AdventHealth Orlando

Prostate cancer (PCa) remains a leading cause of cancer-related mortality in men globally, with castration-resistant prostate cancer (CRPC) representing a particularly challenging stage of disease. Despite therapeutic advances, including androgen receptor inhibitors (ARPIs), taxane-based chemotherapy, and radiopharmaceuticals, durable responses in metastatic CRPC (mCRPC) are limited. Immunotherapy, especially chimeric antigen receptor (CAR) T cell therapy, has revolutionized hematologic malignancies, yet its application in solid tumors like prostate cancer remains under investigation. We conducted a systematic review in accordance with PRISMA guidelines to evaluate all published and registered clinical trials (2014–2024) involving CAR-T therapy in prostate cancer. Databases searched included PubMed, ClinicalTrials.gov, and Cochrane. Studies were screened using stringent inclusion/exclusion criteria and analyzed for trial phase, antigen targets, dosing, safety (cytokine release syndrome [CRS], neurotoxicity, dose-limiting toxicities [DLTs]), and early efficacy outcomes. Data extraction was performed independently by two reviewers with AI-assisted adjudication. Out of 32,565 records, 27 trials met inclusion, of which 8 had published outcomes. Eight early-phase trials investigated CAR-T therapies targeting PSMA, PSCA, and other tumor-associated antigens (e.g., CD70, GD2, TGFβDN). PSMA-directed CAR-T trials showed variable safety and preliminary efficacy, with some reporting PSA reductions > 50% and radiographic partial responses. CRS (Grade 1–2) occurred in up to 100% of patients, with isolated cases of neurotoxicity and fatal adverse events in higher-dose cohorts. Trials employing armored CARs (e.g., TGFβDN, iCasp9 switches) demonstrated improved persistence and early anti-tumor activity. The use of dual-target CARs and gene-editing strategies (e.g., piggyBac transposons, PD-1 knockouts) reflect the field’s evolving precision. CAR-T therapy in prostate cancer, particularly mCRPC, is a promising yet nascent field marked by heterogeneous safety profiles and early signs of efficacy. PSMA remains the most validated target, though antigen escape and tumor microenvironment barriers continue to limit success. Innovative constructs and combinatorial strategies may enhance clinical outcomes. Continued trial development and refinement are critical to unlocking CAR-T’s potential in solid tumors. Question: What are the current advancements and challenges in CAR-T cell therapies for metastatic castration-resistant prostate cancer (mCRPC)? Findings: Multiple phase I/II trials targeting various antigens such as PSMA, PSCA, CLDN6, STEAP2, EpCAM, and others demonstrate partial responses and disease stabilization with variable safety profiles. Novel strategies include PD-1 blockade, incorporation of costimulatory domains like 4-1BB, and targeting unique T-cell subsets such as γδ T cells. Challenges remain with CAR-T cell persistence, tumor microenvironment resistance, and immune-related toxicities. Meaning: CAR-T therapy for mCRPC shows promise but requires multimodal approaches and further optimization to overcome tumor heterogeneity and immunosuppressive microenvironments for improved efficacy and safety.

SUMMARYThe goal of the Molecular Transducers of Physical Activity Consortium (MoTrPAC) is to examine the physiological and molecular basis for health benefits in response to acute and chronic exercise. Prior to COVID-19 suspension, healthy, sedentary participants (N=206, 18-74y) were randomized to endurance exercise (N=80), resistance exercise (N=81), or non-exercise control (N=45) interventions. The prescribed vigorous acute endurance and resistance exercise bouts induced physiological and metabolic perturbations relative to resting homeostasis. The supervised chronic (3d/wk, 12wk) endurance or resistance training programs robustly improved several physiological parameters (i.e., VO2peak, muscular strength). Temporal biospecimen (blood, muscle, and adipose) collections and processing coupled to the acute exercise bouts were highly successful. In most cases, over 90% success was achieved for blood, muscle, and adipose samples. Endurance and resistance exercise induced distinct acute and chronic physiological responses, which provide a framework to interrogate the molecular basis for health adaptations to these two popular exercise modalities. Figure

Introduction: Parapneumonic effusions and empyema cause significant morbidity and mortality. Intrapleural tissue plasminogen activator (tPA) and dornase alfa (DNase) can improve drainage and avoid surgery, but optimal real-world dosing and the comparative effectiveness of combination versus monotherapy are unclear. We assessed the efficacy and safety of a standardized protocol using intrapleural tPA with or without DNase for complicated pleural infections in a large health system. Methods: In this multicenter, retrospective cohort study (Jan 2019–Dec 2020), we included adults with complicated parapneumonic effusions, empyema, or hemothorax receiving intrapleural tPA±DNase via a standardized protocol. The protocol utilized tPA 20-50 mg once daily with optional DNase 5 mg once daily. The primary outcome was treatment success, defined as avoidance of surgery and survival to discharge. Secondary outcomes included change in chest tube drainage, length of stay, mortality, major bleeding, and peri-procedural pain. A post-hoc analysis compared tPA monotherapy with combination therapy. An artificial intelligence language model was used to edit this abstract for clarity, conciseness, and for consistency with the manuscript. The authors maintained full editorial control over the final version. Results: Of 172 patients screened, 120 were included (median age 69, 50.8% male). Treatment success was achieved in 102 patients (85.0%). Median chest tube drainage increased by 488 mL (IQR 73, 979). Major bleeding occurred in one patient (0.8%) and peri-procedural pain requiring analgesics in 69 (57.5%). In a subgroup analysis of combination therapy (n=46) vs. monotherapy (n=74), treatment success was 87.0% vs. 83.8% (p=0.636), respectively. Conclusions: Intrapleural tPA±DNase, guided by a standardized protocol, resulted in a high rate of treatment success and increased pleural drainage. Major bleeding was rare, while peri-procedural pain was common. The post-hoc analysis showed no significant benefit for combination therapy over tPA monotherapy, a finding which requires cautious interpretation due to study limitations. These findings support intrapleural fibrinolytics as an effective and relatively safe real-world strategy, though future prospective studies are warranted to optimize use.

Skeletal muscle (SkM) insulin resistance is a central defect in T2D, yet cell specific molecular determinants remain incompletely understood. Here, we integrate full-length single-nucleus transcriptomics with gold-standard stable isotope-labeled hyperinsulinemic-euglycemic clamps to generate a nucleus-resolved transcriptomic atlas of SkM insulin resistance. We identify previously unrecognized myonuclear populations whose proportions associate with insulin sensitivity across independent cohorts, revealing MYH7B+ myonuclei are metabolically favorable over EGF+ myonuclei. Modeling transcriptional variation against tracer-derived glucose disposal uncovers highly nucleus-specific molecular programs that are obscured when using surrogate fasting indices. Mechanistically, we identify zinc transporter ZIP14 as a positive regulator of insulin-stimulated glucose uptake and implicate EGF signaling in impaired branched-chain amino acid catabolism and inflammatory cross-talk within the SkM niche. Together, these findings redefine SkM insulin resistance as a multicellular, nucleus-resolved process and highlight new cell type specific targets for metabolic intervention.

To compare the ALGO Smart Pump (ALGO), operating in Adaptive Pulsatile Aspiration (APA™) and Static modes, with the Penumbra ENGINE during in-vitro mechanical thrombectomy, and to determine whether adaptive pulsatile aspiration improves complete clot ingestion (CCI) and reduces aspiration time across catheters sizes and catheter-to-artery (C/A) ratios. Apre-specified integrative analysis of two previously completed in-vitro thrombectomy studies was conducted using astandardized middle cerebral artery occlusion model. Atotal of 720 thrombectomy procedures were performed by two experienced operators using twelve commercial catheters (six small-bore, six large-bore). Three aspiration modalities were tested: ALGO APA™, ALGO Static, and Penumbra ENGINE continuous aspiration (n = 30 per catheter-pump pairing). The primary endpoint was CCI; secondary endpoint was aspiration time. Outcome analysis included two-way ANOVA and Chi-squared tests, with catheter, operator, and C/A ratio terms. The ALGO demonstrated ahigher median CCI rate than Penumbra (81.4% vs. 56.1%, χ2(1) = 52.364, p < 0.001). Aspiration times were significantly shorter with ALGO, particularly in APA™ mode (43.8 s vs. 60.6 s, p < 0.001). Two-way ANOVA demonstrated significant interaction between catheter size and pump type (p < 0.001), with ALGO notably improving small-bore catheter performance. CCI correlated positively with catheter-to-artery (C/A) ratio across both systems, with ALGO maintaining higher success across all ratios. Adaptive pulsatile aspiration enhances clot ingestion efficiency and reduces aspiration time in an in-vitro thrombectomy model, particularly for smaller catheters. These findings support further translational studies on optimizing aspiration dynamics to enhance first-pass success in endovascular stroke therapy.

A female patient in her mid-20s presented with fevers, rash and polyarthralgia and was ultimately diagnosed with macrophage activation syndrome (MAS), a widely recognised form of secondary haemophagocytic lymphohistiocytosis in the setting of autoinflammatory disease such as adult-onset Still's disease. Extensive infectious and malignancy workup was negative. Her clinical course was complicated by persistently active disease despite initial immunomodulator therapies, including corticosteroids and anti-interleukin-1 therapy (anakinra). Further escalation of therapy with tocilizumab and etoposide yielded insufficient, partial improvement. Given the refractory nature of her condition, we initiated treatment with emapalumab, an anti-interferon-γ antibody, which led to significant symptom control. We subsequently added Janus kinase inhibitor (JAK), ruxolitinib, and continued anakinra until complete resolution of symptoms and normalisation of laboratory values. The patient was then discharged on a stable dose of ruxolitinib, anakinra and prednisone. This case illustrates the therapeutic challenges in managing refractory MAS and highlights the emerging role of targeted therapies such as emapalumab and JAK inhibitors in treatment-refractory cases.

This review examines the mechanistic pathways linking obesity and cardiovascular disease, with particular emphasis on recent advancements in pharmacologic therapies. It evaluates the cardiovascular effects of novel anti-obesity medications and their integration into current treatment paradigms. Additionally, these pharmacologic strategies are contextualized alongside lifestyle interventions and metabolic bariatric surgery. Incretin agonist therapies, including both glucagon-like peptide-1 (GLP-1) receptor agonists and dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists have shown substantial efficacy in weight reduction and cardiometabolic improvement. Clinical trials have demonstrated that these agents not only reduce body weight by 10-20% but also significantly lower the risk of major adverse cardiovascular events, including cardiovascular death, nonfatal myocardial infarction, and stroke. These benefits have been observed in both patients with and without diabetes mellitus, and the cardiovascular protection extends beyond glycemic control. Tirzepatide, in particular, has shown superior efficacy compared to GLP-1 monotherapy in weight loss. Pharmacologic therapy has become a central pillar in the management of obesity-related cardiovascular risk. The emergence of agents with proven efficacy in both weight reduction and cardiovascular outcome improvement marks a paradigm shift in treatment. These findings support early and sustained use of pharmacotherapy in high-risk individuals, highlighting a need for integrated, personalized care strategies in obesity management.