid and far-western analyses showed that XC_3703 was able to interact with XC_2801, a transcription factor of the LysR family. Mutation of XC_2801 and XC_3703 had partially overlapping effects on the transcriptome of Xcc, and both affected virulence. Electromobility shift assays showed that XC_3703 positively affected the binding of XC_2801 to the promoters of target virulence genes, an effect that was reversed by cyclic di-GMP. Genetic and functional analysis of YajQ family members from the human pathogens Pseudomonas aeruginosa and Stenotrophomonas maltophilia showed that they also specifically bound cyclic di-GMP and contributed to virulence in model systems. The findings thus identify a new class of cyclic di-GMP effector that regulates bacterial virulence

Efficacy of Omaveloxolone in Friedreich's Ataxia: Delayed-Start Analysis of the MOXIe Extension

BACKGROUND: MOXIe was a two-part study evaluating the safety and efficacy of omaveloxolone in patients with Friedreich's ataxia, a rare, progressive neurological disease with no proven therapy. MOXIe part 2, a randomized double-blind placebo-controlled trial, showed omaveloxolone significantly improved modified Friedreich's Ataxia Rating Scale (mFARS) scores relative to placebo. Patients who completed part 1 or 2 were eligible to receive omaveloxolone in an open-label extension study. OBJECTIVE: The delayed-start study compared mFARS scores at the end of MOXIe part 2 with those at 72 weeks in the open-label extension period (up to 144 weeks) for patients initially randomized to omaveloxolone versus those initially randomized to placebo. METHODS: We performed a noninferiority test to compare the difference between treatment groups (placebo to omaveloxolone versus omaveloxolone to omaveloxolone) using a single mixed model repeated measures (MMRM) model. In addition, slopes of the change in mFARS scores were compared between both groups in the open-label extension. RESULTS: The noninferiority testing demonstrated that the difference in mFARS between omaveloxolone and placebo observed at the end of placebo-controlled MOXIe part 2 (-2.17 ± 1.09 points) was preserved after 72 weeks in the extension (-2.91 ± 1.44 points). In addition, patients previously randomized to omaveloxolone in MOXIe part 2 continued to show no worsening in mFARS relative to their extension baseline through 144 weeks. CONCLUSIONS: These results support the positive results of MOXIe part 2 and indicate a persistent benefit of omaveloxolone treatment on disease course in Friedreich's ataxia. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society