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Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer (BC) with limited treatment options. Paclitaxel (PTX) is commonly used, but its effectiveness is hampered by resistance and metastasis. The c-Met receptor, which is often upregulated in TNBC, promotes tumor progression via the HGF/c-Met axis and downstream PI3K/AKT and MAPK pathways. This study explored whether Capmatinib (CAP), a selective c-Met inhibitor, can enhance PTX efficacy in TNBC. MDA-MB-231 and 4T1 TNBC cell lines were treated with PTX and CAP, alone and in combination. Cytotoxicity, apoptosis, and cell cycle effects were assessed via MTT assays and flow cytometry. Cell migration was evaluated via scratch assays. The expression of epithelial-mesenchymal transition (EMT) markers (E-cadherin, vimentin, and Snail) was measured via real-time PCR. In vivo studies in BALB/c mice have evaluated hematological parameters, poor prognostic gene expression (BCL11, FOXC1, FOXM1), histopathology, and survival. In MDA-MB-231 cells, combination therapy increased PTX cytotoxicity, induced G2/M arrest, increased apoptosis, and suppressed migration. Co-treatment upregulated E-cadherin and downregulated vimentin and Snail. A weak synergistic effect was observed in 4T1 cells. In vivo, co-treatment improved hematological indices, reduced the expression of genes related to poor prognosis, inhibited angiogenesis and necrosis, increased lymphocyte infiltration, and prolonged survival. CAP enhances the antitumor activity of PTX in TNBC by targeting c-Met-mediated pathways. This combination therapy shows potential to overcome resistance and improve treatment outcomes in TNBC.

6-Mercaptopurine (6-MP) is a potent chemotherapeutic and immunosuppressive agent; however, its oral administration is limited by poor bioavailability and dose-dependent hepatotoxicity. This study aimed to develop and optimize a colon-targeted, pH-responsive delivery system for 6-MP using Eudragit S100-coated thiolated chitosan/casein microbeads (Eu-S100@TCh/CS) to enhance site-specific release and minimize systemic exposure. The microbeads were fabricated via emulsion cross-linking followed by solvent evaporation and optimized using a central composite design. Physicochemical characterization (FTIR spectroscopy, DSC/TGA, PXRD, and SEM) confirmed efficient drug incorporation in a molecularly dispersed state, thermal stability, and a uniform spherical morphology (541-672 µm). Swelling and dissolution studies demonstrated a clear pH-dependent behavior, with minimal swelling and negligible drug release at pH 1.2 and 6.8, and enhanced release (84.5% at 24 h) at colonic pH 7.4, corresponding to the dissolution of the Eudragit S100 coating and hydration of the polymeric core. Drug-release kinetics indicated Higuchi diffusion for uncoated beads (R 2 = 0.9852; n = 0.624) and anomalous (non-Fickian) transport for the coated beads (R 2 = 0.9994; n = 0.741), governed by combined diffusion and polymer relaxation mechanisms. Acute oral toxicity studies in rats revealed no significant alterations in the biochemical, hematological, or histopathological parameters, confirming systemic safety. In vitro cytotoxicity studies (MTT assay) showed enhanced antiproliferative activity of the 6-MP-loaded microbeads against HCT-116 cells compared to the free drug, attributed to improved solubility and sustained drug availability following release rather than whole-particle internalization. Blank microbeads exhibited high cell viability, confirming carrier biocompatibility. Overall, the Eu-S100@TCh/CS microbead system represents a rationally designed colon-targeted delivery platform with potential to improve local therapeutic efficacy and reduce systemic toxicity. Further studies are warranted to evaluate selectivity using normal colonic cell lines.

Lead (Pb(ii)) exposure poses significant health risks to various organ systems, including the hematological, renal, neurological, and cardiovascular systems. In this study, nano-hydroxyapatite (nano-HAp) was prepared via an ultrasonication-assisted hydrothermal method to remove Pb(ii) from an aqueous solution. The nano-HAp adsorbent was characterized using X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), Brunauer-Emmett-Teller (BET) surface area, and point of zero charge (pHpzc) analyses. The effects of various factors, including pH (2-8), initial Pb(ii) concentration (40-200 mg L-1), adsorbent dose (0.01-0.07 g L-1), and contact time (30-130 min), were investigated, with the residual Pb(ii) concentrations measured via atomic absorption spectroscopy (AAS). The highest removal efficiency of 99.84% was achieved at an optimum pH of 5, an initial Pb(ii) concentration of 40 mg L-1, an adsorbent dose of 0.03 g L-1, and a contact time of 110 min. Based on the coefficients of determination (R 2), the pseudo-second-order kinetic (R 2 = 0.9912) and Langmuir isotherm (R 2 = 0.9993) models best described the adsorption process. The maximum monolayer adsorption capacity was determined to be 133.33 mg g-1. Thermodynamic analysis confirmed that the process was spontaneous and endothermic, as indicated by positive ΔH and negative ΔG values. Furthermore, reusability studies demonestrated that the nano-HAp adsorbent maintained a removal efficiency above 86% after five successive cycles. Therefore, the prepared nano-HAp adsorbent represents a promising, eco-friendly adsorbent for Pb(ii) removal.

δβ-Thalassemia and hereditary persistence of fetal hemoglobin (HPFH) are uncommon hemoglobinopathies. This study aimed to define the molecular epidemiological features of δβ-thalassemia and HPFH in the childbearing-age population of Quanzhou, China, to inform precise prevention strategies and genetic counseling. From a free pre-pregnancy thalassemia screening cohort (n = 19,154), 92 individuals with elevated HbF (≥2%) and 11 control groups with normal HbF (≤2%) were included. DNA analysis of common deletion-type δβ-thalassemia/HPFH mutations (SEA-HPFH, Chinese type Gγ+(Aγδβ)0, Taiwan type β0) and non-deletion-type HPFH mutations was performed by gap-PCR, PCR-reverse dot hybridization, and Sanger sequencing. The correlation between hematological parameters and genotypes was also analyzed. The results suggest that the detection rate of deletion-type HPFH/δβ-thalassemia was 0.063% (12/19154), mainly SEA-HPFH and Chinese Gγ+(Aγδβ)0. The detection rate of γ-globin gene mutations and non-deletion-type HPFH was 0.329% (63/19154). 9 different γ-globin promoter mutations were identified. The most frequently detected variants were HBG2:c.-211C>T, HBG1:c.-29G>A, and HBG1:c.-272_-275dupAGCA. However, based on functional relevance, three key variants were highlighted: HBG1:c.-211C>T, HBG1:c.-249C>T, and the novel HBG2:c.-253_-254dup. The remaining variants (HBG1:c.-29G>A, HBG1:c.-272_-275dupAGCA, HBG1:c.-404A>G, HBG1:c.-417G>C, HBG1:c.-420C>A) are described as benign polymorphisms or variants in strong linkage disequilibrium with HBG2:c.-211C>T. Deletion-type δβ-thalassemia/HPFH is rare in Quanzhou. SEA-HPFH and Chinese Gγ+(Aγδβ)0 are more common. Non-deletion-type HPFH, especially the double heterozygous state HBG1:c.-29G>A/HBG2:c.-211C>T, is significantly more common. These findings reveal the unique molecular epidemiological characteristics of δβ-thalassemia and HPFH in this region, providing important data for genetic counseling and prenatal diagnosis.

Sufficient safety data on juvenile development is not available for Xiao'er Xiexieting Keli (XXTK), a Chinese herbal formula for pediatric diarrhea. Considering the challenges associated with clinical trials of XXTK, this study was aimed at evaluating its toxicity in juvenile rats to obtain a basis for assessing its safety and dosage in children. In acute toxicity study (Study 1), postnatal day (PND) 24 rats were orally administered 253.13 g/kg XXTK and observed over 14 days. In subacute toxicity study (Study 2), PND21 rats were administered 1.74, 8.71, or 32.66 g/kg XXTK daily for six consecutive weeks and allowed to recover for 4 weeks. Clinical signs, body weight, food intake, and timing of vaginal opening and preputial separation were recorded during the dosing period. Hematological, serum biochemical, and histopathological examinations, Irwin's test, and assessment of growth hormone levels, skeletal development, and immune-related indicators were performed mid-administration, and at culmination of dosing and recovery. Urinalysis, ophthalmological assessment, and Morris water maze test were conducted at the end of dosing and recovery periods. No deaths or significant findings occurred in Study 1; maximum tolerated dose was 253.13 g/kg. In Study 2, all changes were reversible, mild, and without toxicological significance. The no-observed-adverse-effect level was 32.66 g/kg/day. XXTK demonstrated a favorable toxicological safety profile in juvenile rats, supporting its potential for extended clinical use in children. Further evaluation of child development-related indicators and validation in pediatric clinical cohorts are recommended.

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Frontline (1L) treatment for transplant-eligible (TE) newly diagnosed multiple myeloma (NDMM) has shifted from triplet (e.g. bortezomib [V], lenalidomide [R], dexamethasone [d]) to quadruplet (e.g. daratumumab with VRd [DVRd]) regimens, based on improved efficacy demonstrated in pivotal trials. This real-world study compared progression-free survival (PFS) in TE patients with NDMM treated with DVRd plus DR or R maintenance (DVRd-DR/R) versus VRd plus R maintenance (VRd-R). Adult TE patients with NDMM who initiated DVRd-DR/R or VRd-R between 1 January 2020 and 30 June 2022 were identified through a retrospective chart review at 10 US sites. PFS was assessed using Kaplan-Meier analyses and propensity score-weighted hazard ratios (HR) were estimated using Cox regression. Overall, 137 patients received DVRd-DR/R and 86 received VRd-R. Over a median follow-up of 26.7 and 39.8 months among the DVRd-DR/R and VRd-R cohorts, respectively, 11 (9.1%) and 32 (29.7%) patients experienced disease progression or death. Median PFS was not reached in either cohort. DVRd-DR/R versus VRd-R was associated with 63% lower risk of disease progression or death (weighted HR: 0.37, 95% confidence interval: 0.17-0.80, p = 0.006). Findings aligned with pivotal trials, demonstrating the significant PFS benefit of 1L DVRd over VRd and supporting its real-world use for TE NDMM.

To estimate recombinant zoster vaccine (RZV) use among adults with cancer since the 2021 US Advisory Committee on Immunization Practices (ACIP) recommendation to vaccinate immunocompromised adults aged ≥ 19 years and gather insights into oncologist practices, perceptions, barriers, and facilitators to RZV vaccination among adults with cancer. In this retrospective cohort study, RZV uptake (≥ 1 dose) and completion (2 doses) were assessed among RZV-naïve, immunocompromised patients aged ≥ 19 years with a solid tumor cancer or hematologic malignancy using IQVIA's open medical and prescription claims. Patients were followed from the ACIP voting date (October 20, 2021) until June 30, 2023. RZV uptake, series completion, time to completion, and dosing schedule compliance were described. Generalized estimation equation models assessed factors associated with uptake. Fifteen oncologists were interviewed regarding their RZV practices, perceptions, barriers, and facilitators, and themes were generated based on responses. Among 388,923 and 277,314 RZV-naïve patients with a solid tumor cancer or hematologic malignancy, cumulative RZV uptake increased gradually, reaching 7.6% and 8.6%, respectively. Series completion rates at 6 and 12 months among those who initiated RZV were 63.2% and 70.9% in the solid tumor cancer cohort and 64.7% and 71.6% in the hematologic malignancy cohort. The odds of RZV uptake varied by cancer type and tended to increase with age and household income. Oncologists reported that they primarily serve an advisory role in vaccination due to workflow and financial challenges and competing patient needs, opting instead to delegate this responsibility to primary care providers and pharmacists. RZV uptake among RZV-naïve immunocompromised patients with cancers has been slow and suboptimal since the 2021 ACIP recommendation, but series completion is likely once initiated.

PurposeTo develop NANDA International (NANDA-I), Nursing Outcomes Classification (NOC), and Nursing Interventions Classification (NIC) (NNN) linkages for the Chronic Pain Syndrome (CPS) (00255) nursing diagnosis.MethodsA six-member expert panel, all active members of the NANDA-I Italian Network Group, was purposively selected based on demonstrated expertise in standardized nursing terminologies and clinical or academic background. The study followed the Iowa NNN linkage development process, supported by a narrative literature review across PubMed/MEDLINE, CINAHL, PsycINFO, and Cochrane Library. Panel members developing a structured linkage table, then convening in iterative consensus meetings to reconcile proposals. Final approval required unanimous consensus, followed by a concluding review by the developers of the NOC and NIC classifications (University of Iowa).FindingsThe NNN linkages for the CPS nursing diagnosis were developed. A total of 57 NOC nursing outcomes were identified to guide care based on the syndrome. The following main NOC to measure the resolution of the diagnosis were identified: Comfort Level (2008); Pain Level (2102); Pain: Disruptive Effects (2101); Self-Care: Activities of Daily Living (ADL) (0300); Self-Care: Instrumental Activities of Daily Living (IADL) (0306), along with outcomes addressing defining characteristics, related factors, and 35 nursing interventions, such as Pain Management: Chronic (1415), Relaxation Therapy (6040), Self-Care Assistance (1800), Emotional Support (5270).ConclusionsChronic pain syndrome is a multifaceted condition that significantly affects both individuals and society, and its complexity requires an interdisciplinary approach. Therefore, the identified NNN linkages provide evidence-based guidance for planning and delivering nursing care to effectively manage chronic pain syndrome.Implication for Nursing PracticeThe NNN linkages for the CPS nursing diagnosis serve as a practical, evidence-based resource to improve nursing research, practice and education, as well as support clinical decision-making and documentation. Ultimately, this enhances recognition and visibility of nursing care in the management of patients experiencing chronic pain.

BACKGROUND Mast cell hyperplasia can present as systemic mastocytosis (SM) or reactive mast cell hyperplasia. Distinguishing between these 2 diseases is a critical challenge. Here, we report a rare case of concurrent mast cell hyperplasia, multiple myeloma (MM), and low-level myeloid blastocytosis. The potential mechanisms underlying the coexistence of the aforementioned 3 diseases were also analyzed. CASE REPORT A patient with muscle pain was initially diagnosed with monoclonal gammopathy of undetermined significance (MGUS). Three years later, she progressively developed pancytopenia and renal function impairment. Three populations of abnormal cells were found in the bone marrow (myeloma cells 10.5%, myeloid blasts 0.18%, and mast cells 10%). Bone marrow biopsy (BMB) showed a single focal mast cell aggregate (>15 cells) with no multifocal dense infiltrates. Tryptase testing and KIT D816V mutation analysis results were negative. CD25 and additional KIT gene sequencing were not performed. Finally, she was diagnosed with multiple myeloma (MM), mast cell hyperplasia, and low-level myeloid blastocytosis. CONCLUSIONS This association among MM, mast cell hyperplasia, and low-level myeloid blastocytosis could either arise from abnormal stem cells of a common origin or result from one disease indirectly inducing or accelerating the progression of the other. Comprehensive immunophenotyping (including CD117, CD2, CD30, and CD25) and KIT mutation analysis are necessary to differentiate reactive mast cell hyperplasia from both systemic mastocytosis (SM) and SM with an associated hematologic neoplasm (SM-AHN). Positive expression of CD2, CD25, or CD30 together with KIT mutation may indicate SM or SM-AHN, and additional diagnostic criteria are required to confirm the diagnosis. If all the above test results are negative, reactive mast cell hyperplasia can be considered. More mechanistic evidence and similar cases are needed to better understand complex multilineage dysplasia.

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Subtotal petrosectomy (STP) is a radical otologic procedure aimed at complete eradication of diseased temporal bone air cells and creation of a closed, sterile cavity. While well established in adult otology, its role in pediatric patients remains insufficiently described. To analyze current indications, outcomes and complication rates of subtotal petrosectomy in a pediatric population, with particular emphasis in age - related patterns of indications. A retrospective review was conducted of 20 children (<18 years) who underwent STP between 2010 and 2024&#x202f;at two tertiary referral centers. Patients were analyzed according to age groups (&#x2264;6 years vs. >6 years) and etiology, categorized as congenital (including congenital malformations, CHARGE syndrome and congenital CSF leaks) or acquired (cholesteatoma, chronic otitis media, traumatic and oncological lesions). Major and minor complications were recorded and analyzed using non - parametric statistical methods. The cohort included 15 boys and 5 girls with a mean follow-up of 4.3&#x202f;&#xb1;&#x202f;1.2 years. Congenital indications predominated in children &#x2264;6 years, whereas acquired pathologies were significantly more common in older children (>6 years) (Fisher's exact test, p&#x202f;=&#x202f;0.018). Patients treated for congenital indications were significantly younger than those with acquired pathologies (p&#x202f;=&#x202f;0.0095). Major complications occurred in 2 of 20 patients (10%, 95% confidence interval 1,2-31,7%), including cholesteatoma recurrence requiring revision surgery and conversion to an open technique. Minor complications were observed in one patient (5%) and consisted of an abdominal hematoma). No cases of implant loss, permanent facial nerve palsy or wound dehiscence were observed. STP is a safe and effective procedure in selected pediatric patients, with low rates of major complications. Indications differ significantly by age, with congenital pathology predominating in younger children and acquired in older patients. In children, STP should be regarded not as salvage procedure but as a reconstructive strategy providing a stable anatomical foundation for long term hearing rehabilitation and disease control.

In women with high-grade serous ovarian cancer, chemotherapy remains the primary standard treatment, despite growing recognition of the disease as highly heterogeneous. Here, we examine the feasibility and clinical utility of comprehensive multimodal molecular profiling to inform treatment decisions. We analyze blood, single-cell and bulk tumor tissue, and malignant ascites using up to eleven technologies (DNA, RNA, protein, and functional assays) within a four-week turnaround time. Hypothetical treatment recommendations are altered for 76% of patients, and multi-omics-guided maintenance therapy is associated with prolonged overall survival in a subset of patients. Subsequent cohort analysis reveals distinct cellular and molecular profiles in ascites-derived single-cells compared to solid tumor tissue, unique per-patient ex vivo drug responses, and a marked increase in cancer cell heterogeneity following chemotherapy exposure. This coincides with genomic signature alterations in whole-genome-amplified patients. Our data suggest that molecularly guided treatments should be tested as adjuvant therapies prior to chemotherapy in the future.

Cellular genomic DNA is continuously exposed to endogenous and exogenous factors that induce various forms of DNA damage. In mammalian cells, the daily burden of DNA damage may reach 104-105 lesions per cell. DNA damage that persists into the S phase can lead to mutations. When such mutations occur in oncogenes, tumor suppressor genes, or genes involved in cell proliferation, they may promote cellular transformation and carcinogenesis. Therefore, DNA damage repair plays a critical role in maintaining genomic stability and preventing cancer development. Assessment of DNA repair capacity is best achieved by measuring the functional activity of DNA repair systems. DNA damage repair pathways and their repair efficiencies are highly relevant to chemotherapeutic drug development, gene function validation, and cancer therapy. Accordingly, investigation of the repair efficiency of individual DNA damage repair pathways has important theoretical and practical significance. This review summarizes the major DNA damage repair pathways, methods used to assess repair efficiency, and the advantages and limitations of these approaches.

Triple-negative essential thrombocythemia (TN-ET) represents a diagnostic and therapeutic challenge. The aim of the present study was to identify prognostic factors useful for tailoring treatment. 241 TN-ET patients with myeloid panel sequencing and confirmatory bone marrow biopsy were selected. Pathogenic/likely pathogenic variants were identified in 19.5% of patients. Mutation carriers were older (median age 66 years vs. 53, p&#x2009;<&#x2009;0.001) and had a higher frequency of prior thrombosis (19.6% vs. 6.5%, p&#x2009;=&#x2009;0.013). Presence of pathogenic/likely pathogenic variants was associated with leukemic progression (HR 12.608; 95% CI: 2.616-60.775, p&#x2009;=&#x2009;0.002) and lower overall survival (HR 3.008; 95% CI: 1.43-6.327, p&#x2009;=&#x2009;0.004). ASXL1 (p&#x2009;=&#x2009;0.004), CBL (p&#x2009;<&#x2009;0.001), EZH2 (p&#x2009;<&#x2009;0.001), and ZRSR2 (p&#x2009;<&#x2009;0.001) mutations were associated with inferior leukemia-free survival. Age over 60 years, previous thrombosis, and cardiovascular risk factors were associated with higher thrombotic risk. Revised IPSET-thrombosis was useful for risk stratification (10-year probability of overall thrombosis: 30%, 15%, and 6% for high-, intermediate-, and very-low risk patients, respectively, p&#x2009;<&#x2009;0.001). ARTS score refined arterial thrombosis stratification (10 years probability: 25% and 6% for high- and low-risk, respectively, p&#x2009;<&#x2009;0.001). Progression to myelofibrosis was a rare event in this cohort (2.5%). These results highlight the biological and prognostic relevance of molecular profile in TN-ET.

&#x3b4;-Aminolevulinic acid dehydratase deficient porphyria (ADP) is an exceedingly rare form of acute porphyria, with only fifteen published cases worldwide. This disorder has historically been considered an hepatic porphyria, as it was thought the overproduction of the toxic metabolite &#x3b4;-Aminolevulinic acid (ALA) solely occurred in the liver. This case report demonstrates that treatments focused on reducing the hepatic ALA production had limited effect on this patient's symptoms. An earlier published hypothesis that patients with ADP also produce substantial levels of bone marrow derived ALA, was retested. We describe a Dutch patient in his early 60s, who has suffered from ADP since birth. His medical history mentions acute neurovisceral attacks, contractures of hand and feet, severe polyneuropathy, developmental delay, and renal insufficiency (eGFR 30-40&#xa0;ml/min). For over a decade he was treated with weekly heme prophylaxis to reduce the frequency of neurovisceral attacks. Despite continuation, his chronic neurological symptoms aggravated and, in an attempt to suppress erythroid ALA production, weekly erythrocyte transfusions combined with hydroxyurea was started. The patient's symptoms improved and stabilized during this treatment. Oral chelation therapy was started to limit secondary iron overload caused by both heme and erythrocyte infusions. Years later we could trial givosiran, an ALAS1-siRNA to suppress the hepatic ALA production. After starting givosiran the heme infusions could be stopped without an increase in symptoms, but discontinuation of erythrocyte transfusions led to new onset neurovisceral attacks. His current schedule consists of continued givosiran and erythrocyte transfusions. This case report illustrates that ADP can be treated successfully with both hepatic and erythroid suppression. It also illustrates the challenges of treating a patient with a rare, complex and poorly understood disease, and the difficulty to balance the complications, side effects and the benefits of treatments.

Epithelial ovarian cancer is associated with an increased incidence of venous thromboembolism. In this single-center cohort study, we investigated risk factors for post-operative venous thromboembolism, prognostic factors, and the association between venous thromboembolism and the tumor-tissue transcriptome. This cohort consisted of 200 patients with stage III or IV ovarian cancer referred to Helsinki University Hospital for primary or interval de-bulking surgery between 2021 and 2024. We collected data on patient characteristics, coagulation biomarkers, surgical details, post-operative venous thromboembolism and survival, and tumor-tissue RNA sequencing from patients with venous thromboembolism and matched controls. Of the 200 patients, 125 underwent primary surgery and 75 underwent interval surgery. High-grade serous carcinoma was the dominant histologic type. Pre-operative fibrinogen, coagulation factor VIII, and D-dimer levels were above the normal range and correlated with inflammation. The incidence of venous thromboembolism was 13.6% in the primary surgery group and 2.7% in the interval surgery group (p = .012), despite 31% of patients receiving pre-operative anti-coagulation. Duration of operation and liver mobilization were also risk factors for venous thromboembolism, whereas perioperative red blood cell transfusions to manage bleeding events seemed protective. Low albumin was negatively associated with overall survival. Tumor RNA sequencing identified increased expression of genes related to oxidative stress and reduced expression of genes linked to anti-inflammatory regulation, which may contribute to venous thromboembolism risk. A thromboinflammatory phenotype in blood is common in ovarian cancer. Primary surgery and extent of surgery are associated with post-operative venous thromboembolism, whereas perioperative red blood cell transfusions have a protective association. Albumin serves as a prognostic biomarker.

Diffuse large B-cell lymphoma (DLBCL) is characterized by profound heterogeneity that underpins varied clinical outcomes. To decipher this complexity, we performed an integrated single-cell and genomic analysis. Using scRNA-seq data (GSE182434), we identified six distinct malignant B-cell subclusters (MB1-MB6) within the DLBCL ecosystem. Cell-cell communication analysis revealed intricate interaction networks, particularly involving the MIF and Complement pathways. Prognostic analysis of bulk transcriptomic data (GSE32918) identified the MB5-related gene signature as the most critical factor associated with poor overall survival. This MB5 subgroup was associated with enhanced proliferative processes, a higher tumor mutational burden, and specific comutations. Leveraging MB5 marker genes, we developed and validated a robust CoxBoost-RSF machine-learning model that effectively stratified patient risk in independent cohorts. Our study defines the MB5 malignant B-cell subgroup as a key driver of DLBCL aggressiveness and provides both a novel prognostic biomarker and a framework for personalized therapeutic targeting.

Fast risk stratification is essential for patients with sepsis, a life-threatening condition associated with high mortality, as it guides clinical decision-making and management. In this study, we aimed to evaluate the predictive performance of a novel model-termed SOLAR-which integrates the lactate dehydrogenase-to-albumin ratio (LAR) with the Sequential Organ Failure Assessment (SOFA) score and lactate for 28-day mortality in sepsis. Data for the derivation cohort were collected from the Medical Information Mart for Intensive Care IV database. The validation cohort was from the Department of Critical Care Medicine at the First Affiliated Hospital of Soochow University. Patients admitted to ICU for sepsis were enrolled. Model performance was analyzed by using multivariable logistic regression and Harrell's c-index. Reclassification ability of the model was evaluated by using net reclassification index (NRI) and Integrated discrimination improvement (IDI). Benefits in clinical decision making was estimated by using decision curve analysis. Super learner analysis was used to identify the optimal machine learning algorithm for model construction. Nomograms and an online calculator were used to deploy the model for point-of-care utilization. The derivation cohort comprised 4936 patients with sepsis and sufficient SOFA, LAR, and lactate data were obtained from MIMIC database. The validation cohort contained 371 patients with sepsis admitted to the First Affiliated Hospital of Soochow University. In both cohorts, an increasing trend of 28-day mortality was observed with elevating SOFA scores, lactate levels, and LAR quartiles. Compared to the SOFA-lactate score, the SOLAR score demonstrated improved 28-day mortality discrimination, reflected by an increase in c-index (Derivation cohort: 0.695 [0.680-0.711] vs. 0.660 [0.644-0.676], P&#x2009;<&#x2009;0.001), Validation cohort: 0.706 [0.651-0.761] vs. 0.638 [0.581-0.695], P&#x2009;<&#x2009;0.001). The SOLAR score also displayed a superior reclassification ability over the SOFA-lactate score (NRI: Derivation cohort: 0.393 [0.335-0.451], P&#x2009;<&#x2009;0.001), Validation cohort: 0.506 [0.302-0.709], P&#x2009;<&#x2009;0.001, IDI: Derivation cohort: 0.034 [0.029-0.039], P&#x2009;<&#x2009;0.001), Validation cohort: 0.044 [0.026-0.062], P&#x2009;<&#x2009;0.001). Super learner analysis showed that the logistic regression model achieved the highest c-index (0.749 [0.694-0.803]) based on the SOLAR score. A simplified online calculator of the SOLAR score was deployed for point-of-care risk stratification. The SOLAR score combining LAR, SOFA score and lactate provides improved accuracy and sensitivity over the SOFA-lactate score for 28-day mortality prediction in sepsis.