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PubMed2026

An Integrated Proteomics and Genomics Approach to Identify Essential Protein Kinases During Human Trophoblast Development.

In the developing human placenta, three subtypes of trophoblast cells, cytotrophoblasts (CTBs), extravillous trophoblasts (EVTs), and syncytiotrophoblasts (STBs), mediate critical functions essential for a successful pregnancy. CTBs constitute the stem/progenitor compartment and differentiate into STBs and EVTs within the floating and anchoring villi, respectively. STBs establish the maternal-fetal exchange interface and secrete human chorionic gonadotropin (hCG), a hormone vital for the maintenance of early pregnancy. EVTs anchor the maternal endometrium and invade the uterine tissue to remodel maternal cells, supporting implantation and progression of pregnancy. In this study, we used human trophoblast stem cells (hTSCs) as a model system and performed quantitative, label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) to profile the proteome and phosphoproteome in TSC stem state (analogous to undifferentiated CTBs) and following their differentiation to STBs and EVTs. Through a multiomics approach, we integrated our proteomics data with global gene expression profiles to correlate cell-type specific gene and protein expression during human trophoblast development. We also identified global phosphoproteome and analyzed kinases that are specifically active in hTSC stem state, as well as in differentiated STBs and EVTs. We experimentally validated specific kinases, such as BUB1B, PAK6, PKYMT1, and TNIK, that are essential for maintaining the hTSC stem-state. Additionally, atypical protein kinase C isoforms PKCζ are essential for STB development, whereas PTK2B, SRC, TRIO, and LYN are important for EVT development. Our findings highlight key kinases uniquely required for specific stages of trophoblast development during human placentation and suggest that pharmacological inhibition of these kinases could negatively impact the placentation process during pregnancy.

Humans↗

PubMed2026

Development of a cell-based nanoluciferase reporter system for high-throughput screening of HBV cccDNA inhibitors.

Hepatitis B virus (HBV) persistence is sustained by the viral covalently closed circular DNA (cccDNA) minichromosome, which remains a major barrier to curative antiviral therapies. The lack of reliable quantitative cccDNA detection methods and surrogate markers has hindered efforts to target cccDNA in antiviral high-throughput screening (HTS). Here, we established a novel inducible cccDNA-dependent nanoluciferase (NLuc) reporter cell line, designated HepBLE12, by inserting an in-frame 11-amino acid split-NLuc HiBiT tag into the precore (pC) coding region of an HBV transgene. The resulting 1.3-kDa HiBiT tag on pC serves as the detection module of the split NLuc system, generating quantitative luminescence upon high-affinity complementation with the cognate 18-kDa LgBiT subunit in cell lysates. Notably, the HiBiT assay enables direct detection of intracellular HiBiT-pC protein rather than secreted HBeAg, providing a reporter signal more closely linked to cccDNA activity. HepBLE12 cells exhibited inducible and robust viral DNA replication, and the cccDNA-dependent HiBiT signal was validated under diverse experimental conditions that modulate cccDNA formation or transcription. We further miniaturized the assay to a 384-well format and optimized key parameters following standard HTS assay development practices. The assay was successfully automated and demonstrated excellent performance in a multi-day variability study and a pilot screen, with signal-to-background (S/B) ≈ 9, coefficient of variance (CV) < 10%, and average Z-factor value of 0.74, exceeding canonical HTS quality benchmarks. Together, the HepBLE12 cell-based HTS platform provides a robust and practical tool for identifying inhibitors targeting HBV cccDNA.

Hepatitis B virus↗

PubMed2026

Safety and efficacy of immune checkpoint inhibitors as a bridge to allogeneic hematopoietic stem cell transplantation in classical Hodgkin lymphoma: A systematic review and meta-analysis.

Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for relapsed or refractory classical Hodgkin lymphoma (cHL); however, a substantial subset of patients ultimately requires allogeneic hematopoietic stem cell transplantation (allo-HCT) to achieve long-lasting disease control. The use of ICIs as a bridge to allo-HCT has therefore gained increasing clinical interest, though concerns persist regarding post-transplant complications and incompletely-defined safety profiles. Accordingly, this systematic review and meta-analysis was conducted to evaluate outcomes of ICIs administered prior to allo-HCT in cHL. Following PRISMA guidelines, a comprehensive literature search was conducted across online databases through January 2026. Eligible studies included observational designs reporting survival and transplant-related outcomes in cHL patients treated with ICIs followed by allo-HCT. Pooled proportions for overall survival, progression-free survival, non-relapse mortality, and graft-versus-host disease (GVHD) incidence were calculated using a random-effects model. Seven studies comprising 739 patients were included. Post-transplant survival outcomes were favorable, with high pooled estimates across timepoints. Transplant-related mortality remained low, with NRM rates consistently within an acceptable range through long-term follow-up. Acute GVHD was observed at a meaningful frequency, including a smaller subset of severe cases, while chronic GVHD occurred in approximately one-quarter of patients at follow-up. Overall, these findings suggest that ICI therapy prior to allo-HCT in cHL is associated with encouraging survival and disease control and does not appear to confer excessive non-relapse mortality, supporting its use as a feasible and effective bridging strategy, while underscoring the need for future prospective studies to clarify optimal timing, risk mitigation strategies, and patient selection.

Humans↗

PubMed2026

Is There a Difference in Occurrence of Complications Between Adults With Hemoglobin SS and Hemoglobin SC Disease: An Extended Systematic Review.

Sickle cell disease (SCD) is characterized by both acute and chronic complications. The clinical manifestation of these complications differs between genotypes. Given the large amount of research already published, this systematic review aims to offer a complete overview of types of sickle cell complications between adults in the most common genotypes Hemoglobin SS (HbSS) and Hemoglobin SC (HbSC), putting options for further research into perspective. An extensive literature search was performed to study all available evidence on these complications. This review was performed according to the "Preferred Reporting Items for Systematic Reviews and Meta-Analyses" (PRISMA) statement guidelines, and was performed on January 2, 2024. A total of 710 references were identified. After careful screening, 521 records were excluded based on title and abstract and other exclusion criteria. In total, 158 articles were excluded after full-text assessment. Our analysis of 31 studies highlights key differences in complications between HbSS and HbSC genotypes in sickle cell disease (SCD). Vaso-occlusive crises (VOCs) remain the most common acute complication in both genotypes. HbSS patients experience more frequent VOCs, while HbSC patients generally have a milder clinical course when it comes to acute complications. Chronic complications, particularly in the ocular and pulmonary systems, are more prevalent in HbSC patients. However, as acute complications are more common in HbSS and chronic complications more common in HbSC, both genotypes face progressive organ damage due to recurrent ischemic injury and inflammation.

Humans↗

PubMed2026

Role of omentin-1 in the global proteome of porcine pituitary cells: insights into proliferation- and apoptosis-related processes.

The anterior pituitary integrates endocrine regulation, cellular growth, and adaptive responses. Adipokines, secreted mainly by adipose tissue, act as hormonal signals linking metabolism, inflammation, appetite, and reproduction. They regulate hypothalamic-pituitary-ovarian axis by modulating hormone secretion and intracellular signaling. The presence of adipokine receptors in anterior pituitary suggests local metabolic-endocrine interactions. Omentin-1, predominantly expressed in visceral adipose tissue, participates in glucose metabolism and ovarian steroid regulation. Recent findings indicate that omentin-1 modulates tropic hormones, their receptors, and adipokine balance in anterior pituitary cells. We hypothesized that omentin-1 affects protein expression and signaling pathways involved in pituitary cell proliferation and apoptosis. This study examined its effects in anterior pituitary cells from Large White and Meishan pigs. Proteomic analysis identified 230 candidate differentially abundant proteins after omentin-1 treatment: 30 downregulated and 3 upregulated in Large White pigs, and 107 downregulated and 90 upregulated in Meishan pigs, associated with enriched 116 Gene Ontology terms. Key proteins were associated with cell cycle, DNA replication, gene expression, and posttranscriptional/posttranslational regulation. Responses differed between breeds. CDK5RAP2 and SIX1 were linked to proliferative control in Large White pigs, whereas AKT1S1 and RHOA were among the proteins associated with the broader proteomic response observed in Meishan pigs. Meishan pigs showed dynamic apoptotic protein regulation, including HTRA2, PARP2, and DFFA. Complementary in vitro experiments demonstrated that omentin-1 downregulated cyclins and caspase-3, upregulated BCL2, increased BCL2/BAX ratio, and modulated ERK1/2, AKT, AMPKα, and STAT3 phosphorylation. Together, these findings suggest that omentin-1 modulates proteomic networks and intracellular signaling associated with anterior pituitary cell function during the mid-luteal phase of the estrous cycle.

Animals↗

PubMed2026

Diagnostic value of plasma cell-free DNA metagenomic next-generation sequencing in patients with suspected infections and exploration of clinical scenarios-a retrospective study from a single center.

BACKGROUND: Plasma cell-free DNA metagenomic next-generation sequencing (mNGS) is a non-invasive comprehensive method for the etiological diagnosis of various infectious diseases. However, research on the early diagnosis and real-world clinical impact of plasma mNGS in patients with suspected infection are still limited. MATERIALS AND METHODS: This study retrospectively included 140 patients with suspected infections who underwent early plasma mNGS and conventional culture testing. Referring to the clinical diagnosis of infectious diseases, the diagnostic performance of plasma mNGS and culture tests was compared, and the application scenarios and clinical effects of plasma mNGS were evaluated. RESULTS: The positive rate of plasma mNGS was significantly higher than that of culture methods (55.71% vs 25.10%, p < 0.001) and blood cultures (55.71% vs 12.86%, p < 0.001). Regarding clinical diagnosis, the sensitivity of plasma mNGS was significantly higher than that of culture (58.27% vs 37.80%, p = 0.002). The combination of mNGS and culture achieved a higher detection sensitivity (69.29%), especially in patients with multi-site co-infections (73.68%) and blood infections (73.17%). Plasma mNGS demonstrated higher sensitivity in patients with procalcitonin (PCT) index > 5 ng/ml or human neutrophil lipocalin (HNL) index > 200 ng/ml. In terms of treatment, a total of 69 patients (54.33%) benefited from plasma mNGS. CONCLUSION: This study highlights the significant improvement in pathogen detection performance by combining conventional culture with plasma mNGS detection, especially in patients with multi-site co-infections and blood infections. Early use of plasma mNGS as an adjunct to culture can better guide clinicians to initiate appropriate anti-infective therapy.

Humans↗

PubMed2026

ScRNA-seq analysis reveals the effects of nitrite stress on the endocrine system of the eyestalk in Litopenaeus vannamei.

Nitrite is a harmful substance generated in Litopenaeus vannamei farming systems, largely originating from the inadequate breakdown of surplus feed and shrimp feces. Its accumulation in the water can affect the growth and physiological functions of shrimp, damage the immune system, and even cause mass mortality, thus becoming a key environmental factor restricting the green development of the industry. Under nitrite stress, the eyestalk, as an important neuroendocrine regulatory center in crustaceans, participates in the stress adaptation of the organism and exerts a protective effect by regulating energy metabolism and immune function. However, the molecular regulatory mechanism of the eyestalk in response to nitrite stress remains unclear. In this study, single-cell RNA sequencing (scRNA-seq) technology was used to analyze the heterogeneity of eyestalk cells in L. vannamei under nitrite stress. A total of 18, 394 high-quality cells were obtained, and six major cell subpopulations, including Neurosecretory cell, Motor neuron, Sensory neuron, Interneuron, Neurogliocyte, and Support cell, were identified. Differential expression analysis identified 839 differentially expressed genes, and different cell types showed distinct specific responses to nitrite stress. Functional enrichment analysis indicated that pathways such as glycolysis, oxidative phosphorylation, ribosome function, and endoplasmic reticulum protein processing were significantly activated, while signal transduction and DNA repair-related pathways were inhibited. Further analysis revealed that nitrite stress could induce mitochondrial function changes and trigger oxidative stress, thereby affecting the neuroendocrine system function of the eyestalk. This study provided insights into transcriptomic responses of the eyestalk to nitrite stress at the single-cell level, laying a theoretical foundation for the management of aquaculture environments.

Animals↗

PubMed2026

Stage shift, histological differentiation, and survival patterns of lung squamous cell carcinoma versus adenocarcinoma in low-dose CT screening.

BACKGROUND: Whether LDCT-associated stage shift translates into similar survival patterns across lung cancer histologies remains uncertain. We compared stage shift, histological differentiation, tumor characteristics, and survival between lung squamous cell carcinoma (LUSC) and adenocarcinoma (LUAD) in the National Lung Screening Trial. METHODS: Among participants diagnosed with LUSC or LUAD, stage distribution and histological differentiation were compared between LDCT and chest X-ray (CXR) arms. Survival among diagnosed cases was measured from randomization. Multivariable models tested screening arm-by-histology interactions. Screen-detected LDCT tumors were compared by histology. RESULTS: During 6.5 years of median follow-up, 498 LUAD and 249 LUSC cases were diagnosed in the LDCT arm, and 374 and 212, respectively, were diagnosed in the CXR arm. LDCT was associated with higher odds of stage I disease for LUAD (adjusted odds ratio [aOR], 2.48; 95% CI 1.88-3.28) and LUSC (aOR, 1.71; 95% CI 1.17-2.48), without significant interaction (P = 0.116). LDCT was associated with lower hazard of lung cancer-specific death among diagnosed LUAD cases (adjusted hazard ratio [aHR], 0.54; 95% CI 0.43-0.66), but not among diagnosed LUSC cases (aHR, 1.04; 95% CI 0.78-1.39; P for interaction<0.001). LUSC had lower screening sensitivity, more frequent detection in annual screening rounds, greater prediagnostic tumor size increase, and fewer well-differentiated stage I tumors than LUAD. CONCLUSION: LDCT was associated with stage shift for both subtypes, but favorable survival patterns among diagnosed cases were mainly observed for LUAD. Lower screening sensitivity, greater prediagnostic tumor size increase, and poorer histological differentiation may help explain why stage shift did not translate into similar survival patterns for LUSC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00047385.

Humans↗

PubMed2026

From buffalo to human: Klebsiella pneumoniae in high-somatic cell count milk as an overlooked link in the one health chain.

High somatic cell count (SCC) is a critical indicator of udder health and milk quality in buffalo milk production. However, in many low-income regions, SCC monitoring is often underemphasized, allowing a proportion of high-SCC buffalo milk to enter the food chain and potentially compromising food safety and public health. Klebsiella pneumoniae (K. pneumoniae) is a common zoonotic pathogen found in high-SCC milk, yet systematic investigations into the prevalence and characteristics in high-SCC buffalo milk remain limited. In this study, 23 K. pneumoniae strains were screened out from 460 bacterial isolates obtained from high-SCC buffalo milk samples from Guangxi, China, with an isolation rate of 5.0%. These isolates were comprehensively characterized using whole-genome sequencing and comparative genomic analyses. The results revealed that 78.26% (18/23) of the isolates shared high genomic similarity with the human reference strain ATCC 13883, and the ST37 clone exhibited a pronounced potential of cross-species transmission. All isolates harbored core adhesion factors and intrinsic resistance genes. Notably, several strains displayed high-risk features: strain 419 carried the K1 capsular serotype, strain 326 possessed a complete yersiniabactin synthesis gene cluster, and strain 320 exhibited a multidrug-resistant phenotype. Phenotypic assays further demonstrated a positive correlation between biofilm formation capacity and virulence in Galleria mellonella. Metabolic pathway enrichment analyses suggested that K. pneumoniae has undergone substantial adaptation to the nutrient-rich buffalo milk environment. Collectively, these findings confirm that raw high-SCC buffalo milk serves as a significant reservoir for high-risk zoonotic K. pneumoniae. While industrial thermal processing effectively eliminates viable pathogens, the resilient antimicrobial resistance determinants within these isolates pose a persistent risk of horizontal gene dissemination along the food chain, providing critical evidence for enhancing pre-processing milk quality regulations within a One Health framework.

Animals↗

PubMed2026

Alternative End Joining Dependency Imposed by miR-21-5p Defines Radiation Resistance and a Targetable Vulnerability in Oral Squamous Cell Carcinoma.

PURPOSE: Clinical control of oral squamous cell carcinoma (OSCC) is constrained by heterogeneous radiosensitivity driven by divergent DNA damage response programs. The architecture and functional contribution of alternative end joining (Alt-EJ), an error-prone DNA double-strand break (DSB) repair pathway frequently upregulated in cancer, to radiation resistance remains poorly defined. METHODS AND MATERIALS: We profiled microRNAs in radioresistant OSCC clones and performed multiomic integration across an institutional OSCC cohort, an external OSCC cohort from the Gene Expression Omnibus, The Cancer Genome Atlas pan-cancer tumors, and cell lines characterized by Sanger Genomics of Drug Sensitivity in Cancer to infer DNA damage response characteristics, genomic scar features, drug sensitivity, and radiation therapy outcomes. DSB repair capacity and pathway usage were validated using functional assays, including Alt-EJ reporters and droplet digital PCR quantification of microhomology-mediated repair events. Core Alt-EJ effectors such as PARP1 and POLQ were perturbed genetically and pharmacologically. Therapeutic efficacy of PARP or POLQ inhibition with or without irradiation was tested in a syngeneic OSCC model, followed by bulk tumor transcriptomics to assess pathway engagement. RESULTS: Upregulation of miR-21-5p was not only selectively detected in radioresistant OSCC, but also modulated radiosensitivity in vitro and in vivo, and was associated with inferior postradiation therapy survival. A calibrated miR-21-5p target-gene signature tracked Alt-EJ activity across patient and mouse tumors and cancer cell lines, correlated with microhomology-mediated indels and broader genomic scarring, and predicted sensitivity to clinically available PARP inhibitors. Functionally, enforced miR-21-5p expression increased Alt-EJ usage and accelerated DSB repair, whereas inhibition or depletion of key Alt-EJ effectors reduced repair efficiency and restored radiosensitivity. In vivo, Alt-EJ targeting with PARP or POLQ inhibitor abrogated miR-21-5p-driven radiation resistance; transcriptomic profiling supported suppression of Alt-EJ programs as the operative mechanism. CONCLUSIONS: These findings establish a mechanistic link between miR-21-5p activity and Alt-EJ dependence, provide a clinically deployable signature to identify Alt-EJ-dependent OSCC, and support rational combinations of Alt-EJ targeting agents with radiation therapy to overcome treatment failure and advance precision radiation oncology.

MicroRNAs↗

PubMed2026

PPRC1 is a prognostic biomarker and key regulator of mitochondrial oxidative phosphorylation in multiple myeloma.

BACKGROUND: Multiple myeloma (MM) remains an incurable haematological malignancy, underscoring the need for novel prognostic biomarkers and therapeutic targets. This study aimed to investigate the clinical and biological significance of peroxisome proliferator-activated receptor gamma coactivator-related protein 1 (PPRC1) in MM. METHODS: Expression and clinical data were obtained from public databases and an independent local cohort. Kaplan-Meier and Cox regression analyses were performed to evaluate prognostic value. Differential expression analysis, pathway enrichment analysis and single-cell RNA-seq data analysis were used to explore biological functions. PPRC1 was silenced in MM cell lines using siRNA to assess its effects on cell survival and oxidative phosphorylation. RESULTS: PPRC1 was significantly upregulated in MM and was associated with advanced disease stage and poor overall survival. Multivariate Cox analysis identified PPRC1 as an independent prognostic factor. A nomogram incorporating PPRC1 and revised-ISS improved survival prediction. Functional analyses revealed that PPRC1 was positively correlated with oxidative phosphorylation and oncogenic signalling pathways. A potential connection between PPRC1 expression and immune cell infiltration was observed. PPRC1 knockdown inhibited cell proliferation, induced cell cycle arrest and apoptosis and impaired oxidative phosphorylation in MM. CONCLUSIONS: PPRC1 acts as a prognostic biomarker and metabolic regulator in MM by sustaining mitochondrial oxidative phosphorylation. These findings highlight PPRC1 as a potential therapeutic target in MM.

Humans↗

PubMed2026

ER proteostasis failure in HYOU1 deficiency alters B cells, neutrophils, and interferon signalling.

Hypoxia upregulated 1 (HYOU1) is a stress-inducible ER chaperone. We investigated 2 unrelated patients carrying biallelic HYOU1 variants and presenting with primary immunodeficiency. Patient 1, homozygous for p.Pro444His, displayed failure to thrive, hypoglycemia, B cell lymphopenia, and neutropenia. Patient 2, compound heterozygous for p.Arg262Gln and p.Pro757_Glu758insAla, exhibited recurrent infections, enteropathy, and hypogammaglobulinemia. In Patient 1, while HYOU1 transcription was preserved, the protein was severely reduced. Tunicamycin treatment of dermal fibroblasts showed a blunted unfolded protein response and defective induction of ER stress-responsive genes. Immunophenotyping showed near-absence of circulating B cells, and single-cell RNA sequencing of bone marrow identified an arrest at the pro-B cell stage. Neutrophils displayed hypogranulation and dysregulated IFN- and apoptosis-associated transcriptional signatures, unresponsive to G-CSF. HYOU1 deficiency hence results in ER stress-induced proteostasis failure that simultaneously impairs adaptive immunity through B cell developmental arrest and innate immunity through neutrophil dysfunction and IFN pathway imbalance. This work expands the spectrum of HYOU1 deficiency and further identifies ER proteostasis as a central determinant of immune homeostasis.

Journal Article↗

PubMed2026

To Treat or Not to Treat: Navigating Early-Stage CLL in the Era of Targeted Therapy.

Chronic lymphocytic leukemia (CLL) is most frequently diagnosed at early, asymptomatic stages (Rai 0/Binet A), in which a watch-and-wait strategy remains the standard of care, based on historical trials demonstrating no overall survival benefit from early treatment. Over the past two decades, however, substantial advances in genomic profiling-including immunoglobulin heavy-chain variable region (IGHV) mutational status, TP53 disruption, recurrent gene mutations, and complex karyotype-have uncovered marked biological heterogeneity among early-stage patients and substantially improved prediction of disease progression. In parallel, targeted therapies such as Bruton tyrosine kinase (BTK) inhibitors and venetoclax-based combinations have transformed the management of symptomatic CLL, raising renewed interest in whether early intervention might favorably alter the natural history of biologically high-risk disease. In this review, we critically examine the evolution of prognostication in early-stage CLL, integrate contemporary molecular and clinical risk models, and summarize evidence from both historical chemotherapy-era studies and modern early-intervention trials. We discuss key unresolved controversies, including reliance on surrogate endpoints, the risks of overtreatment, and the persistent absence of an overall survival benefit across all early-treatment strategies. Finally, we outline future research priorities, including refined genomic stratification, minimal residual disease-driven (MRD)-driven approaches, and combination targeted therapies currently under investigation. Despite renewed interest in preemptive treatment, available evidence supports continued observation for asymptomatic patients outside clinical trials.

Humans↗

PubMed2026

Secretory Phospholipase A2 in Patients With Sickle Cell Disease Hospitalized for Vaso-Occlusive Pain Episodes.

BACKGROUND: Secretory phospholipase A2 (sPLA2) is an inflammatory mediator linked to acute chest syndrome (ACS) in sickle cell disease (SCD), a serious complication that can develop during an acute vaso-occlusive pain episode (VOE). Plasma sPLA2 levels have been proposed as a potential biomarker for predicting ACS onset. OBJECTIVE: To assess serial plasma sPLA2 levels in 105 pediatric patients hospitalized for SCD-VOE and determine the effects of arginine therapy compared to placebo. PROCEDURES: This is a pharmacokinetics/pharmacodynamics and randomized controlled trial of intravenous arginine therapy. Statistical methods included t-tests, chi-square, and correlation analyses. RESULTS: Mean age was 12.7 ± 3.7 years, 48% were male, 67% had Hb-SS, and 70% were prescribed hydroxyurea. Using a previously established SCD-specific cutoff of 48 ng/mL, presenting sPLA2 levels were elevated in 33% of patients (mean sPLA2 level 85.7 ± 32.9 ng/mL). SPLA2 elevation in the emergency department was more common in patients with ACS compared to those without ACS (64% vs. 30%; p = 0.02; negative predictive value of 94%). Peak sPLA2 levels were significantly higher in febrile (n = 34) versus afebrile patients (n = 71;101.0 ± 45.3 vs. 48.7 ± 35.4 ng/mL; p < 0.0001). Among subjects with elevated baseline sPLA2, arginine therapy resulted in a significant reduction in sPLA2 levels by discharge compared to placebo (-27.8 ± 38.1 ng/mL; p = 0.002; n = 23 vs. -15.0 ± 41.2 ng/mL; p = 0.23; n = 12). CONCLUSIONS: SPLA2 is an underutilized biomarker of ACS given accumulating evidence of its role. In particular, low levels may identify patients at low risk for ACS. Arginine therapy may modulate inflammation in patients with SCD during VOE and/or ACS. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02447874; NCT02536170.

Humans↗

PubMed2026

Volumetric bone marrow cellularity (VBMC) assessment from routinely processed trephines using three-dimensional x-ray histology and gaussian peak modelling.

Objective.Bone marrow cellularity is routinely estimated from a small number of two-dimensional histology sections, making assessment sensitive to section representativeness, processing artefacts and observer interpretation. Three-dimensional (3D) x-ray histology (XRH), using x-ray computed microtomography (µCT), enables non-destructive whole-block imaging of trephine biopsies. This study evaluated whether XRH combined with Gaussian peak modelling could provide a pragmatic whole-block volumetric bone marrow cellularity (VBMC) estimate from formalin-fixed paraffin-embedded (FFPE) trephine biopsy blocks.Approach.Six routinely processed FFPE bone marrow trephine blocks were imaged using µCT-based XRH at ∼15 µm spatial resolution. VBMC was defined as the red-marrow (RM) fraction of the marrow soft-tissue compartment, RM/(RM + intra-biopsy wax), with wax serving as the volumetric proxy for adipocyte/yellow marrow space. Whole-volume greyscale histograms were modelled using a three-peak Gaussian approach representing intra-biopsy wax, RM and demineralised trabecular matrix. Peak-height and area-under-the-curve metrics were compared with whole-volume 3D segmentation and clinical two-dimensional (2D) cellularity estimates.Main Results.Gaussian peak modelling successfully approximated the segmented tissue-phase distributions. The peak-height-derived VBMC metric showed the closest agreement with whole-volume 3D segmentation, with an average absolute percentage difference of 9.3%, compared with 18.6% for clinical expert 2D cellularity estimates. The area-under-the-curve metric followed similar trends but consistently overestimated VBMC. Clinical 2D cellularity broadly followed whole-biopsy trends but showed one discordant case not explained by slice-position sampling alone. XRH also enabled unrestricted virtual reslicing and visualisation of sectioning-associated artefacts prior to further microtomy.Significance.Pre-sectioning XRH combined with Gaussian peak modelling provides a rapid, segmentation-free route to volumetric cellularity estimation from intact clinical FFPE trephine blocks. The approach supports objective whole-biopsy assessment while remaining compatible with routine histopathology workflows, reflecting the expected limitations of section-based visual estimation despite its role as the current clinical standard. In the near term, it could provide a non-disruptive adjunct to conventional 2D cellularity reporting, pending larger validation studies.

Imaging, Three-Dimensional↗

PubMed2026

Pembrolizumab-Chemotherapy Versus Pembrolizumab in Head and Neck Squamous Cell Carcinoma: A PD-L1 CPS-Stratified Analysis of Updated KEYNOTE-048 Data.

Based on KEYNOTE-048, pembrolizumab monotherapy and pembrolizumab-chemotherapy are established category 1 first-line treatments for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) with programmed death ligand-1 (PD-L1) combined positive score (CPS) ≥ 1. We compared their efficacy using updated trial data. We analyzed 4-year progression-free survival on next-line therapy (PFS2) and 5-year overall survival (OS) data from KEYNOTE-048 by reconstructing time-to-event data using KMSubtraction. Efficacy was compared in CPS 1-19 and CPS ≥ 20 subgroups using Kaplan-Meier estimates, Cox models, restricted mean survival time (RMST), and landmark analyses. Among 499 patients with CPS ≥ 1, 240 (48.1%) had CPS 1-19 and 259 (51.9%) had CPS ≥ 20. In the CPS 1-19 subgroup, pembrolizumab-chemotherapy showed numerically longer median PFS2 (10.1 vs. 8.0 months; hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.62-1.06) and OS (12.8 vs. 10.8 months; HR: 0.87; 95% CI: 0.67-1.15) versus monotherapy, without statistical significance. For CPS ≥ 20 patients, efficacy was comparable between regimens, with similar median PFS2 (11.3 vs. 11.7 months; HR: 0.95) and OS (14.7 vs. 14.9 months; HR: 0.96). RMST and landmark analyses showed an early PFS2 benefit and a trend toward OS benefit with pembrolizumab-chemotherapy in CPS 1-19, with comparable outcomes in CPS ≥ 20. Pembrolizumab-chemotherapy showed a trend toward improved outcomes in the CPS 1-19 subgroup, with comparable efficacy in the CPS ≥ 20 subgroup, supporting a refined first-line strategy: monotherapy for CPS ≥ 20 to minimize toxicity, and combination therapy for CPS 1-19 to potentially enhance disease control.

Humans↗

PubMed2026

Patient-reported outcomes with tarlatamab in extensive-stage small cell lung cancer after platinum-based chemotherapy: results from the phase 3 DeLLphi-304 trial.

BACKGROUND: Extensive-stage small cell lung cancer (ES-SCLC) is associated with a high symptom burden and impaired health-related quality of life (HRQoL). This prespecified analysis from the phase 3 DeLLphi-304 trial evaluated patient-reported outcomes (PROs) for tarlatamab versus standard-of-care (SoC) chemotherapy following first-line platinum-based therapy. METHODS: DeLLphi-304 is a multicenter, open-label, randomized phase 3 study in adults with ES-SCLC. PROs were assessed using validated instruments, including the EORTC QLQ-C30, EORTC QLQ-LC13, FACT-G GP5, BPI-SF, and the EQ-5D-5L visual analogue scale. Change from baseline, response rates, and time to deterioration in these PROs were analyzed. RESULTS: PRO data from all 509 patients enrolled were evaluated. Compliance with QLQ-C30 and QLQ-LC13 assessments remained above 69% through 19 weeks. A higher proportion of patients receiving tarlatamab achieved symptom or functional improvement at 19 weeks compared with SoC in chest pain (19% vs 10%), cough (35% vs 26%), dyspnea (22% vs 7%), physical functioning (13% vs 8%), and global health status (23% vs 15%), respectively. Tarlatamab also delayed deterioration in symptoms, physical functioning, and pain at worst relative to SoC. FACT-G GP5 results indicated that patients receiving tarlatamab were less bothered by treatment side effects over time. CONCLUSIONS: In addition to its previously reported antitumor activity, tarlatamab demonstrated clinically meaningful improvements in symptoms and HRQoL compared with SoC. These findings support a favorable benefit-risk profile of tarlatamab in patients previously treated for ES-SCLC.

Humans↗

PubMed2026

Prophylactic folinic acid prevents pemetrexed myelosuppression: A randomized trial toward safer treatment with chemotherapy in non-small cell lung cancer.

Background Pemetrexed is a cornerstone in advanced non-small cell lung cancer treatment. Although generally well tolerated, severe myelosuppression occurs in 26% of patients. Preventing chemotherapy-associated toxicity has become increasingly important with the introduction of osimertinib combined with pemetrexed-based chemotherapy. Due to substantial toxicity, this regimen is often not administered to frail patients. Folinic acid prophylaxis can mitigate pemetrexed-induced toxicity, however its preventive use has not been routinely studied. We aimed to investigate the efficacy of folinic acid prophylaxis to reduce myelosuppression. Methods Fifty patients treated with pemetrexed were randomized (1:1) to receive pemetrexed with or without oral folinic acid prophylaxis on days 2-4 after each chemotherapy cycle. The primary endpoint was absolute neutrophil count (ANC) after the first chemotherapy cycle. Secondary endpoints included ANC after the second cycle, grade neutropenia, treatment efficacy, renal function and incidence of dose modifications. Results Twenty-four patients received folinic acid and twenty-six served as controls. Higher ANC were observed in the folinic acid group after the first cycle (median 3.79; IQR 2.22-4.93 vs. 1.85; IQR 1.43-3.78; p.

Humans↗