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Abstract WP364: Recombinant irisin therapy attenuates post-stroke neuroinflammation and ischemic injury in middle-aged female rats
No full textIntroduction: Irisin, a muscle-derived hormone released during exercise, improves ischemic stroke outcomes, though the mechanisms remain unclear. The current study tests the hypothesis that post-stroke recombinant irisin therapy attenuates neuroinflammation, assessed by inflammasome complex protein levels and microglial reactivity.
Methods: Middle-aged female Sprague-Dawley rats underwent transient middle cerebral artery occlusion (tMCAO; 90 min) and were divided into two cohorts. One cohort received saline or irisin (PeproTech, 0.2 µg/g BW) treatment at 4.5 h post-surgery and was survived 1 or 3 days for cortical tissue collection followed by Western blotting for apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and caspase-1. A second cohort received saline or irisin treatment at 4.5 h post-tMCAO and weekly for 1 month. Following treatment, brains were collected for histological analysis of microglial activation. Two-dimensional morphometric analysis was performed using ImageJ, and Sholl analysis was conducted with the NIH ImageJ Sholl Analysis Plugin (v1.0).
Results: Western blotting revealed significantly (p<0.05) reduced ASC and caspase-1 levels in irisin-treated rats at 3 days post-tMCAO compared to saline controls, suggesting that irisin suppresses ASC expression or promotes its degradation to limit inflammasome assembly. Sholl analysis demonstrated that irisin-treated rats exhibited significantly (p<0.05) greater branching complexity at distal radii consistent with a more ramified state. Morphometric analysis also revealed 21% smaller soma areas in irisin-treated animals compared to saline. Together, our results indicate that irisin reduces microglial activation into an amoeboid, pro-inflammatory phenotype characterized by retracted processes and enlarged somas.
Conclusion: The current findings suggest that irisin promotes neuroprotection by limiting inflammasome complex protein levels and microglial activation, though further studies are needed to clarify the underlying mechanisms
A phase 1b/2 study on the efficacy and safety of BXQ-350, a first-in-class sphingolipid metabolism modulator, in combination with mFOLFOX7 and bevacizumab in newly diagnosed metastatic colorectal carcinoma
No full textTPS273 Background: Ceramides and sphingosine-1-phosphate (S1P) are key bioactive signaling molecules. Ceramides are proapoptotic and mitigate chemoresistance. Conversely, S1P promotes cancer cell proliferation, activates multiple oncogenic pathways, and stimulates immuno-suppressor cell populations promoting a pro-tumoral microenvironment. Several studies in colorectal cancer patients have shown high levels of ceramides are associated with improved survival, while high S1P levels are associated with a poor prognosis. Hence, modulation of sphingolipid metabolism could be a promising therapeutic approach. BXQ-350 is a nanovesicle of Saposin C, an allosteric activator of sphingolipid metabolism, that lowers systemic S1P and increases C18 ceramide. BXQ-350 was investigated in a Phase 1 dose-escalation safety study in cancer patients with advanced solid malignancies (NCT02859857). BXQ-350 was safe and well-tolerated (no DLT, no MTD). Methods: BXQ-350 is being investigated in a Phase 1b/2 study in combination with mFOLFOX7 and Bevacizumab in newly diagnosed mCRC patients (NCT05322590) to assess the efficacy and safety of BXQ-350. Design of the Phase 1b (open label study): A safety dose escalation part to establish the RP2D: patients will initially receive 1.8 mg/kg BXQ-350 in combination with mFOLFOX7 and Bevacizumab. If safe (no MTD), dose of BXQ-350 will be increased to 2.4 mg/kg and 9 additional patients will be entered at this dose level. If safe, then this dose will be the RP2D and 21 additional patients will be enrolled, completing a 30-patient expansion cohort. Efficacy will then be evaluated for all patients entered at the RP2D. Primary objectives of the Phase 1b are to assess safety, identify RP2D, and assess preliminary efficacy of BXQ-350 in this combination. A secondary objective is to determine if BXQ-350 decreases CIPN. Design of the Phase 2, a double-blinded, placebo-controlled study: Eligible patients (up to 160 patients) will be randomized in a 1:1 fashion to receive either BXQ-350 or placebo with mFOLFOX7 + Bevacizumab. Primary and secondary objectives include efficacy, safety and CIPN incidence. Enrollment in the Phase 1b dose escalation portion is completed. After review of the safety results, the DSMB approved enrollment of the expansion cohort, with a planned 30 patients at the Phase 2 dose. Primary endpoints are Cumulative Oxaliplatin Dose, ORR and Safety. Secondary endpoints are OS, PFS, DCR, CIPN, PK/PD and biomarkers. Clinical trial information: NCT05322590
GPT-5 and open-weight large language models: Advances in reasoning, transparency, and control
No full textThe rapid evolution of Generative Pre-trained Transformers (GPTs) has revolutionized natural language processing, enabling models to generate coherent text, solve mathematical problems, write code, and even reason about complex tasks. This paper presents a scientific review of GPT-5, OpenAI’s latest flagship model, and examines its innovations in comparison to previous generations of GPT. We summarize the model’s architecture and features, including hierarchical routing, expanded context windows, and enhanced tool-use capabilities, and survey empirical evidence of improved performance on academic benchmarks. A dedicated section discusses the release of open-weight mixture-of-experts models (GPT-OSS), describing their technical design, licensing, and comparative performance. Our analysis synthesizes findings from recent literature on long-context evaluation, cognitive biases, medical summarization, and hallucination vulnerability, highlighting where GPT-5 advances the state of the art and where challenges remain. We conclude by discussing the implications of open-weight models for transparency and reproducibility and propose directions for future research on evaluation, safety, and agentic behavior.
•Reviews GPT-5, OpenAI’s latest generative language model.•Details innovations: hierarchical routing and long-context windows.•Examines tool-use and benchmark performance in academia.•Introduces GPT-OSS: open-weight experts with transparent design.•Synthesizes findings on reasoning, bias, hallucination, summarization.•Explores transparency and reproducibility with open-weight models.•Suggests future work on evaluation, safety, and agentic behavior.•Contributes to discourse on information systems and AI transparency
Status and Operative Outcomes of the Fontan Procedure Performed Beyond the First Decade of Life in the United States
No full textThe Fontan operation is typically performed between two and five years-of-age in the United States. In this study, we analyzed the immediate outcomes of the Fontan operation performed beyond the first decade of life in the United States using a large administrative database.
Kids' Inpatient Database (2003-2019) and Nationwide Inpatient Sample (2016-2021) datasets were used; 10,245 pediatric patients undergoing the Fontan operation were identified. The cohort was divided into: Traditional Fontan (TF, 2-5 years-of-age, n = 9,900) and Late Fontan (LF, ≥10 years-of-age, n = 345); Survivor and non-survivor status were based on discharge mortality. Demographic and clinical characteristics were assessed using standard statistical tests.
Only 3% of the Fontan procedures (n = 345/10,245) belonged to the LF group. LF was comprised predominantly of non-Caucasian ethnicity, higher socioeconomic class, and had a greater comorbidity burden. Heterotaxy syndrome and total anomalous pulmonary venous return were more common in the LF group as compared with hypoplastic left heart syndrome in the TF group. Patients in the LF group experienced higher postoperative morbidity but similar mortality and often required specialized healthcare post-discharge. Multivariate regression analysis revealed inferior survival among Fontan patients with ECMO use, atrioventricular septal defect, coagulopathy, acute kidney injury, infection, prolonged mechanical ventilation, but not age at Fontan.
The proportion of patients undergoing LF compared with TF has decreased over time signalling a move toward earlier timing of the Fontan procedure. However, within the LF group, the number of LF patients has increased over time signifying an extended application of the Fontan operation. The patients in the LF group experienced greater postoperative morbidity with an associated higher baseline comorbidity but not short-term mortality after the Fontan procedure
2 - Pregnancy of Unknown Location, Early Pregnancy Loss, Ectopic Pregnancy, and Cesarean Scar Pregnancy
No full textPregnancy is an inefficient process. A large proportion of early pregnancies end in miscarriage or early pregnancy failure. Ectopic pregnancies (EPs), those located outside of the proper anatomic boundaries of the uterus, can cause significant maternal morbidity and mortality. This chapter will review the utility of ultrasound (US) in early pregnancy, when its use is essential in the differentiation of normal and abnormal gestation. The evaluation of pregnancy of unknown location, early pregnancy loss/failure, EP, and cesarean scar pregnancy is reviewed. The US findings of normal and abnormal pregnancies, as well as the synthesis of clinical, laboratory, and imaging findings, are described. Emphasis is placed on accurate diagnosis without overdiagnosis, which can place normal pregnancy at risk
97 - Ovarian and Other Adnexal Masses in Pregnancy
No full textThis chapter offers a comprehensive look at the epidemiology of adnexal masses during pregnancy. It delves into the different categories of adnexal masses, examines the diagnostic characteristics distinguishing benign and malignant masses, and explores suitable management strategies for clinicians managing the intricacies of pregnancy. The overarching goal is to offer clarity while consistently assessing the risks and benefits to both mother and fetus to guide informed decision-making that prioritizes optimal maternal-fetal outcomes in clinical practice
Patient Perspective: Closing the Gap
No full textFunctional neurological disorder (FND) is a neuropsychiatric disorder that manifests with involuntary neurologic symptoms because of a brain network dysfunction, arising from variable biopsychosocial etiologies. Symptoms have positive clinical features of inconsistency, like tremor entrainment or distractibility, and incongruence with typical or well-understood neurophysiology/neuroanatomy. FND is not a diagnosis of exclusion and diagnostic criteria are available for many FND phenotypes
Integrated histopathology of the human pancreas throughout stages of type 1 diabetes progression
No full textType 1 diabetes (T1D) is a progressive autoimmune condition that culminates in loss of insulin-producing beta cells. Pancreatic histopathology provides essential insights into disease initiation/progression yet an integrated perspective onto in situ pathogenic processes is lacking. Here, we combined multiplexed immunostaining, high-magnification whole-slide imaging, digital pathology, and semi-automated image analyses to interrogate pancreatic tail and head sections across T1D stages, including at-risk and at-onset cases. Deconvolution of architectural features, endocrine cell composition, immune cell burden, and spatial relations of ~25,000 islets effectively contextualizes previously established and additional pancreatic hallmarks in health and T1D. Our results reveal a spatially homogenous and islet size-contingent architectural organization of the endocrine pancreas, a notable coordination of organ-wide pathogenic processes, and multiple histopathological correlates that foreshadow distinctive T1D histopathology already at the preclinical stage. Altogether, we propose a revised natural history of T1D with implications for further histopathological investigations and considerations of pathogenetic modalities
Bypass of blocking lesions by RNAPII reveals a novel stress induced by DNA damage
No full textPlatinum-based compounds and ultraviolet (UV) irradiation produce bulky DNA lesions that stall RNA polymerase II (RNAPII), activating transcription-coupled nucleotide excision repair (TC-NER), RNAPII degradation, and global transcriptional shutdown. However, the consequences of RNAPII bypassing such lesions remain unclear. We identified the acetyltransferase p300 as a key regulator of TC-NER-dependent RNAPII removal from damaged chromatin via a USP7-dependent mechanism. Loss of p300 permits RNAPII to bypass transcription-blocking lesions, sustaining transcription and full-length mRNA production despite DNA damage. This leads to continued translation, endoplasmic reticulum (ER) stress, and activation of the unfolded protein response (UPR), compromising cell viability. Notably, this stress response resensitizes tumors resistant to platinum-based chemotherapy. Our findings reveal a vulnerability in tumor cells that evade transcriptional shutdown and define a synthetic lethal interaction between p300 inhibition and platinum-induced DNA damage, offering a targeted strategy to overcome chemoresistance