Citations

ABSTRACT Beta‐lactam antibiotics (beta‐lactams) are first‐line treatments for most major infectious syndromes in acutely ill patients, with in vitro activity against common pathogens, demonstrated efficacy in trials, and a perceived low risk of adverse effects. The current dosing approach, informed by population‐level data, tends to be simplistically reduced to a “one size fits all” dosing method which only accounts for body weight (i.e., in pediatrics) and end organ function to estimate drug clearance (e.g., estimated glomerular filtration rate); this approach results in substantial variability in observed serum concentrations in acutely ill patients, which can compromise real‐world effectiveness and safety. Beta‐lactam dose individualization, therefore, defined as a dosing regimen for one patient informed by measured concentrations from that patient, has been recommended in international clinical guidelines. Comprehensive guidance on best practices for beta‐lactam dose individualization is lacking. To address this knowledge gap and develop guidance, a multidisciplinary panel of international experts was assembled from the disciplines of infectious diseases, critical care, pharmacometrics, and laboratory medicine, representing both adults and pediatrics. The panel systematically evaluated the literature, using the GRADE approach where feasible, to address broad thematic questions pertaining to whether beta‐lactam dose individualization should be pursued, for what indications beta‐lactam dose individualization is warranted, and the most critical considerations and best practices for implementation of beta‐lactam individualization. The resultant consensus recommendations will equip healthcare professionals caring for acutely ill patients treated with beta‐lactam therapy with the evidence and tools necessary to guide optimal use of beta‐lactam dose individualization.

Abstract Introduction and Purpose: Immune checkpoint signaling represents a major barrier to effective antitumor immunity by suppressing cytotoxic T-cell activity. Cytokine-inducible SH2-containing protein (CISH) is a genetically validated intracellular immune checkpoint that constrains cytotoxic T-cell and natural killer cell signaling. Emerging evidence supports a critical, T cell-intrinsic role for CISH in lymphoma. Despite strong biological validation, CISH targeting has thus far been limited to genetic manipulation in adoptive cell therapies. We sought to establish CISH as a drug-tractable target by discovering a first-in-class, cell-permeable small-molecule CISH inhibitor/degrader suitable for scalable immunotherapy development. Methods: CISH biology was characterized using datasets of patients with B-cell lymphoma and isogenic cellular models to define target-dependence benchmarks. Structure-guided small-molecule discovery was enabled through homology modeling and AlphaFold-based predictions of CISH structure. A focused library of covalent CISH binders was synthesized using systematic variation of SH2-engaging motifs and electrophilic warheads. Compounds were evaluated using biophysical binding assays, mass spectrometry–based covalent engagement, cellular degradation, and signaling readouts. Results: Cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) analysis identified CISH as one of the most highly expressed genes in intratumoral T cells associated with a poor prognosis in patients with non-Hodgkin lymphoma, supporting disease relevance and target enrichment. Genetic ablation or knockdown of CISH in a T cell model (KARPAS299) induced reproducible, target-dependent phenotypes, including enhanced S-phase entry and augmented STAT5 phosphorylation following IL-2 stimulation, establishing rigorous cellular benchmarks for pharmacologic modulation. We designed and synthesized over 50 candidate CISH binders incorporating covalent SH2-domain engagement. Multiple compounds showed direct binding to CISH by thermal shift analysis and selective covalent modification at Cys144 by mass spectrometry. Introduction of a masked phosphate motif significantly improved intracellular exposure, confirmed using a BODIPY-labeled analog. Lead compounds demonstrated target engagement by cellular thermal shift assay and induced rapid, concentration-dependent degradation of endogenous CISH within 4 hours in cells, while maintaining high selectivity over related SOCS family members, demonstrating both target engagement and specificity. Conclusions: This work establishes CISH as a chemically tractable intracellular immune checkpoint and reports the discovery of the first selective, cell-permeable small-molecule CISH degrader. These data provide a strong foundation for further structure activity relationship optimization and position CISH degradation as a promising drug discovery strategy to modulate T cell function and enhance antitumor immunity. Citation Format: Hao Xie, Xinyi Tang, Sujeewa Ranatunga, Stephen M. Ansell. Discovery of a small-molecule degrader targeting the intracellular immune checkpoint CISH [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr B049.

ABSTRACT As a principal metabolite of ginsenosides, compound K (CK) exhibits remarkable antioxidant, anti‐inflammatory, antidiabetic, and anticancer bioactivities. However, CK is naturally scarce in ginseng and its industrial application is limited by the lack of efficient deglycosylating enzymes for large‐scale CK bioproduction. Here, we report a synthetic biology‐driven approach for high‐yield CK production via recombinant β‐glycosidase‐mediated bioconversion of the polar ginsenoside Rb1. The β‑glycosidase‐encoding gene was introduced into Escherichia coli BL21 (DE3), and the resulting engineered strain produced 2.1 g/L β‑glycosidase in shake flasks and 10.1 g/L in a 5‐L fermentor. The crude β‐glycosidase exhibited excellent enzymatic activity; at a concentration of 1.5 g/L, it converted 95% of the Rb1 substrate (initial concentration 10 g/L) to CK within 4 h. In vitro studies demonstrated CK's high cytocompatibility and potent anti‐aging effects, including suppression of reactive oxygen species ( via upregulation of superoxide dismutase, catalase, and glutathione peroxidase), enhanced collagen I, Ⅲ and elastin synthesis, and matrix metalloproteinase‐1 inhibition. These findings highlight CK as a promising candidate for anti‐wrinkle formulations, supported by the feasibility of scalable bioproduction.

Background The current classification of pulmonary hypertension (PH), based largely on expert opinion, has limitations in prognostication and guiding therapies. We hypothesize that novel PH clusters that predict survival will reveal mechanistic phenotypes associated with biomarkers of vascular health across all PH groups. Methods We first identify novel PH clinical clusters by performing unsupervised clustering analysis on the CC‐PH (Cleveland Clinic PH) registry (N=1529). We develop classification models to predict the new PH clusters and then apply them to the multicenter PVDOMICS (Pulmonary Vascular Diseases Phenomics) cohort (N=853) for validation. We compare transplantation‐free survival across the new PH clusters. We quantify metabolites of the arginine‐nitric oxide pathway and D‐dimer levels and calculate global arginine bioavailability (arginine/[ornithine+citrulline]) to assess endothelial function and activation in the new clusters and link these biomarkers to clinical outcomes. Results Clustering analysis identify 3 clear clusters in CC ‐ PH that are validated in PVDOMICS and outperform conventional classifications in predicting transplantation‐free survival. The phenotype associated with the worst survival is characterized by reduced lung diffusion capacity, decreased arginine bioavailability and nitrate levels, and elevated D‐dimer levels, consistent with loss of pulmonary microcirculation and endothelial dysfunction. Conclusions We identify new informative PH phenotypes associated with mortality and defined by biomarkers of endothelial function and activation. Loss of endothelial health and pronounced pulmonary vascular rarefication contribute more substantially to mortality across the spectrum of PH than right heart function. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02980887.

Most genetic variants associated with complex traits are hypothesized to regulate gene expression. To understand the genetics underlying gene expression variability, we characterized 14,324 RNA-sequencing samples from the Trans-Omics for Precision Medicine program and performed expression and splicing quantitative trait locus (e/sQTL) analyses in six tissues and cell types, including whole blood ( n = 6454) and lung ( n = 1291). We detected tens of thousands of secondary cis-e/sQTLs, showing that secondary cis-e/sQTL discovery remains unsaturated. We fine-mapped UK Biobank–derived genome-wide association study (GWAS) signals from 164 traits and identified e/sQTL colocalizations for 10,611 GWAS signals, including 7096 that colocalize with secondary e/sQTLs. Our results suggest that even larger e/sQTL analyses will uncover additional secondary e/sQTLs, further benefiting GWAS interpretation.

Context.— One objective of the College of American Pathologists/American College of Medical Genetics Cytogenetics Committee is to ensure the accurate detection and clinical interpretation of abnormalities observed by fluorescence in situ hybridization (FISH) analysis when evaluating hematologic neoplasms. Objective.— To report a 20-year performance summary (2005–2024) of FISH challenges focusing on hematologic neoplasms. Design.— A retrospective review was performed from 2005 through 2024 to identify FISH challenges specifically addressing hematologic neoplasms. The overall performance of participants was evaluated to identify potential recurring errors of clinical relevance. Results.— A total of 124 hematologic neoplasm FISH challenges from 2005 to 2024 were provided to participating laboratories, including 45 paper challenges (results and/or images were provided for interpretation purposes), 43 liquid challenges (bone marrow aspirate or peripheral blood), and 36 formalin-fixed paraffin-embedded (FFPE) tissue challenges. Of the 124 challenges, 120 (97%) exceeded the required 80% consensus for grading purposes. Of the 4 failed challenges (3%), 2 (1 liquid, 1 paper) involved the interpretation of atypical FISH signal patterns; 1 (paper) involved the interpretation of FISH signal patterns correlating involvement by myeloid versus lymphoid interphase nuclei; and 1 (liquid) likely involved a specimen processing or handling error that resulted in discordant participant responses. All 36 FFPE tissue challenges exceeded the 80% consensus for grading purposes. Conclusions.— This 20-year retrospective review demonstrates that clinical cytogenomic laboratories have been and continue to be highly proficient in the detection and interpretation of FISH abnormalities associated with hematologic neoplasms.

ABSTRACT Background Olfactory neuroblastoma (ONB) exhibits variable recurrence patterns, with significant late recurrences occurring years after treatment. We investigated cutoff periods to define late recurrence and identified predictors that distinguish patients at risk of late recurrence from those considered cured. Methods From a multi‐institutional cohort of 219 ONB patients treated at nine centers, we analyzed 77 patients with documented recurrence. Using a 48‐month cutoff to define early (< 48 months) versus late (≥ 48 months) recurrence, we evaluated 35 clinical, anatomic, and treatment variables using Firth penalized logistic regression across three comparisons: (1) late versus early recurrence timing, (2) late recurrence versus no recurrence, and (3) early recurrence versus no recurrence. Results Thirty‐four of the 77 (44.2%) recurrences were classified as late. Among the 77 patients who recurred, smaller tumor volume (OR 0.243, p = 0.035) and lower novel Dulguerov staging (OR 0.802, p = 0.038) were associated with late, rather than early recurrence. When patients with late recurrence were compared to those who remained disease‐free, radiographic skull base bone involvement was the strongest independent predictor (OR 2.90, 95% CI 1.14–8.64, p = 0.025), and this effect strengthened after adjusting for tumor volume (OR 3.80, p = 0.029). Pathologic dural invasion (OR 3.29, p = 0.013), Kadish stage (OR 2.02, p = 0.026), and T‐stage (OR 1.32, p = 0.040) were also significant. Conclusions A 48‐month cutoff effectively stratifies ONB recurrence risk. Skull base bone involvement independently predicts recurrence when compared to nonrecurrent cases and uniquely persists as a risk factor for late recurrence. These findings establish skull base bone involvement as a novel biomarker for risk‐stratified surveillance protocols.

Abstract Objective. Modern stereotactic neurosurgery increasingly relies on bilateral and multi-trajectory workflows (e.g. deep brain stimulation (DBS), stereoelectroencephalography (sEEG)), which can exceed the reach and flexibility of conventional frame-based systems. Building on our skull-mounted Navinetics D1 platform, we present a stereotactic frame (Navinetics E1) intended to expand the reachable work envelope, enable independent bilateral targeting, and preserve mechanical accuracy and patient comfort. Approach. We designed the Navinetics E1 stereotactic frame using a center-of-arc architecture with five degrees of freedom per hemisphere ( X, Y, Z , Arc, Collar) and two operating modes: Double Arm (independent left/right arms for simultaneous bilateral targeting) and Single Arm (mechanically coupled arms). The system was designed in CAD and fabricated via carbon fiber-reinforced polylactic acid (PLA-CF) additive manufacturing. Collision-aware MATLAB simulations quantified work volume and admissible approach directions. Mechanical targeting accuracy was evaluated on a ground truth fixture (GTF) platform, with mixed-effects modeling to assess target- and trajectory-dependent effects. Operative feasibility was assessed through an intraoperative entry-point replication test relative to the D1 system. Main results. Compared to the D1, the E1 frame significantly expanded key geometric ranges, including, most notably, 0°–360° Collar rotation and posterior Y -axis reach, thereby increasing the work volume and trajectory range by factors of 3.39 and 8.42, respectively. Mean GTF targeting deviation was 0.78 ± 0.38 mm in Single Arm mode and 1.23 ± 0.36 mm (right) and 1.65 ± 0.47 mm (left) in Double Arm mode. Entry-point replication across 17 clinical cases achieved 76.5% success in overlapping the reference points, providing preliminary evidence of feasibility under real operative conditions. Significance. The E1 frame extends a compact skull-mounted platform to support broader stereotactic reach and trajectory while enabling independent bilateral workflows. These features may reduce intraoperative reconfiguration for complex DBS and sEEG cases. Future work will focus on increasing structural stiffness, improving angular readout/setting, and developing MRI-compatible implementations.

Scattered tubular-like cells (STCs) are dedifferentiated renal tubular cells that repair other damaged kidney cells. This study shows that renovascular disease (RVD) induces site-specific 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) modifications in DNA associated with transcriptional changes and impaired proliferative capacity of swine STCs, which could be mitigated in RVD-STCs treated with an epigenetic modulator. Therefore, our observations may contribute to the development of novel approaches to preserve the reparative capacity of STCs in individuals with RVD.

BACKGROUND: Some symptomatic patients manifest pulmonary hypertension (PH), despite normal pulmonary vascular resistance and pulmonary artery wedge pressure—a condition termed unclassified PH. Although hypothesized to reflect increased flow as seen in congenital heart disease, broader clinical implications remain unknown. METHODS: The current analysis included pulmonary vascular disease phenomics participants with either no PH or unclassified PH who underwent dynamic right heart catheterization and transpulmonary metabolomics. In a validation cohort, patients with no PH or unclassified PH underwent exercise right heart catheterization. In exploratory cohorts to understand the impact of increased flow, the prevalence of unclassified PH was assessed in (1) adult congenital heart disease and (2) high output heart failure. RESULTS: The overall prevalence of unclassified PH in pulmonary vascular disease phenomics (n=1046) and the validation cohort (n=1202) was 7.8% (175/2248), which was comparable to the 6.6% (66/1005) prevalence in adult congenital heart disease (n=1005), and lower than high output heart failure (n=159, prevalence 14.5% [23/159]; P =0.006). Increased flow occurred in a minority of unclassified PH from both pulmonary vascular disease phenomics (28%; 15/53) and the validation cohort (11%; 13/122). Unclassified PH (n=53) was associated with greater adiposity, higher heart failure with preserved ejection fraction (HFpEF)–age, body mass index, atrial fibrillation score probability, and more left heart remodeling compared with those with no PH (n=216). Metabolomics revealed lower glycine metabolites in unclassified PH indicative of metabolic dysfunction. Left heart remodeling, quality of life, exercise capacity, and glycine levels were all abnormal in unclassified PH relative to healthy controls (n=96). In the validation cohort, pulmonary artery wedge pressure, pulmonary vascular resistance, and pulmonary artery compliance were subtly abnormal at rest in unclassified PH (n=122) compared with no PH (n=312). With exercise testing, 59% (72/122) with unclassified PH had exertional pulmonary artery wedge pressure elevation consistent with undiagnosed HFpEF. CONCLUSIONS: The presence of PH without obvious cause most often reflects subclinical left heart and metabolic dysfunction consistent with unrecognized early-stage HFpEF. Dynamic provocation during right heart catheterization can unmask unrecognized HFpEF in over half of unclassified PH, which may help guide appropriate initiation of proven HFpEF therapies to improve symptoms and functional status. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02980887.