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Pressure and Pain: A Qualitative Pilot Study Describing the Complexity of Unhoused Women’s Experiences with Reproductive Care
No full textIntroduction: While there is extant literature surrounding barriers to reproductive care in the unhoused population—especially regarding access to contraception—little attention has been given to patient perspectives and the quality of care that is received. The unhoused population, which is disproportionately persons of color and low income, has a higher prevalence of psychiatric and physical disabilities. This is a population that has historically been a victim of eugenics and coercive practice.
Study Objective: The purpose of the study is to qualitatively understand the experiences of currently unhoused women with pregnancy, birth control, and sterilization, as well as analyze their perspectives in their clinical encounters over their lifetime.
Materials and Methods: Participants (n = 10) were recruited from two shelters in a midwestern city. The sample consisted of those assigned female at birth, are currently experiencing homelessness, and have experience with obstetrical and gynecological health care. A semistructured interview was conducted with each participant utilizing a question bank. Audio was recorded, transcribed, and coded for themes.
Results: The main themes coded from the interviews were negative birthing and/or sterilization experience, lack of shared decision-making for birth control and/or sterilization, pressure to undergo sterilization and/or go on birth control, the desire for a nonjudgmental provider, and sexual violence experience.
Conclusions/Implications: Our data indicate that women experiencing homelessness (WEH) may prefer contraceptive conversations that are trauma-informed and rooted in a shared decision-making model, which in turn may help WEH develop more agency around their reproductive health care. This pilot study also emphasizes the need for more qualitative research to evaluate experiences directly in the population of interest
PRMT5:MEP50 Are Mediators of Treatment‐Induced Neuroendocrine Differentiation in Prostate Cancer
No full textBackground: Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer responsible for an estimated 20%-30% of castration-resistant prostate cancer (CRPC) deaths. While NEPC can arise spontaneously, the majority of these cases emerge as treatment-induced NEPC (tNEPC). Our clinical and computational analyses identified increased expression of protein methyltransferase 5 (PRMT5) and its cofactor methylosome protein 50 (MEP50) in tNEPC.
Methods: Here we generated an in vitro cell culture and mouse model of prostate cancer to recapitulate tNEPC induced upon treatment with the androgen receptor (AR) inhibitor, enzalutamide. The role of PRMT5 and its cofactor MEP50 were determined by overexpression. Depletion of these genes and pharmacological inhibition of PRMT5 were followed by analysis of cell viability, neurite growth, and effects on neuroendocrine-related gene transcription using immunofluorescence, immunohistochemistry, and Western blot. PRMT5 and MEP50 protein expression levels were comprehensively analyzed for clinical correlation in NEPC patient prostate tissue samples.
Results: Elevated PRMT5 and MEP50 correlated with increased recurrence in prostate cancer patients receiving androgen deprivation therapy. Depletion of PRMT5 and MEP50 prevented neuroendocrine differentiation (NED)-induced by enzalutamide both in vitro and in a xenograft mouse model. Conversely, overexpression of PRMT5 and MEP50 was sufficient to induce NED in prostate cancer cells. Evaluation of a genetically engineered mouse model, in which PRMT5 and MEP50 were overexpressed in the prostate, similarly indicated NEPC development.
Conclusions: Our data suggest that PRMT5:MEP50 are regulators of tNEPC. PRMT5/MEP50 expression could serve as a predictive biomarker and therapeutic target for aggressive forms of prostate cancer
Baseline terminal ileal CT and MRI measurements are associated with imaging outcomes in pediatric Crohn’s disease: a cohort study
No full textBackground: Cross-sectional imaging is increasingly used for both initial diagnosis and long-term monitoring of Crohn's disease. The quantitative morphology of the terminal ileum may predict treatment response.
Objective: We aimed to identify baseline qualitative and quantitative imaging features that are associated with clinical and radiologic treatment response in a large cohort of children with Crohn's disease.
Materials and methods: This was a retrospective study of the RISK cohort study in pediatric Crohn's disease. This multicenter study included 1,136 children <18 years from 28 sites in North America. Subjects enrolled with newly diagnosed Crohn's disease who underwent endoscopy with baseline and follow-up CT or MRI were considered for this study. Exclusion criteria were incomplete data or surgical resection prior to follow-up imaging. Imaging analysis included assessing a qualitative terminal ileum (TI) categorical score based on SAR-AGA consensus definitions ((1) normal, (2) inflammation only without luminal narrowing, (3) inflammation with luminal narrowing, or (4) stricture with pre-stenotic dilation ≥3 cm) and quantitative measurements (maximum bowel wall thickness and maximum/minimum lumen diameter). Two endpoints were considered: (1) clinical response (off corticosteroids and quiescent Physician Global Assessment at follow-up imaging) and (2) CT and MRI response (follow-up imaging normalization). Multivariable logistic regression analyses were developed for each endpoint.
Results: Ninety-six subjects were included. Clinical response endpoint was achieved in 38% (n=36) of participants, and imaging normalization was achieved in only 20% (n=19) of participants. Follow-up imaging showed disease progression in 24 (25%) patients, 7 (7%) of whom were radiologically normal at baseline (7%). A higher baseline TI categorical score was associated with lower odds of imaging normalization during follow-up (OR 0.4 [0.2, 0.8], P=0.009). Larger TI minimum lumen diameter (OR 1.1 [1.01, 1.3], P=0.04) and smaller maximum bowel wall thickness at baseline (OR 0.8 [0.6, 0.97], P=0.03) were associated with imaging normalization. There were no baseline imaging measurements associated with clinical response.
Conclusions: Baseline increased terminal ileal minimum lumen diameter and decreasing wall thickness were associated with imaging normalization at follow-up, but not clinical response
Systematic comparison of methods for offline breath sampling
No full textHarnessing the potential of exhaled breath analysis is an emerging frontier in medical diagnostics, given breath is a rich source of volatile organic compound (VOC) biomarkers for different medical conditions. A current downfall in this field, however, is the lack of standardized and widely available methods for offline sampling of exhaled VOCs. Herein, strides are taken toward the standardization of breath sampling in Tedlar bags by exploring several factors that can impact VOC heterogeneity, including tubing material, chemical composition of collection bags, breath fractionation, exhalation volume, and transfer flow rate. After bag-based sampling standardization, performance was benchmarked using two offline breath sampling methods, Tedlar bags and the Respiration Collector for In Vitro Analysis (ReCIVA). Three volunteers from the laboratory with no known respiratory diseases donated ≥ n = 5 samples collected onto adsorption tubes via each method, which were analyzed through thermal desorption (TD) coupled with gas chromatography-mass spectrometry (GC-MS). Data processing revealed a set of 15 highly reliable on-breath VOCs detected across volunteers, and most analytes (except indole) demonstrated higher sensitivity using Tedlar bags. Calculating relative standard deviation (RSD) values showed Tedlar bags were also significantly more reproducible compared to the ReCIVA (p < 0.03). Agreement between the two methods was demonstrated through correlating VOC signals with high statistical significance (R2 = 0.70), indicating both devices are well situated for biomarker discovery applications
Progressive Choreiform Movements in a Child: Early Recognition and Management of Sydenham Chorea
No full textBackground: Sydenham chorea, a rare neurological manifestation of acute rheumatic fever, persists in developed countries due to rheumatogenic strains of group A streptococcus.
Phenomenology shown: This case demonstrates the evolution from subtle early symptoms to definitive severe choreiform movements in Sydenham chorea in a 10-year-old female.
Educational value: This case highlights the importance of early recognition, multidisciplinary management, and vigilance in medication administration to optimize outcomes in rare conditions such as Sydenham chorea.
Highlights: This case highlights the diagnostic and management challenges of Sydenham chorea, showcasing its progression from subtle early symptoms to definitive severe choreiform movements. It demonstrates the importance of early recognition, multidisciplinary care, and cautious medication administration to optimize outcomes in this rare neurological condition associated with rheumatic fever
Group B Streptococcal Membrane Vesicles Induce Proinflammatory Cytokine Production and Are Sensed in an NLRP3 Inflammasome-Dependent Mechanism in a Human Macrophage-like Cell Line
Get PDFGroup B Streptococcus (GBS) is a major cause of fetal and neonatal mortality worldwide. Many of the adverse effects of invasive GBS are associated with inflammation; therefore, understanding bacterial factors that promote inflammation is of critical importance. Membrane vesicles (MVs), which are produced by many bacteria, may modulate host inflammatory responses. While it is known that mice injected intra-amniotically with GBS MVs exhibit large-scale leukocyte infiltration, preterm birth, and subsequent fetal death, the immune effectors driving this response remain unclear. Here, we hypothesized that THP-1 macrophage-like cells respond to GBS-derived MVs by producing proinflammatory cytokines and are recognized through one or more pattern recognition receptors. We show that THP-1s produce high levels of neutrophil- and monocyte-specific chemokines in response to MVs derived from different clinical isolates of GBS. Using antibody microarrays and multiplex Luminex assays, we found that GBS MVs elicit significantly (p < 0.05) higher levels of CCL1, CCL2, CCL20, CXCL1, CXCL10, and IL-1β relative to untreated THP-1s. Using chemical inhibitors in combination with caspase-1 activity assays and Luminex assays, we further demonstrate that GBS MVs upregulated IL-1β production in a caspase-1 and NLRP3-dependent manner, ultimately identifying NLRP3 as a sensor of GBS MVs. These data indicate that MVs contain one or more pathogen-associated molecular patterns that can be sensed by the immune system and show that the NLRP3 inflammasome is a novel sensor of GBS MVs. Our data additionally indicate that MVs may serve as immune effectors that can be targeted for immunotherapeutics
BCL-XL Protects ASS1-Deficient Cancers from Arginine Starvation-Induced Apoptosis
Get PDFPurpose: Argininosuccinate synthetase 1 (ASS1) silencing in carcinomas and sarcomas leads to a dependence on extracellular arginine for survival. Arginine deprivation therapies, such as PEGylated arginine deiminase (ADI-PEG20), have shown limited effectiveness, which may be due to underlying mechanisms that inhibit apoptosis.
Experimental design: The effects of ADI-PEG20 on cell-cycle regulation, apoptosis, and BCL-XL-mediated survival pathways in ASS1-deficient cancer cells were determined. The mechanism of cell death protection was determined by assessing caspase and PARP cleavage, CDK2 activity, MCL1 expression, and the interactions among BCL-XL, BAX, and BAK. In vitro synergy was determined, and in vivo efficacy was modeled.
Results: Treatment with ADI-PEG20 led to reduced CDK2 activity and inhibited cell-cycle progression but did not induce significant cell death. BCL-XL was found to bind to BAX and BAK, preventing the initiation of apoptosis despite arginine starvation. Inhibition of BCL-XL allowed proapoptotic BAX and BAK to initiate the intrinsic apoptosis pathway, leading to increased cell death. This was found to be synergistic in vitro and efficacious in combination in vivo.
Conclusions: The study identifies BCL-XL as a key factor limiting the efficacy of arginine starvation therapies. Combining BCL-XL inhibitors with arginine deprivation strategies may overcome this resistance and enhance therapeutic outcomes. These findings provide a strong preclinical rationale for testing this combination approach in phase 1 clinical trials for ASS1-deficient cancers
