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Abstract C009: Transcriptional regulation of CD19 by IKZF1 enhances CAR T-Cell immune targeting in mantle cell lymphoma
No full textMantle cell lymphoma (MCL) remains difficult to cure, and responses to chimeric antigen receptor (CAR) T-cell therapy vary in part due to modulation of target-antigen levels. We hypothesized that enhancing Ikaros transcription factor IKZF1, either directly by lentiviral overexpression or indirectly through inhibition of casein kinase 2 alpha (CK2α), a negative regulator of IKZF1 stability, would increase CD19 transcriptional output and thereby enhance CAR T-cell recognition and clearance of MCL cells. Human MCL cell lines JeKo-1 and Mino were engineered to overexpress IKZF1 using lentiviral vectors (controls: parental, empty-vector). Parallel experiments leveraged CK2α inhibition with silmitasertib to increase endogenous IKZF1 protein stability via reduced proteasomal turnover. CD19 surface density was quantified by flow cytometry with calibrated beads, CD19 transcripts by RT-qPCR, and promoter activity using CD19-luciferase reporters. Antitumor activity of CD19-directed CAR T cells was assessed in short-term co-cultures across effector:target (E:T) ratios, with target-cell viability (plate reader and flow cytometry) and cytokines (Lumit bioluminescence-based assay) collected at defined timepoints. For in vivo validation, luciferase-RFP-tagged JeKo-1/Mino xenografts were established in NSG mice followed by CAR T-cell infusion; tumor burden (bioluminescence) and survival were monitored longitudinally. IKZF1 overexpression increased CD19 mRNA and protein in JeKo-1 and Mino cells by ∼2.5- and 2.30-fold. CK2α inhibition produced a concordant phenotype, elevating endogenous IKZF1 and yielding proportional increases in CD19 surface density and transcript abundance. Promoter-reporter assays showed increased CD19 promoter activity. In vitro, CAR T-cell killing was enhanced by IKZF1 modulation: at E:T 1:1, viable target cells at hour 4 were 41.5% (IKZF1-OE) vs 63% (control), and the survival AUC decreased by 21.5%. CAR T-cell function mirrored antigen upregulation, with elevated IFN-γ, TNF, and IL-2 secretion (all p < 0.001) and reduced exhaustion-marker induction at 24 hours. CK2α-inhibited conditions similarly enhanced CAR T activation, supporting a mechanistic link between IKZF1 stabilization, heightened antigen availability and increased CAR T-cell target recognition and killing. In conclusion, increased IKZF1, either by direct overexpression or through CK2α inhibition, upregulates CD19 transcription and surface density in MCL, resulting in more rapid and durable CAR T-cell cytotoxicity in vitro and in vivo. These findings identify CK2α–IKZF1 as a druggable regulatory axis controlling antigen availability and highlight a complementary strategy to enhance CAR T-cell responses in MCL by maintaining or boosting CD19 expression. Ongoing CHIP-seq experiments will define IKZF1 occupancy at the CD19 locus and durability and safety across additional MCL in vivo models
Routine collection of patient-reported outcomes in HIV clinics: lessons learned after more than 130,000 assessments have been completed
No full textPatient-reported outcomes (PROs) provide important information to improve healthcare and facilitate research but can be difficult to implement in busy care settings.
We integrated PRO collection into HIV care (2008-2024) with results summarized for providers to improve clinical care.
PWH presenting for HIV care at nine clinics across the US in the CFAR Network of Integrated Clinical Systems (CNICS) were asked to complete a touch-screen-based PRO assessment at routine clinic visits using a web-based application.
21,725 PWH completed the CNICS clinical PRO assessment 132,240 times (mean 6.1 assessments per PWH). Mean age at initial assessment was 43.8 years, 24.9% screened in for depression, 35.5% reported heavy episodic (binge) drinking, 38.9% smoking, 10.9% methamphetamine use, 11.7% recent intimate partner violence, and 8.4% reported unstable housing in the prior 30 days.
We implemented a PRO assessment into HIV care at nine geographically dispersed clinics. PRO responses in domains known to drive adverse outcomes such as substance use were identified as were situational concerns such as unstable housing. This study demonstrated that use of a well-designed PRO platform can address many of the barriers of paper and interview-based collection and be sustainable over time even as clinic flow and content priorities evolve. It demonstrated that PROs done for clinical care are useful to address clinically relevant research questions and institutional needs. Finally, this study demonstrated the feasibility of wide-spread implementation of a clinical PRO assessment into busy HIV clinical care settings with >130,000 assessments completed to date
Ketamine is Associated with Increased 24-Hour Mortality Following Traumatic Brain Injury Compared with Other Induction Medications, a Retrospective Study
No full textKetamine is a dissociative anesthetic often used for airway management in trauma. While perceived to preserve hemodynamic stability, concerns exist regarding its effects on intracranial pressure and cardiac output in critically ill patients. There is a lack of studies evaluating outcomes after ketamine administration in the setting of traumatic brain injury (TBI). This study aimed to investigate the effects of ketamine on outcomes and physiological responses in a large cohort of TBI patients. We hypothesized that ketamine administration would not be associated with differences in survival, vital signs, or disposition outcomes compared with other induction medications when administered following TBI. This was a retrospective, observational study utilizing data from the Linking Investigations in Trauma and Emergency Services registry (2017-2021). Subjects were divided into two groups: those who received only ketamine (n = 429) and those who received other induction medications (etomidate and/or propofol; n = 993). We compared 24-h mortality, initial in-hospital vital signs (systolic blood pressure [SBP], respiratory rate, heart rate, and Glasgow Coma Scale [GCS]), and hospital discharge disposition; a propensity score analysis adjusted for potential confounders including race, injury type, pre-hospital GCS, initial pre-hospital SBP and site location. Ketamine-exposed subjects were younger and presented with a worse clinical profile, including lower pre-hospital GCS (5 vs. 6, p < 0.01) and lower SBP (126.5 vs. 144.0 mmHg, p < 0.01) compared with the ketamine-unexposed group. Unadjusted analysis showed a significantly higher 24-h mortality rate in the ketamine-exposed group (3.5% vs. 1.4%, p = 0.02), as well as lower initial in-hospital vital signs. After propensity score adjustment, the odds of 24-h mortality remained significantly higher for the ketamine-exposed group (OR 2.358, p = 0.042). Hospital discharge disposition was not different between groups in any analysis. In this retrospective analysis, ketamine administration for pre-hospital airway management in TBI patients was associated with an increased 24-h mortality and lower in-hospital SBP, even after adjusting for baseline differences. However, injury severity and the length of time examined for mortality may explain the significant mortality association for ketamine in this study. Prospective studies are needed to examine the relationship between ketamine administration and mortality following TBI
Utilization of Dry Blood Spot in Clinical Diagnostics
No full textThis work evaluates the clinical viability of dried blood spot (DBS) sampling as an alternative to traditional venous blood collection for diagnostic applications. While conventional phlebotomy remains the standard, it is often limited by logistical, economic, and accessibility constraints, particularly in large-scale and resource-limited settings. DBS sampling offers a minimally invasive approach with advantages including simplified collection, enhanced analyte stability, and reduced storage and transport requirements.Two DBS-based diagnostic assays were developed and analytically validated. The first, a quantitative testosterone assay using liquid chromatography–tandem mass spectrometry (LC-MS/MS), demonstrated excellent analytical performance, including high linearity (0.1–100 ng/mL), low limits of detection and quantification, and strong agreement with serum measurements (R² ≈ 0.99). Precision and accuracy met established validation criteria, and analyte stability was maintained for up to 30 days under various conditions. The second assay, an RT-PCR–based genotyping method, evaluated 16 single nucleotide polymorphisms associated with type 2 diabetes risk. This assay showed high concordance (>85%) with conventional venous blood methods and strong reproducibility, confirming the suitability of DBS for molecular genetic analysis.Collectively, these findings demonstrate that DBS is a robust and versatile platform capable of supporting both biochemical and molecular diagnostics. The validated assays highlight the potential of DBS-based testing to expand diagnostic accessibility, facilitate decentralized and large-scale screening, and support preventive healthcare strategies.</p
Chapter 37 - Extracellular ATP in sensory disorders with a focus on protective purinergic hearing adaptation
No full textExtracellular adenosine 5'-triphosphate (ATP) is a key homeostatic regulator of sensory systems, with signal transduction via ATP-gated ion channels (P2X receptors) prominent across a broad range of mechanisms. This dependency of sense organs on ATP signaling is highlighted in the cochlea. Local autocrine/paracrine signaling by extracellular ATP within the cochlear partition is activated by sustained elevated noise and leads to protective desensitization of the outer hair cell-mediated “cochlear amplifier” and hence protects against glutamatergic excitotoxicity at the inner hair cell-type I spiral ganglion neuron synapses. Single-nucleotide polymorphisms of the P2RX2 gene encoding P2X2 receptor (P2X2) channels have been identified, which demonstrate the significance of this adaptive mechanism for sustained resistance to noise- and age-related hearing loss (DFNA41 autosomal dominant nonsyndromic hearing loss). The “purinergic hearing adaptation postulate” delineated here considers the purinergic interactome engaging P2X2 signaling, which likely drives a spectrum of vulnerability to hearing loss inherent to the diversity in the strength of the signaling process. This encompasses factors affecting how acoustic energy drives ATP release within the cochlear partition, the production and trafficking of P2X2 to the endolymph-facing membrane surfaces of the sensory hair cells, supporting cells, and epithelial tissues, as well as degradation processes (ecto-nucleotidases) and downstream signaling cascades associated with Ca2+ dynamics. All these “physiological elements” affected by gene expression, protein translation and posttranslational modifications, trafficking and chaperone proteins, in toto, confer unique individual profiles of otoprotection that likely in part contribute to the breadth of diversity in vulnerability to hearing loss in the population
Advances in Minimally Invasive General Surgery: A Narrative Review of Techniques, Technologies, and Patient Outcomes
No full textMinimally invasive general surgery (MIGS) encompasses a broad spectrum of contemporary operative techniques and technologies, including laparoscopy, robotic assistance, novel access approaches, advanced energy platforms, enhanced imaging, and emerging digital tools. This narrative review, conducted through a structured literature search of major medical databases, critically examines the evolution of these innovations and their impact on surgical practice, patient outcomes, and healthcare systems. Evidence from randomized controlled trials, meta-analyses, and large observational studies published over the past decade indicates that MIGS is generally associated with reduced postoperative morbidity, shorter hospital stay, reduced postoperative pain, faster functional recovery, improved cosmetic outcomes, and enhanced patient-reported quality of life compared with open surgery. However, important limitations persist, including heterogeneity in study design, limited long-term outcome data for emerging technologies, steep procedural learning curves, and disparities in global access. Particular emphasis is placed on the incorporation of artificial intelligence (AI), machine learning (ML), and simulation-based training, which hold the potential to enhance operative precision and accelerate skill acquisition but require rigorous validation and ethical oversight. Cost-effectiveness and international dissemination remain central concerns, underscoring the need for scalable innovations and standardized training models to achieve equitable adoption. Sustainable advancement in MIGS will depend on rigorous evidence generation, structured training pathways, cost-conscious implementation, and policies that promote equitable access across healthcare systems
Androgen and glucocorticoid receptor activation is co-regulated via tissue-specific metabolism by 11[beta]-hydroxysteroid dehydrogenases
No full textPrognostic Factors and Progression Biomarkers in AL Amyloidosis: Mapping Current Knowledge and Critical Gaps
No full textThe therapeutic landscape for systemic immunoglobulin light chain (AL) amyloidosis has beenrevolutionized by daratumumab-based regimens, achieving 76% five-year overall survival in thelandmark ANDROMEDA trial. However, the current prognostic models were developed using patientpopulations treated with now-suboptimal therapies, creating a critical gap between riskstratification models and contemporary outcomes. This comprehensive review analyses prognosticfactors and progression biomarkers in AL, categorizing them into disease-specific (clone-relatedand organ-related) and patient-specific factors. Notably, traditional baseline biomarkers includingdifference between involved and uninvolved free light chains (dFLC) and bone marrow plasma cellburden are losing prognostic significance with effective clone-directed therapies. Emergingapproaches show promise, including dynamic markers such as minimal residual disease by free lightchain mass spectrometry, cardiac imaging parameters such as global longitudinal strain, andfunctional measures. There is an urgent need for validation studies and prognostic model refinementto identify high-risk patients who may benefit from interventions beyond anti-plasma cell therapy
Інвазійні комахи-шкідники інтродукованих рослин дендрологічного парку “Олександрія” НАН України. Повідомлення 3: щодо біології Pineus orientalis (Dreyfus, 1889) (Heteroptera: Adelgidae)
No full textThe article discusses problems associated with the introduction of plants and the accompanying invasion of new species of insect pests into park plantings. It emphasises the urgent need to study their biology. The paper describes some biological features of one of the invasive species of pests – the Eastern pine adelgid, Pineus orientalis. The data on phenology, feeding and reproductive features, number of generations, composition of life cycle morphs, and damage caused by P. orientalis to its forage plants are presented.У статті розглядаються проблеми, пов’язані з інтродукцією рослин та супутнім вторгненням нових видів комах-шкідників у паркові насадження. Підкреслюється нагальна необхідність вивчення їхньої біології. В статті описано деякі біологічні особливості одного з інвазійних видів – східного соснового хермеса (Pineus orientalis). Вперше представлені дані про фенологію, особливості харчування і розмноження, числу генерацій, складу морф життєвого циклу, а також шкодочинність P. orientalis
Selective Private Disclosure: Is Silence Golden?
No full textI present evidence that market participants use Reg FD filings to learn about and price protect against firms' material selective private disclosure ("SPD") activity. Using an expectation of SPD activity based on observable firm events associated with informed trading, I document that market participants price protect whenever Reg FD filings deviate (positively or negatively) from that expectation. Intuitively, market participants price protect more when Reg FD filings exceed their expectations, consistent with higher-than-expected Reg FD filings being interpreted as an indication of higher-than-expected SPD activity. However, market participants also price protect more when Reg FD filings fall short of their expectations, suggesting that market participants do not interpret lower-than-expected Reg FD filings as a signal of lower-than-expected SPD activity, but rather as an indication that the firm has not transparently disclosed that activity. Collectively, my analyses suggest that, although imperfect Reg FD disclosure fails to curtail SPD ex-ante, it does provide useful information against market participants' expected benchmarks ex-post.</p