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Design And Synthesis Of Aminoglycoside-Based Heparan Sulfate Mimetics For Structure-Activity Relationship Studies Of Heparan-Binding Proteins
Get PDFCancer remains a formidable challenge in modern medicine, demanding innovative approaches and treatments. Among the emerging strategies, inhibiting heparanase and fibroblast growth factor 2 (FGF2) has garnered considerable attention in recent years. This dissertation presents a novel approach to designing and synthesizing a diverse library of heparan sulfate (HS) mimetics derived from aminoglycosides to study their binding to two heparin-binding proteins involved in cancer development and metastasis. Heparanase cleaves HS polysaccharide chains in the extracellular matrix (ECM) and is a regulator of aggressive tumor behavior. Clinical studies have illustrated that aberrant heparanase expression correlates with increased tumor size, amplified tumor angiogenesis, and enhanced metastasis. Heparanase cleaves GlcAβ(1,4)GlcNS bonds of HS, releasing sequestered pools of HS oligosaccharide-binding growth factors, thereby promoting tumor angiogenesis and growth. Cleavage of HS chains degrades the structural integrity of the ECM, allowing the migration of malignant cells into the bloodstream and promoting cancer metastasis. Thus, heparanase is a viable target for cancer therapeutics. Although small molecules, saccharides, and antibodies have been developed, only four sugar molecules have advanced to clinical trials. While these molecules were successful in mouse models, adverse side effects terminated or halted their clinical advancement in humans. To date, anti-heparanase-based therapy has not yet been implemented in the clinic. In the first section, we report cost-effective strategies for the expedient and scalable synthesis of selective heparanase inhibitors from aminoglycosides (7-12 steps). This strategy significantly reduces the number of synthetic steps compared to the traditional synthesis of HS oligosaccharide mimetics (24-32 steps) prepared from selectively protected monosaccharides. Structure-activity relationship studies indicated that N-sulfated tobramycin derivatives are better inhibitors compared to kanamycin and apramycin, as well as their corresponding O-sulfated derivatives. Interestingly, incorporating a lipophilic scaffold onto specific regions of the designed inhibitors further enhanced their potency. The lead compounds exhibit high inhibition (IC50: 50 200 nM) against heparanase and are highly selective for this enzyme. Unlike natural heparan sulfate/heparin, these compounds show little or no off-target effects toward heparin-binding proteins. The second section builds on our results from the first project, recognizing the interplay between heparanase activity and the release of HS-bound growth factors. This section includes screening our ligand library and designing new ligands to improve binding to FGF2 and its primary receptor, FGFR1. Overall, both heparanase and FGF2 require a balance of structural and functional modifications of the ligands to achieve greater binding activity
Practitioners\u27 Perceptions Of Mental Health/help-Seeking Behaviors Among Black Indigenous Muslim Women Of Color
No full textThis study explored practitioner perceptions on individual, community and societal barriers impacting how Black Indigenous Muslim Women of Color (BIMWOC) may access mental health services. This study also explored the historical utilization of mental health services by (BIMWOC) and the cultural values that may impact mental health seeking behaviors and care. In addition, this study highlights the need to expand holistic culturally responsive mental health models and practice with Indigenous women
Equity And Resilience Of Aging Drinking Water Distribution Systems
No full textABSTRACTEQUITY AND RESILIENCE OF AGING DRINKING WATER DISTRIBUTION SYSTEMS by FELICE GIANLUCA SPERONE December 2024 Advisor: Dr. Shawn P. McElmurry Major: Civil Engineering Degree: Doctor of Philosophy The 20th century saw significant advancements in water infrastructure by enhancing global water reliability and quality; particularly in the United States, where these improvements contributed to major public health gains and have extended life expectancy. New challenges, such as changing climatic conditions, old infrastructure and shrinking cities, threaten system resilience and water quality. This research addresses the urgent need to equitably enhance drinking water distribution systems, particularly in vulnerable communities that are disproportionately affected by inadequate and old infrastructures. This dissertation focuses on three main aims: (1) to evaluate factors associated with boil water notices (BWNs) during extreme weather events, (2) derive a data-driven approach for resizing old infrastructure pipes in oversized systems, and (3) assessing the equity of these resizing approaches. During Winter Storm Uri, data from Texas public water systems were more likely to issue BWNs following the severe weather, and these periods of recovery were longer in marginalized communities. Based on water distribution system models of Flint, Michigan, indices, or Diameter Assessment Factors (DAF), were developed to identify which pipes can be downsized while ensuring system resilience during fire events. Results suggest that downsizing pipes identified as oversized based on pipe water velocity (i.e., DAFV) is the best approach for identifying which pipes can be downsized while maintaining system pressure. Finally, potential equity issues associated with downsizing pipes in Flint, Michigan when using the DAF methods were also explored. Socio-economic factors were found to be integrally linked to DAF scores. These results will help policymakers and water system managers develop proactive, equitable right-sizing strategies
Arbiters of Ugliness: A Review of Strategies for Describing Offensive Archival Materials
Get PDFAs archivists increasingly concede that neutrality is impossible, we suggest that non-action is still action. It follows that to treat reasonably offensive records as any other record is to apply an interpretation that they are innocuous, unremarkable, and uncontroversial. Archivists may perceive the stakes of describing these materials as particularly high, but they lack a comprehensive set of descriptive strategies in consideration of interpretive ethics. As a result, existing practices are likely to be local or ad hoc. This research aims to identify and explore descriptive strategies archivists use which serve to construct (or concede) the meaning that certain historical materials are potentially offensive using a combination of literature review, evaluation of finding aids and descriptive metadata, and exploratory interviews with archivists and other memory institution professionals. Results supported the assumption that strategies are largely ad hoc practices and local norms influenced by a handful of culturally sensitive descriptive protocols; underscored that strategies are contextually implemented; and revealed practical and philosophical divisions between archivists working with largely offensive collections and those working with largely uncontroversial ones. These findings suggest that while a comprehensive set of descriptive strategies may support a community grappling with its professional legacy, there may be no strategy capable of reconciling matters of ethics and discoverability, and the highly contextual practices are incompatible with overly rigid frameworks
HIF Expression in Clear-Cell Renal Cell Carcinoma (ccRCC) Tumors of Adults with and without Obstructive Sleep Apnea (OSA)
Get PDFIntroduction: Upregulation of hypoxia-inducible factors (HIF) is an important pathological feature shared by clear cell renal cell carcinoma (ccRCC) and obstructive sleep apnea (OSA). However, it is unclear whether OSA alters the pathogenesis of ccRCC via HIF expression.
Methods: A retrospective cohort of adults undergoing nephrectomy for ccRCC was identified electronically (IRB#16040-1). The diagnosis of OSA was established with preoperative STOP-BANG scores or polysomnography. A consecutive sample of 20 individuals with and 20 without OSA was selected. Clinical characteristics and pathology results were reviewed. Resected tumor sections were immunohistochemically stained for HIF-1& HIF-2 at antibody dilutions of 1:150. Intensity and percentage of staining as determined by an expert uropathologist were used to calculate a histoscore (0-12).
Results: Individuals with OSA exhibited a higher prevalence of hypertension (95% vs. 50%, p-value 0.00138) and a greater median BMI (34.8 vs. 29.05, p-value 0.00578). Tumor grades and stages were not statistically different between groups. The prevalence of positive HIF-1 expression (histoscore \u3e2) was higher in the OSA group (80% vs. 50%, p=0.0466). Nonetheless, median histoscores were not statistically different (4 vs. 2.5, p = 0.2187) between groups. A suboptimal staining quality precluded reliable HIF-2 histoscores.
Conclusion: In individuals with OSA, ccRCC tumors exhibit a higher prevalence of positive HIF-1 staining. Statistically significant differences in terms of HIF-1 histoscores, tumor grade, and stage were not identified. Future studies can use our results to perform formal sample size calculations, optimize HIF-2 staining procedures, and elucidate the role of OSA in the pathogenesis of ccRCC
Bone Fractures With and Without Sickle Cell Disease in the Pediatric Population
Get PDFBackground: Individuals with sickle cell disease are restricted from certain physical activities due to the increased risk of complications including fractures secondary to osteopenia. However the exact incidence and outcomes of fractures amongst these patients is unknown.
Objectives: (1) describe the incidence, epidemiology, and outcomes of fractures in patients with SCD. (2) to compare fracture patterns and outcomes in patients with and without SCD.
Methods: This is a retrospective, cohort study of patients aged 0-25 years old with HbSS, HbSC, or HbS-β-thalassemia with a fracture evaluated at a pediatric emergency department from April 2009-April 2022. Eligible patients were identified using a combination of ICD billing codes and a preexisting hematology clinic database. Patients were age/gender matched with non-SCD patients with fractures. Data on demographics, number and types of fractures and outcomes were collected.
Results: 753 patients with SCD were identified during the study period. SCD patients with fractures were more likely to have multiple comorbidities, lower mean vitamin D levels and were less likely to be on vitamin D supplementation compared to those without fractures. The most common etiology was fall and carpal bones were most commonly fractured. Non-SCD patients with fractures were more likely to be obese and require surgical repair compared to their SCD peers.
Conclusions: Fracture incidence among SCD patients is low. Male gender, multiple comorbidities, and lack of vitamin D supplementation are associated with increased risk of fracture. SCD patients with a fracture were less likely to require surgical treatment compared to their non-SCD counterparts
Six- Month Report Assessing the Feasibility and Effectiveness of Amniotic Bladder Therapy in Patients with Chronic Radiation Cystitis
Get PDFIntroduction: In view of the pathophysiology of chronic radiation cystitis (CRC) that is mainly caused by activation of an inflammatory cascade leading to chronic inflammation, vascular damage and fibrosis, amniotic membrane (AM) based therapy has emerged as a potential therapeutic approach for radiation-induced tissue injury due to its immunomodulatory, vasculogenic and anti-fibrotic properties. We have previously reported that amniotic bladder therapy (ABT) provides symptomatic improvement in refractory CRC patients for up to 3 months. Herein, we evaluated the durability of ABT up to 6 months.
Methods: CRC patients recalcitrant to multiple therapies were eligible for the study and received intra-detrusor injections under general anesthesia of reconstituted 100mg micronized AM. The Interstitial Cystitis Symptom Index (ICSI), Interstitial Cystitis Problem Index (ICPI), Bladder Pain/ Interstitial Cystitis Symptom Score (BPIC-SS), Overactive Bladder (OAB) Assessment Tool, SF-12 Health Survey were repeated at pre-op and up to 36 weeks post-injection. Cystoscopy and uroflow were done pre-injection, 12, 24, and 36 weeks.
Results: Five consecutive patients (average age: 64 ± 20 years) exhibited a progressive improvement from their baseline lower urinary tract symptoms to 20 weeks (Figure 1). At 24 weeks, the improvement was maintained in four of the patients, however diminishing benefit of ABT was seen at 36 weeks. This coincided with an initial improvement in uroflow assessment (Table 2). One patient’s symptoms rebounded at 24 weeks and worsened at 36 weeks.
Conclusion: This data suggests most CRC patients have durable benefit after ABT, however some patients may have symptoms rebound at 36 weeks
Exploring the Effects of Amniotic Bladder Therapy on Female Sexual Dysfunction in Interstitial Cystitis/Bladder Pain Syndrome Patients
Get PDFIntroduction and Objectives: Female sexual dysfunction (FSD) is commonly associated with Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS). FSD manifests as abnormalities in sexual desire, arousal, orgasm, pain, distress, and satisfaction. Our primary objective was to assess the impact of micronized amniotic membrane injections (AM) on FSD and lower urinary tract symptoms using comprehensive measures, including the multi-domain Female Sexual Function Index (FSFI), the Pain Visual Analog Scale (VAS), and the Interstitial Cystitis Symptom Index (ICSI) and Interstitial Cystitis Problem Index (ICPI).
Methods: Study participants included patients diagnosed with IC/BPS and FSD refractory to traditional therapies. Under general anesthesia, these patients received intra-detrusor injections of reconstituted 100mg micronized AM. We collected data on ICSI, ICPI, FSFI, and VAS scores before the procedure and at 4, 8, 12, and 24 weeks post-injection. Our primary study endpoint was the impact of amniotic bladder therapy (ABT) on sexual function, with a parallel evaluation of injection safety.
Results: Eleven consecutive patients, with an average age of 49 ± 12 years, demonstrated progressive improvements in their baseline IC/BPS symptoms over the 24-week study duration. These improvements were mirrored by enhanced FSFI scores, and reduced pain (VAS) related to intercourse over the 24-week study period. No adverse events were observed.
Conclusions: Our findings suggest that ABT holds promise for IC/BPS patients, particularly females with refractory FSD symptoms. However, further research is imperative to deepen our understanding of the mechanisms through which ABT effectively addresses these complex disorders. Additionally, the long-term durability of this treatment response warrants investigation
Six-Month Report Assessing the Feasibility and Effectiveness of Amniotic Membrane Injections in Patients with Short, Anterior, Urethral Strictures
Get PDFIntroduction: Urethral stricture treatment has high recurrence rates and adjunct injectable agents have been explored. Amniotic membranes (AM) promote apoptosis of pro-inflammatory cells, prevent differentiation of pro-fibrotic cells, and decrease scar formation. These tissues generated interest in reconstructive urethral surgery. Thus, we performed urethral dilation combined with micronized AM injection in urethral scar tissue for treatment of urethral stricture.
Materials and Methods: Adult males with strictures ≤12Fr in diameter and ≤2 cm in length, International Prostate Symptom Score (IPSS) ≥11 and maximum flowrate \u3c15 ml/s. Reconstituted 100mg micronized AM was injected at the time of urethral dilation. Primary study end point was anatomical success (≥14Fr by cystoscopy) at 6 months. Secondary end points were questionnaires, flow rate, and post void residual. Outcomes assessed at baseline, 5 days, 14 days, 3 months, and 6 months post-injection. Safety was analyzed.
Results: Ten men, mean age of 52 ± 15 years, were included. There were 7 patients with no prior endoscopic treatment and 3 patients with one prior dilation. At 6 months, 7 of 10 patients (70%) demonstrated recurrence on cystoscopy. Improvements in flow rate, PVR and IPSS and USS-PROM symptom scores noted in 10 of 10 patients at 3 months and 3 of 10 patients at 6 months. No adverse events observed.
Conclusions: This is the first study evaluating single layer amnion as an adjunct treatment at time of urethral dilation. The urethral stricture rate of recurrence did not improve with the injection of AM despite the hypothesized benefits of anti-fibrotic and anti-inflammatory properties
The Long-Term Economic Implications of Burn Injury for Burn Survivors
Get PDFIntroduction: The long-term economic implications of burn injury on patients and payors has not been well described. Burn injury can be costly due to prolonged intensive care, wound care, rehabilitation, psychological care, and reconstructive surgery that may be required well after the initial injury. We investigated index and post-acute payor and out-of-pocket (OOP) costs related to burn injury for in-patient care at 30 days, and up to 36 months post-discharge to understand the long-term economic implications for burn survivors.
Methods: An observational cohort study was conducted using a commercial claims database from IBM Watson Health® Marketscan. Patients age ≤ 65 years with an ICD9/10 diagnosis code of burn injury between 2011 and 2016 were identified and tracked for a three-year period following the injury. This was used to determine the payor and OOP costs for burn care during the initial treatment and the three-year period following discharge through 2019.
Results: We identified 11,815 patients who were admitted for in-patient care for a burn injury between 2011 to 2016. The inflation-adjusted index out-patient evaluation or emergency room costs ranged from 942 during the study period. For the index admission, length of stay (LOS) ranged from 5.4 days to 6.2 days, 30-day complication rates ranged from 15.6% to 21.7%, and 30-day readmission rates ranged from 7.2% to 9.6% within this timeframe. The payor costs for burn care ranged from 3,944 at 30 days, and 5,166 at 36-months post discharge, for each year from 2011 to 2016. The OOP costs ranged from 217 at 30 days, and 263 at 36-months post discharge, respectively, for each year from 2011 to 2016 (Table 1).
Conclusions: Burn injury creates significant financial burdens associated with care in the following years which are highly impactful to both patients and providers. Further investigation of the long-term economic implications related to burn injury is an area of interest in burn care