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The Embodiment of Negative Desires in Early Modern Women's Poetry
No full textThe early modern women Lucy Hutchinson, Katherine Philips, and Aphra Behn all embody their loved ones—friends, lovers, fellow artists—in verse. I argue that through embodiment these poets express negative desires, desires which can never be consummated or productive, and are forestalled by the poetry itself. In doing so, I push against readings of these women’s work that focuses either on more passive emotions, such as Hutchinson’s melancholy, or more idealistic readings of Philips’ lesbian retreat or Behn’s Golden Age sexual utopia. Instead, I examine how Hutchinson uses her poetry to represent desires for vengeance, how Philips represents her desire for control, and Behn represents creativity as the zenith of sexuality, with the presence of bodies resulting instead in abjection. I trace how these poets convey their negative desires and how the mode of textual transmission affects their embodied representation of their loved ones, from Hutchinson as the least circulated writer during her lifetime, to Behn who was widely published in both print and manuscript. Throughout, I interrogate to what extent such embodiments can be termed “queer” or “queer-feminist” and the stakes for queer feminist critique within the field of early modern women’s poetry.</p
Essays on Urban Ecology and Natural Capital in Miami-Dade's Water Systems
No full textThis interdisciplinary dissertation consists of four essays that draw from the disciplines of urban ecology, economics, spatial econometrics, and climate change science. These essays explore (1) the ability of distinct natural capital valuation techniques to both estimate the intertemporal welfare from, and recover the marginal value of, a natural resource, and (2), the question of whether climate exposure has been internalized in institutional property tax rate (millage) setting behavior. The first essay discusses the nexus between urban ecology and natural resource economics, and the second essay derives the natural capital asset pricing equation from Fenichel and Abbott (2014) and extends it to the pink shrimp (Farfantepenaeus duorarum) bait fishery in Biscayne Bay, Florida, USA. The third essay extends the Gisser and Sanchez (1980) hydro-economic model to the unconfined Biscayne aquifer in southeastern Florida, to compare the difference in intertemporal welfare between the optimal management of a public water system and the myopic exploitation of a coastal aquifer, subject to extraction induced saltwater intrusion and encroachment. The fourth essay uses the theoretical and empirical methodologies of spatial panel econometrics to estimate the impact of climate exposure on the property tax revenues from South Florida municipalities.</p
Glial KCNQ K+ Channels Control Neuronal Output by Regulating GABA Release from Glia in C. elegans
No full textKCNQ channels are voltage-gated K+ channels that are evolutionarily conserved across species. Among the five genes responsible for encoding KCNQ channels in humans, four are expressed in the nervous system. KCNQs display a low threshold of activation and non-inactivating current, features that make these channels good regulators of cellular excitability. In the nervous system, KCNQ channels are expressed in neurons, where they regulate neuronal excitability. Indeed, mutations in KCNQ channels have been associated with neuropsychiatric conditions such as Self-Limited Neonatal Epilepsy, Developmental and Epileptic Encephalopathy, and Autism Spectrum Disorder (ASD) in children. However, KCNQ channels are also expressed in glial cells, and the function of KCNQ channels in glia remains unclear. Previous work from the Bianchi’s Lab has shown that the C. elegans KCNQ homolog channel kqt-2 is needed in amphid sheath glia for the nematode response to 1-octanol. Strikingly, at a cellular level loss of glial kqt-2 leads to reduction of amphid sheath glia activity but to increase in neuronal excitability. Here, I show that glial KCNQ channels are needed in glia to mediate GABA release from these cells upon stimulation with 1-octanol. Further, I show that KCNQs are needed in glia to maintain a membrane potential that is favorable for the activity of voltage-gated Ca2+ channel egl-19 and, therefore, for intracellular Ca2+ increase in glia. Finally, I found that pathogenic KCNQ mutations expressed in glia affect the resting membrane potential and post-stimulus repolarization in these cells, as well as GABA release, suggesting that glial KCNQ channels contribute to the pathogenesis of KCNQ associated disorders. These data suggest glial KCNQ channels are potential novel targets for the treatment of KCNQ-associated conditions.</p
Bxq-350 in combination with FOLFOX7 and bevacizumab: Evaluation of effect on oxaliplatin-induced CIPN—A phase 1b/2 trial to assess the efficacy and safety of BXQ-350, a first-in-class sphingolipid metabolism modulator, in newly diagnosed metastatic colorectal carcinoma
No full text105 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a significant side effect associated with many cancer drugs and is highly prevalent in mCRC patients receiving oxaliplatin-based regimens. CIPN can severely impact quality of life (QoL) and may require dose vacation, reduction or interruption. CIPN pathology is complex and not completely understood; preclinical and clinical data have shown inflammatory (IL-6, Il-8, IL-10) and immune involvement as well as elevated levels of sphingolipids, a class of bioactive signaling molecules. BXQ-350 is a nanovesicle formulation of Saposin C, an allosteric activator of sphingolipid metabolism that normalizes dysregulated sphingolipid metabolism by lowering S1P, GM3 and GluCer levels while it increases ceramide level, promoting a return to homeostasis. In a single agent Phase 1 study, BXQ-350 was safe and well-tolerated and showed signs of activity. Among patients with PFS > 6 months, there were 4 recurrent CRC patients: 1 is still on study after 7 years. One patient self-reported an improvement of their pre-existing CIPN symptoms after BXQ-350 administration; this observation was confirmed in 4 of 10 patients with established CIPN at the time of enrollment. Methods: BXQ-350 is being investigated in a Phase 1b/2 study in combination with mFOLFOX7 and Bevacizumab (SoC) in newly diagnosed mCRC patients (NCT05322590). Primary objectives are to assess safety and preliminary efficacy of this combination, and to determine cumulative oxaliplatin dose. Secondary objectives include intensity, frequency and time to onset of CIPN. Results: The Phase Ib trial enrolled 33 oxaliplatin dosing evaluable patients; all patients completed the primary treatment period (6 months of SoC treatment plus BXQ-350). Amongst the 33 patients, 19 completed the full 12 Cycles of oxaliplatin dosing, 28 completed at least 8 Cycles with only 2 patients having dosing halted before Cycle 8 due to CIPN. There were no reported Grade 4 and only 3 reported Grade 3 CIPN AEs, all occurred after Cycle 12. Analysis of Neurofibrillary Light Chain (NfL) biomarkers suggests concordance with physician and patient reported outcomes. Conclusions: Results show that BXQ-350 was safe and well tolerated in the combination. Data suggest that BXQ-350 may provide additional clinical benefits and may reduce intensity or delay onset of CIPN, allowing for increased cumulative dosing of oxaliplatin and relative dose intensity in 1L mCRC. Clinical trial information: NCT05322590
Abstract PR026: A bypass gateway from cholesterol to sex steroid biosynthesis circumnavigates CYP17A1
No full textThe Role of the Boston Keratoprosthesis in Severe Ocular Surface Disease and Autoimmune Diseases
No full textTo synthesize contemporary evidence on Boston KPro outcomes in autoimmune cohorts and outline practical strategies to improve anatomic retention and visual results.
A review.
The Boston keratoprosthesis (KPro) is the most widely implanted artificial cornea and a critical option for visual rehabilitation in patients at high risk of graft failure. Autoimmune disorders, including Stevens-Johnson syndrome (SJS), Sjögren's disease (SjD), ocular mucous membrane pemphigoid (OMMP), and ocular graft-versus-host disease (oGVHD), create highly inflammatory, cicatricial ocular surface environments characterized by severe dry eye, limbal stem cell deficiency, and corneal neovascularization, all of which undermine conventional keratoplasty. While selected patients with a relatively "wet" and medically quiet surface can benefit from Type 1 KPro, most end-stage cicatricial phenotypes are better served by Type 2 KPro or alternative mucous-membrane-covered devices. Across studies, autoimmune etiology is consistently associated with higher rates of tissue melt, infectious/sterile keratitis, retroprosthetic membrane, glaucoma, and vitreoretinal complications compared with non-autoimmune eyes. A structured perioperative bundle, systemic disease quiescence for ≥3 months, rheumatology co-management, prophylactic glaucoma drainage devices when indicated, long-term bandage contact lens wear, and intensified antibiotic ± antifungal prophylaxis appear to mitigate risk. Emerging approaches (biologics, donor-carrier crosslinking, γ-irradiated tissue, and newer KPro designs) show promise but require standardized endpoints and multicenter registries.
Despite substantial challenges, the Boston KPro remains a vision-restoring option for carefully selected autoimmune patients when performed within multidisciplinary programs using rigorous preventive protocols
Imetelstat improves patient-reported outcomes and quality of life in lower-risk myelodysplastic syndromes: results from the phase III IMerge study
No full textRed blood cell (RBC) transfusions for anemia associated with lower-risk myelodysplastic syndromes/neoplasms (LR-MDS) often contribute to reduced quality of life (QOL). Thus, reduction in RBC transfusion dependency (TD) is a primary therapeutic goal. Imetelstat is a firstin-class, competitive telomerase inhibitor approved to treat certain adult patients with LR-MDS with RBC-TD anemia who have not responded to, have lost response to, or are ineligible for erythropoiesis-stimulating agents. In the phase III IMerge study (NCT02598661), treatment with imetelstat resulted in clinically meaningful, statistically significant increases in the primary endpoint of ≥8-week RBC transfusion independence (TI) versus placebo. Because patients with LR-MDS experience detrimental effects on numerous facets of QOL (physical, emotional, social, and functional), these exploratory analyses assessed patient-reported outcomes using the Functional Assessment of Chronic Illness Therapy-Fatigue, Quality of Life in Myelodysplasia Scale, and Functional Assessment of Cancer Therapy-Anemia questionnaires as part of the phase III IMerge study. Nominal P values were reported. Fewer imetelstat-treated patients experienced deterioration in fatigue and more imetelstat-treated patients experienced sustained improvement in fatigue and QOL versus placebo. In the imetelstat group, 8-week, 24-week, and 1-year RBC-TI responders had sustained improvements in predefined significance thresholds versus nonresponders for fatigue (70%, 73%, and 88%, respectively, vs. 37%, 41%, and 44%, respectively; P
Evaluating the Performance of the Paris System in Neobladder Cytology: The Role of Cellularity and Volume Adequacy Criteria
No full textUrinary diversion (UD) including neobladder (NB) samples play a crucial role in diagnosing recurrent urothelial carcinoma (UC) following cystectomy. However, urine cytology (UCy) interpretation in this setting is challenging due to degenerative changes and a necroinflammatory background. The diagnostic performance of UCy using The Paris System (TPS) has not been well established for NB specimens. Moreover, given the distinct characteristics of NB samples compared to other urine specimens, the application of specific adequacy criteria may be necessary.
This retrospective study analyzed 442 NB urine specimens from 243 patients who underwent cystectomy with UD. One-year surgical pathology or cytology follow up was collected. All specimens were prepared using the cytospin technique, stained with Papanicolaou stain, and assessed using TPS criteria. The presence of preserved benign urothelial cells and urine volume were analyzed to determine specimen adequacy. Youden's index and likelihood ratio testing were applied to identify an optimal volume cutoff.
By applying TPS, positive cytologic diagnoses (atypical or higher) were identified in 3.39% of NB specimens. Among 139 cases with histological or cytological follow-up, UC was confirmed in 10.8%, with 86% being high-grade UC (HGUC). The sensitivity and specificity of TPS for detecting HGUC were 61.5% and 96.8%, respectively. Notably, 60.5% of NB specimens in this cohort lacked preserved urothelial cells. Redefining adequacy criteria to require the presence of at least one preserved urothelial cell markedly increased sensitivity (100%) with only modest changes in specificity and overall diagnostic accuracy. A specimen volume ≥ 45 mL emerged as the optimal cutoff for identifying atypical urothelial cells or higher TPS categories, although statistical significance remained limited (p = 0.12). Applying this threshold led to a modest improvement in the sensitivity of UD cytology (66.67%).
The diagnostic performance of TPS for NB samples was comparable to the performance of pre-TPS cytology in the UD setting, as reported by other studies. Incorporating adequacy criteria based on the presence of at least one preserved benign urothelial cell substantially improves the sensitivity of UCy in NB samples. Additionally, a minimum specimen volume of approximately 45 mL may serve as an adequacy indicator for NB cytology, although its impact on diagnostic performance is limited
Application of the STAAR Framework in Detecting Rare Variant Associations with Alzheimer's Disease and Related Dementias: Insights and Implications
No full textRare genetic variation is considered a potential source of heritability in individuals with sporadic Alzheimer's Disease and related dementias (ADRD). The STAAR framework leverages multiple functional annotations of genetic variants and combines association statistics from multiple variant aggregation-based methods, including burden, SKAT, and ACAT-V, into a single measure of significance. Using whole genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP), we comprehensively examined the association of rare genetic variation with ADRD in 23,454 individuals (37% ADRD cases) and with cognitively healthy elder status in 13,292 individuals (13% cognitively healthy elders) from diverse populations via the STAAR framework. We identified several genes significantly associated with ADRD or cognitively healthy status. However, our analysis revealed several limitations within the STAAR framework incorporating ultra-rare variants with dichotomous outcomes. To enhance the robustness of the framework, we proposed several computational refinements, including creating a burden of ultra-rare variants and employing more precise annotations to match with expected mechanism. After implementing the proposed modifications, the association with ADRD for ZNF200 was no longer statistically significant (α=1x10
), while TBX19, PLXNB2, CARD11, and LINC01880 remained significantly associated with cognitively healthy status. We identified and addressed the computational limitations in the STAAR framework that could lead to potential spurious results for ultra-rare variant aggregates with an extremely low cumulative minor allele count. Our proposed refinements produced more robust results for associations with rare variants in the context of dichotomous outcomes
