Pakistan journal of pharmaceutical sciencesShuhui Dai, Xuanhe Zhang, Zhen Qiao, Liudan Li, Litong Ye
BACKGROUND: Chemotherapy-induced neutropenia (CIN) is a common dose-limiting toxicity in patients with solid tumors, often leading to infections, treatment delays, or dose reductions. However, studies on the dynamic patterns of CIN across multiple chemotherapy cycles and their prediction remain limited. OBJECTIVES: To longitudinally observe CIN evolution across two consecutive cycles, develop a predictive model for severe CIN in cycle 2 (T2) based on cycle 1 (T1) characteristics, and classify patients by early recovery capacity to form a personalized bundle care strategy. METHODS: This single-center retrospective cohort study using electronic medical record (EMR) data enrolled 138 patients with solid tumors (89.1% breast cancer) who received ≥2 chemotherapy cycles between January 1, 2015, and January 31, 2025, at Zhuhai Maternal and Child Health Care Hospital, China. Neutrophil kinetic parameters were collected for T1 and T2. A multivariable logistic regression model predicted grade 3-4 CIN in T2 using T1 variables, with internal bootstrap validation. K-means clustering based on T1 recovery patterns identified patient subgroups. RESULTS: Severe CIN incidence decreased from 88.0% in T1 to 42.7% in T2 (p<0.001); neutrophil nadir rebounded from 0.40 × 109/L (IQR: 0.10-0.70) in cycle 1 to 1.05 × 109/L (IQR: 0.50-1.80) in cycle 2 (p<0.001). The prediction model (age, T1 nadir, T1 days to nadir, T1 recovery duration) achieved a test AUC of 0.677 and an accuracy of 78.6%. Out of the 138 total patients, 120 with complete recovery data were utilized for clustering analysis, identifying three groups: rapid (n=21), similar (n=79) and slow (n=20). The slow-recovery group exhibited significantly higher rates of febrile neutropenia (25.0% vs. 10.1% and 4.8%, p=0.043) and chemotherapy delays (35.0% vs. 15.2% and 9.5%, p=0.021). CONCLUSION: CIN severity generally improves from first to second cycle, but with substantial inter-individual heterogeneity. A T1-based prediction model combined with recovery stratification can identify high-risk patients for personalized CIN management. Further validation in diverse populations is warranted.
Journal of the peripheral nervous system : JPNSChrister Sawaya, Mark Fabian, Agustín Sancho Saldaña, Chinar Osman, Robert Hadden, Haider Katifi
BACKGROUND AND AIMS: Amyloid-like immunoglobulin deposition neuropathy is a rare cause of polyneuropathy, characterised by unique clinical and histological features in combination with proteomics that distinguish it from both amyloidosis and anti-MAG neuropathy. While light microscopic findings resemble amyloidosis with 'amyloid-like deposits', they are negative for Congo-red stain and have granular ultrastructure appearances under electron microscopy, unlike the characteristic fibrillary appearance of amyloid. METHODS: We present five cases of polyneuropathy associated with IgM paraprotein, without anti-MAG antibodies, with a distinctive phenotype: predominant neuropathic pain, skin changes or neuropathic ulcers, and a progressive distal sensory neuropathy. RESULTS: All patients demonstrated an axonal sensorimotor neuropathy and histopathology of 'amyloid-like' (Congo-red negative) material with predominant granular deposition on electron microscopy consistent with a combination of heavy and light chain deposition. Skin involvement demonstrated similar histological features, but there was no evidence of renal or cardiac involvement. Most patients had treatment for their underlying haematological disorder and subsequently had no further progression in their neuropathy. DISCUSSION: Amyloid-like immunoglobulin deposition neuropathy is a slowly progressive painful axonal polyneuropathy associated with paraproteinaemia. Diagnosis is made with biopsy and electron microscopy. Treatment targets the source of the paraproteins and controls disease progression, leading to favourable survival compared to AL amyloidosis.
Human vaccines & immunotherapeuticsXiaolong Tian, Yingping Zhang, Chen Zhang, Dongdong Liu, Yanmin Ma
This study aims to analyze the global research patterns and emerging trends in CAR-T cell therapy for ALL through a bibliometric analysis. Publications were retrieved from the Web of Science Core Collection database. The bibliometric analysis utilized VOSviewer, CiteSpace, and the R package "bibliometrix" to visualize collaborations, keyword co-occurrences, and emerging research trends. A total of 844 articles from 253 journals by 6,459 authors across 44 countries were analyzed, showing an annual growth rate of 40.08%. The USA (372 articles, 38,065 citations) and China (275 articles, 5,636 citations) dominated research output. The University of Pennsylvania (353 articles), Memorial Sloan Kettering Cancer Center (170), and Children's Hospital of Philadelphia (131) were the most productive institutions, while Blood (41 articles) published the most articles. Stephan A. Grupp (38 articles, H-index = 30), Carl H. June (26 articles, H-index = 24), and Shannon L. Maude (25 articles, H-index = 20) were the most influential authors. Keyword analysis revealed five research clusters, including basic mechanisms, CAR design, population treatment integration, clinical outcomes, and toxicity management. Burst keyword analysis showed the evolution from basic science (2010-2013) to clinical translation (2014-2016), toxicity management (2017-2019), and recently to long-term outcomes and risk assessment (2020-2024), with "term follow-up" and "risk" as the only keywords with active bursts in 2024. This bibliometric analysis reveals that research on CAR-T therapy for ALL has progressed from foundational concepts to clinical implementation and now focuses on optimizing long-term outcomes and patient selection. Future research should prioritize biomarker development, next-generation CAR designs, and combination strategies to overcome persistence, toxicity, and resistance limitations in ALL treatment.
PulmonologyCláudia Chaves Loureiro, Filipa Carriço, Ulisses Brito, Inês Belchior, Rosa-Anita Fernandes, Nuno Sousa, Ana Mendes, Carlos Loureiro, Cecília Pardal, Anna Soko…
BACKGROUND AND OBJECTIVES: Severe eosinophilic asthma (SEA) is often inadequately controlled. The BETREAT study evaluated the real-world effectiveness of benralizumab, an anti-IL-5 receptor monoclonal antibody, in Portugal, focusing on treatment persistence, asthma control, exacerbation rates, and quality of life (QoL). STUDY DESIGN AND METHODS: Retrospective, observational study including SEA adults who received benralizumab between July 2019 and October 2020 across 16 sites in Portugal. Data from electronic medical records were analysed over 24 months, with evaluations at 3, 6, 12, and 24 months after treatment initiation. Key outcomes included exacerbation rates, oral corticosteroid use, asthma and lung function, and QoL. RESULTS: Of the 74 patients (mean ± SD age 56 ± 11 years and 73.0% female), 66.2% were biologic-naïve. After initiating benralizumab, median eosinophil counts decreased to 0 cells/µL after 3 months. Exacerbation rates decreased from a mean annual rate of 3.12 at baseline to 0.48 by 24 months. Patient-reported asthma control and QoL improved, with ACT and CARAT scores reaching well-controlled levels in most patients by 24 months. Notably, 20.0% of patients achieved clinical remission by the end of the study. CONCLUSIONS: Benralizumab significantly improved SEA outcomes and contributed to clinical remission over a 24-month period, demonstrating potential for long-term disease control and QoL improvement.
Multiple myeloma (MM) is a malignant disorder of plasma cells. Combinations of bortezomib (BTZ) with other therapeutic agents remain the mainstay of MM treatment. However, the rising incidence of drug resistance among patients with MM underscores an urgent need for novel therapeutic strategies. The present study identified triptonide (TN), a small‑molecule monomer extracted from the traditional Chinese herb Tripterygium wilfordii Hook. f., as a synergistic agent that enhanced the anti‑MM activity of BTZ, following a screening of 198 compounds from a ubiquitination‑focused library. TN effectively inhibited cell proliferation, induced apoptosis, and reduced cell viability in MM cells. Furthermore, the synergistic anti‑MM effect between TN and BTZ was validated across MM cell lines, primary MM cells, and xenograft mouse models of MM. Mechanistic investigations revealed that TN synergizes with BTZ by enhancing DNA damage through the suppression of TRIP13‑mediated DNA repair pathways, including non‑homologous end joining and homologous recombination. Notably, TRIP13 knockdown attenuated TN‑induced DNA damage and apoptosis, and diminished the synergistic effect of TN and BTZ on MM cells. Collectively, TN represents a novel anti‑MM agent, and the combination of TN with BTZ constitutes a promising therapeutic strategy for the treatment of MM.
Journal of medical economicsU H Oron, G Koek, R Fijn
AIMS: The prevalence of inflammatory bowel disease (IBD) in the Netherlands is approximately 100,000 individuals currently (578 per 100,000 inhabitant), and is rising. Iron deficiency anaemia (IDA) is common in patients with IBD, secondary to chronic blood loss and impaired iron absorption. Intravenous iron is recommended as first-line treatment in patients with clinically active IBD, with previous intolerance to oral iron and in patients who need erythropoietin stimulating agents. The objective was to evaluate the difference in treatment costs and consequential costs of ferric derisomaltose (FDI) versus ferric carboxymaltose (FCM) in patients with IBD and IDA in the Netherlands, based on a casemix model using hospital data from the DBC (Diagnose Behandel Combinatie) system. This study aims to elucidate the differences in budget impact, from a health insurers perspective. MATERIALS AND METHODS: In order to model the hospital business, a coding analysis was done, to identify the relevant codes, tariffs, and volumes. In a casemix scenario analysis, the clinical differences between the use of FCM and FDI have been modelled, with a time horizon of 5 years. RESULTS: The analysis showed that with FDI the overall costs were lower than with FCM. With full use of FDI in the eligible population, the potential annual savings excluding complications in the national health insurer perspective is €2.9 million (excl. VAT) on iron infusion cost only. Including related costs and complications, the potential annual savings are €28.2 million. The sensitivity analyses proved the outcome to be robust. LIMITATIONS: Whilst using the DBC data would seem to reflect the real-life clinical behavior, it is known that the DBC system may show some underreporting. The analysis timeframe is limited to 5 years. CONCLUSIONS: Results showed that FDI significantly reduces healthcare expenditures versus FCM in patients with IBD and IDA in the Netherlands.
Hematology (Amsterdam, Netherlands)Ojan Ghodsi, Ali Ghasemi, Saleh Ahangari
OBJECTIVE: Gastrointestinal bleeding (GIB) is a major cause of morbidity in von Willebrand disease (vWD), most commonly resulting from angiodysplasia. Current obscure gastrointestinal bleeding (OGIB) algorithms are primarily anatomy-based and often overlook underlying hemostatic disorders, delaying diagnosis and promoting recurrent bleeding. This review summarizes current evidence on the molecular basis, diagnosis, and management of vWD-associated GIB and proposes a mechanism-oriented diagnostic framework. METHODS: A comprehensive narrative review of experimental, translational, and clinical studies was conducted, focusing on inherited vWD, acquired von Willebrand syndrome (AvWS), gastrointestinal angiodysplasia, endothelial biology, and diagnostic and therapeutic strategies. RESULTS: Deficiency or dysfunction of high-molecular-weight von Willebrand factor (vWF) multimers promotes angiodysplasia by disrupting Weibel-Palade body homeostasis, enhancing Ang-2/Tie2 and VEGF signaling, impairing integrin αvβ3 function, and fostering pro-inflammatory endothelial activation. Genetic and epigenetic modifiers, including FLI1, STXBP5, ABO blood group, and miR-24, further influence vascular susceptibility. Based on these mechanisms, we propose a four-stage diagnostic framework integrating bleeding assessment, platelet function screening, and targeted vWF testing with conventional endoscopic evaluation to facilitate earlier recognition of vWD/AvWS in patients with recurrent or obscure GIB. This strategy supports mechanism-based treatment combining hemostatic replacement therapies with selected anti-angiogenic approaches. CONCLUSION: vWD-associated GIB should be regarded as a systemic vascular-hemostatic disorder rather than an isolated structural gastrointestinal disease. Integrating hemostatic evaluation into OGIB pathways may improve diagnostic accuracy, reduce unnecessary procedures, and enable personalized management of patients with recurrent bleeding.
Hematology (Amsterdam, Netherlands)Changqun He, Meiting Long, Yiming Yang, Zhenglian Yao, Linqiang Shen, Fufei Dai, Rong Gao, Xiaoyan Yang
OBJECTIVE: This study aims to analyze the temporal trends, age‒sex patterns, and disease burden of thalassemia in China from 1990 to 2021 using the Global Burden of Disease (GBD) 2021 data, so as to optimize resource allocation and health strategy planning. METHODS: Data on incidence, prevalence, death, and disability-adjusted life years (DALYs) for thalassemia in China and worldwide are extracted from the GBD 2021 database. Trends are analyzed using Joinpoint regression, and the autoregressive integrated moving average (ARIMA) model is applied to forecast the burden over the next 15 years. RESULTS: Compared to the global average, China demonstrates a more pronounced decline in age-standardized mortality rate (ASMR) and age-standardized DALYs rate (ASDR). In contrast, the age-standardized incidence rate (ASIR) and age-standardized prevalence rate (ASPR) remained stable and significantly higher than the global level. The disease burden was higher in males and concentrated in children under five, with a visible shift toward older age groups. Projections indicate a potential rise in ASIR, stable ASPR with minor fluctuations, and continued decline in ASMR and ASDR over the next 15 years. CONCLUSION: China has made significant progress in reducing the disease burden associated with thalassemia. However, the disease burden remains higher than the global average, with persistent disparities by sex. These findings underscore the need for sustained and targeted public health strategies.
Human vaccines & immunotherapeuticsShahrier Hossain, Giada Bianchi
B-cell maturation antigen (BCMA) is a highly expressed transmembrane receptor on malignant plasma cells, mediating cell survival. These characteristics make it an attractive target for novel cellular and immunotherapies. Elranatamab is a bispecific antibody targeting BCMA on plasma cells and CD3 on T cells. This leads to immune cell activation and the release of granzymes and perforins, with attendant killing of target cells. Overactivation of the immune system can lead to cytokine release syndrome (CRS) and immune cell associated neurotoxicity syndrome (ICANS). Compared to similar agents, elranatamab has a favorable safety profile with robust efficacy. It is currently approved for relapsed/refractory multiple myeloma with clinical trials evaluating its use in combination and in earlier lines of therapy.
Brain research bulletinYonca Cam, Jingyi Zhang, Igor Dedkov, Amy Ouyang, Josiah B Lewis, Michael M Binkley, Amy E Mirro, Slim Fellah, Heather Roberts, Joshua S Shimony, Hongyu An, Ji…
Sickle cell anemia (SCA) is associated with chronic anemia and cerebrovascular dysfunction, leading to progressive brain atrophy. Hydroxyurea (HU), a disease-modifying therapy, improves hematologic parameters and reduces stroke risk, but its long-term effects on brain development remain unclear. Even though clinician guidelines recommend initiation of HU in infancy, there is a persistent underuse of HU. We examined whether HU use initiated during childhood and long-term HU use can mitigate the changes in gray matter volume (GMV), white matter volume (WMV), total brain volume, and cortical thickness in children with SCA. We used FreeSurfer derived volumetrics to conduct historical longitudinal analyses on 330 MRI scans (2004-2024) from participants with SCA and healthy controls to understand the effects of HU on brain development. Linear mixed-effects models showed that SCA participants who started using HU before the age of 9 (+HU<9yo) and those who did not (-HU<9yo) showed reduced total brain volume, GMV, and WMV compared to healthy controls. However, specifically for GMV, the + HU< 9yo group exhibited higher values than -HU< 9yo group, which suggests that early HU initiation might have a neuroprotective effect. Also, compared to the controls, only the -HU< 9yo group showed a decrease in cortical thickness. Furthermore, participants who used HU for at least 1 year prior to scan (+HU>1 yr) had higher total brain volume and GMV compared to those who did not (-HU>1 yr). An interaction between age and long-term HU treatment indicated that long-term HU treatment may be more advantageous at early ages with effects diminishing across development.
Blood cells, molecules & diseasesMay AlMoshary, Ahmad Ali Alharbi, Ekremah A Alzarea, Alia Alfaraedi, Shaimaa M Hassan, Lamia Abdelbary Gad, Ezeldine K Abdalhabib, Mohammad Saeed Aldosari, Moh…
BACKGROUND: Sickle Cell Disease (SCD) poses a significant public health burden in the Arab world. Yet, its impact on Health-Related Quality of Life (HRQoL) remains understudied, particularly across different MENA countries. Most existing research has focused on clinical and pharmacological outcomes, with limited attention to the socioeconomic and adherence-related determinants of patient well-being. METHODS: This cross-sectional study was conducted between November 2025 and January 2026. Data were collected using the WHOQOL-BREF, the 5-item Medication Adherence Report Scale (MARS-5), and a researcher-designed demographic and clinical questionnaire. We compared the countries, analyzed relationships using Pearson correlation, and used multiple linear regression models to find out what affects the overall quality. RESULTS: This study enrolled 443 SCD patients from Saudi Arabia (n = 235) and Egypt (n = 208). Saudi participants reported significantly higher overall QoL and superior scores in psychological and environmental domains, while Egyptian patients demonstrated higher medication adherence. All WHOQOL-BREF domains correlated significantly with MARS total scores, with psychological health showing the strongest association (r = 0.34). The regression model explained 44% of the variance in overall QoL (R2 = 0.44). Insurance coverage and medication adherence were the strongest positive predictors, followed by higher income, older age, and university education. Frequent hospitalization and chronic SCD complications were the strongest negative predictors. Despite these associations, medication non-adherence was highly prevalent in both cohorts (Egypt: 63.5%; Saudi Arabia: 59.6%; p = 0.191). A separate regression model identified older age, university education, higher income, insurance coverage, hydroxyurea use, and Saudi nationality as independent predictors of better adherence (R2 = 0.26), while frequent hospitalization and chronic complications independently predicted poorer adherence. CONCLUSION: Socioeconomic status and healthcare access substantially shape the burden of SCD, which extends beyond clinical severity. Universal insurance coverage, structured adherence support interventions, and addressing broader social determinants of health are essential priorities for improving QoL in SCD patients across the MENA region.
Annals of medicineRossarin Karnpean, Sanita Singsanan, Kasama Wongprachum, Punchita Rujirachaivej, Rawiporn Tiyasirichokchai, Prapaporn Panichchob, Paweesuda Rattanakoch, Praew …
BACKGROUND: Hemoglobin (Hb) Bart's hydrops fetalis is a major public health concern in Southeast Asia, particularly in Thailand. Current screening strategies target the two most common α0 -thalassemia deletions (--SEA and --THAI). METHOD: In this study, we developed a single-tube multiplex real-time PCR assay for the simultaneous detection of four clinically relevant α0-thalassemia deletions (--SEA, --THAI, --CR, and --SA). The assay was validated using 538 clinical samples with diverse thalassemia genotypes and compared against conventional gap-PCR as the reference method. Analytical performance, including sensitivity, specificity, and limit of detection (LOD), was evaluated. In addition, clinical utility was assessed in 22 prenatal diagnosis cases at risk of Hb Bart's hydrops fetalis. RESULTS: The study cohort demonstrated substantial genetic heterogeneity, comprising 43 distinct genotypes. The developed assay achieved 100% sensitivity and specificity for all targeted deletions, with complete concordance with gap-PCR results. No cross-reactivity was observed with α+-thalassemia. The assay demonstrated a high analytical sensitivity with a LOD of 9.76 × 10-3 ng per reaction. Whereas in prenatal diagnosis, all 22 fetal genotypes were accurately identified, including five cases of homozygous --SEA and one rare compound heterozygous --SEA/--CR fetus. CONCLUSIONS: This study presents a rapid, accurate, and cost-effective multiplex real-time PCR assay capable of detecting both common and rare α0-thalassemia deletions in a single reaction. The assay demonstrates strong potential for implementation in routine clinical laboratories and large-scale population screening, contributing to improved prevention and control of severe thalassemia syndromes in high-prevalence regions.
OBJECTIVE: Acute myeloid leukemia (AML) is a severe and life-threatening malignant disease of the hematopoietic system. Our previous research found that ANP32B is regulated by super enhancers in pediatric AML and regulates the progression of AML by modulating histone H3K27ac. Using virtual screening technology, we discovered that Raloxifene may be a small-molecule inhibitor targeting ANP32B. METHODS: Proliferation and apoptosis analysis were used to evaluate the effect of Raloxifene on AML cells. By establishing a xenograft model in NSG mice, 10.0 mg/kg of Raloxifene or a control solvent was intraperitoneally injected into the mice daily, and the tumor progression was monitored. Additionally, RNA sequencing, qRT‒PCR and WB were used to measure gene expression levels after Raloxifene treatment. RESULTS: The CCK-8 assay showed the IC50 value of Raloxifene in AML cells. The number and size of colony-forming AML cells treated with Raloxifene significantly decreased, and cell apoptosis increased in a dose-dependent manner. The fluorescence values in NSG mice treated with Raloxifene was significantly lower than control group. RNA sequencing revealed that Raloxifene inhibited the expression of the MYC pathway genes in MV4-11 cells. CONCLUSION: Raloxifene exhibits anti-AML activity both in vitro and in vivo. By targeting ANP32B, Raloxifene effectively inhibits the proliferation of AML cells, induces cell apoptosis, and reduces the expression of C-MYC. Raloxifene may potentially serve as a candidate drug for the treatment of acute myeloid leukemia.
Acute myeloid leukemia (AML) is a highly aggressive malignancy with frequent therapeutic resistance, necessitating the identification of novel molecular targets. This study aims to elucidate the role of the deubiquitinase OTUD5 in AML progression by regulating SLC7A11 to suppress ferroptosis. We analyzed OTUD5 expression in AML patient samples and cell lines using RNA sequencing and quantitative PCR. Functional roles were assessed through OTUD5 silencing and overexpression in AML cell lines (THP-1, HL-60), followed by proliferation, colony formation, and ferroptosis assays (ROS, labile Fe2 +, GSH, MDA). Co-immunoprecipitation and ubiquitination assays confirmed OTUD5-SLC7A11 interactions, while in vivo xenograft models validated findings. Molecular docking and transmission electron microscopy further elucidated mechanisms. OTUD5 was significantly upregulated in AML, correlating with ferroptosis suppression. OTUD5 directly interacted with and deubiquitinated SLC7A11, enhancing its stability and promoting AML cell survival. OTUD5 silencing induced ferroptosis, marked by increased labile iron, ROS, and mitochondrial damage, which was reversed by SLC7A11 overexpression or GSH supplementation. In vivo, OTUD5 knockdown reduced tumor growth, an effect mitigated by SLC7A11 overexpression or GSH. The OTUD5-SLC7A11 axis drives AML progression by suppressing ferroptosis, offering a novel therapeutic target to exploit ferroptosis sensitivity and overcome treatment resistance in AML.
BACKGROUND: A subset of patients with chronic myelomonocytic leukemia (CMML) carries NRAS mutations, which are associated with shorter overall survival and an increased risk of transformation to acute myeloid leukemia. However, the effects of NRAS mutations on the bone marrow microenvironment (BME) remain unclear. METHODS: We used a CMML mouse model driven by a single Nras G12D allele mutation to investigate alterations in the BME and the potential role of CD69 in immune suppression. Nras G12D-mutated CMML mice were treated with an anti-CD69 monoclonal antibody. Flow cytometry, hematoxylin-eosin staining, and RNA sequencing were performed to evaluate treatment-related changes. RESULTS: Nras G12D-mutated CMML mice showed increased infiltration of regulatory T (Treg) cells and CD69+ T cells in the BME, whereas CD69 expression on peripheral blood T cells remained lower than that on bone marrow T cells. Anti-CD69 monoclonal antibody treatment was associated with reduced generation of granulocyte-macrophage progenitor cells, prolonged survival, and decreased Treg accumulation in the BME. CONCLUSION: Our findings suggest that CD69 may serve as a biomarker of BME immunological dysfunction in CMML.
Renal failureIrem Pamuk, Taha Enes Cetin, Beyza Hilal Kindan, Omer Faruk Akcay, Saliha Yildirim, Halit Nahit Sendur, Mahi Nur Cerit, Sevim Gonen, Burak Mert Akhan, Ulver De…
BACKGROUND: Vitamin K deficiency impairs the activation of calcification inhibitors such as matrix Gla protein, promoting vascular calcification in CKD. Protein induced by vitamin K absence-II (PIVKA-II) is a filtration-independent marker of vitamin K status validated in hemodialysis, yet no data exist in peritoneal dialysis (PD). METHODS: Sixty prevalent PD patients at a single tertiary center were prospectively followed for 1 year. Serum PIVKA-II, dephosphorylated uncarboxylated matrix Gla protein (dp-ucMGP), and bone morphogenetic protein-2 (BMP-2) were measured at baseline and 12 months. Carotid plaque was assessed by ultrasonography. Independent predictors of plaque were identified by multivariable logistic regression and ROC analysis. RESULTS: Carotid plaque was present in 36 patients (60%). Vitamin K deficiency (PIVKA-II >40 mAU/mL) was identified in 43.3% and was more prevalent in plaque-positive patients (55.5% vs 25.0%; p = 0.019). All three biomarkers were significantly elevated in the plaque group. Age (OR 1.26; 95% CI 1.07-1.42; p = 0.004) and PIVKA-II (OR 1.71; 95% CI 1.09-2.70; p = 0.022) independently predicted plaque. The area under the ROC curve was 0.766 (p = 0.001) with an optimal cutoff of 35.09 mAU/mL (sensitivity 86.1%, specificity 50.0%). Over 12 months, plaque prevalence rose to 70%; baseline BMP-2 was the sole predictor of new plaque development (p = 0.022). CONCLUSION: PIVKA-II-assessed vitamin K deficiency is common in PD and independently associated with carotid plaque. A threshold of 35 mAU/mL may be more sensitive than the conventional 40 mAU/mL cutoff, supporting PIVKA-II screening and targeted supplementation trials in PD.
OBJECTIVE: This study was initiated to resolve a discrepancy between conventional genetic findings and clinical presentation in a proband with α-thalassemia. The initial genotype (-α4.2/-α4.2) was inconsistent with the Hb H disease phenotype, suggesting the presence of an undetected pathogenic variant. METHODS: To characterize the underlying genetic defect, we employed a multi-technique approach. The proband's DNA was analyzed using multiplex ligation-dependent probe amplification (MLPA), third-generation sequencing (TGS), and copy number variation sequencing (CNV-seq). Prenatal diagnosis was performed because the husband carried the --SEA/αα genotype. RESULTS: Investigations revealed a novel, large deletion on the α-globin gene cluster. Unlike MLPA and TGS, which indicated a deletion but could not precisely define its breakpoints due to its telomeric location, CNV-seq successfully mapped the deletion to chr16:97840-230167. This represents a 132,327 bp (132 kb) deletion, which we designated the 'Dongxing' (--DX) deletion. The proband's corrected genotype was confirmed as --DX/-α4.2. Prenatal diagnosis revealed the fetus had Hb H disease (--SEA/-α4.2). CONCLUSIONS: We identified and characterized a novel α-thalassemia deletion (Dongxing deletion) using CNV-seq. This case highlights the limitations of conventional genotyping and underscores the importance of comprehensive genetic analysis in cases of genotype-phenotype discrepancy.
Accurate and early screening of acute myeloid leukemia (AML) is critical for timely intervention and improved patient prognosis. This study presents a self-powered dual-mode biosensing platform for the ultrasensitive detection of AML-associated fusion gene UBA2-WTIP. The platform innovatively integrates a AuNPs/MoS2-graphdiyne (GDY) heterojunction as a high-performance substrate, a structurally stable three-dimensional hexahedral DNA nanopillar as a molecular scaffold, and a cascaded signal amplification strategy driven by target-triggered rolling circle amplification (RCA) and DNAzyme walker-mediated hybridization chain reaction (HCR). The Au/MoS2-GDY heterojunction provides an efficient conductive network that facilitates rapid electron transfer, significantly enhancing the output signal. The engineered hexahedral DNA nanostructure offers abundant binding sites and superior stability for subsequent nucleic acid assembly. Upon target recognition, protect DNA is displaced, activating RCA process to generates long DNA strands containing numerous DNAzyme units. These DNAzymes, in the presence of Mg2+, cleave substrates to release initiator strands, which in turn trigger an autonomous HCR on the electrode. This cascade results in the in situ formation of extended dsDNA polymers, which entrap the electrochromic molecule methylene blue, producing easily measurable electrochemical response and distinct color change. The proposed biosensor demonstrates a wide linear range from 0.1 fM to 10 nM for UBA2-WTIP, with low detection limits of 27.7 aM (electrochemical) and 49.4 aM (colorimetric) (S/N = 3), alongside built-in self-verification and correction for enhanced reliability. This work establishes a powerful and reliable sensing strategy, highlighting the great potential of integrated DNA nanotechnology and bioenzyme-based biofuel cells for the early diagnosis of hematological malignancies.
Biochemical and biophysical research communicationsYuta Okuda, Miho Watanabe-Takahashi, Kiyotaka Nishikawa
Chronic myeloid leukemia (CML) is a myeloproliferative disorder driven by the fusion protein p210 BCR-ABL. In addition to activating canonical cytosolic signaling pathways, p210 BCR-ABL has been shown to translocate to the mitochondria upon mitochondrial damage through the interaction between its pleckstrin homology domain and cardiolipin, a mitochondria-specific phospholipid. We recently demonstrated that a fraction of p210 BCR-ABL localizes to the mitochondria in CML cells and promotes cell survival through mitochondria-associated signaling. However, whether mitochondria translocation of p210 BCR-ABL affects the major downstream signaling pathways activated by p210 BCR-ABL remains unclear. Here, we investigated the effects of mitochondrial translocation of p210-BCR-ABL on the JAK2/STAT5-, PI3K/AKT-, and RAS/MAPK-pathways using HEK293T cells expressing p210 BCR-ABL. Carbonyl cyanide m-chlorophenylhydrazone (CCCP), which induces mitochondrial damage and subsequent mitochondrial translocation of p210 BCR-ABL, markedly reduced ERK activation, whereas STAT5 and AKT activation were largely unaffected. Consistently, phosphorylation of SHC1, an adaptor protein directly phosphorylated by p210 BCR-ABL and required to ERK activation, was also suppressed by CCCP treatment. In contrast, CCCP did not affect EGF-induced ERK activation, indicating that the observed effect was specific for p210 BCR-ABL signaling. Moreover, N-acetylcysteine inhibited CCCP-induced reactive oxygen species production, prevented mitochondrial translocation of p210 BCR-ABL, and fully restored ERK-activation. These findings suggest that intercellular relocation of p210 BCR-ABL dynamically rewires downstream signaling networks, potentially optimizing the signaling balance required for CML cell survival and proliferation.
PulmonologyLaura Bergantini, Irene Paggi, Tommaso Pianigiani, Sara Biancucci, Miriana d'Alessandro, Elena Bargagli, Paolo Cameli
RATIONALE: Severe eosinophilic asthma (SEA) is driven by type 2 (T2) inflammation, characterised by dysregulated cytokine release and aberrant expression of adhesion molecules involved in immune cell trafficking and activation. Despite the established role of intercellular adhesion molecules (ICAMs) and L-selectin (CD62L) in these processes, their dysregulation in SEA and their potential remodulation in response to biologic therapy remain unclear.To investigate the expression of adhesion molecules (ICAM-1, ICAM-3, CD62L) on T-cell subsets in SEA, their modulation by IL-25 and IL-33, and the immunological impact of benralizumab therapy. METHODS: Peripheral blood from SEA patients and healthy controls were analysed using flow cytometry and live-cell imaging. A subset of patients was re-evaluated after 6 months of benralizumab therapy to assess changes in T-cell phenotype, adhesion molecule expression, proliferation, and cytotoxicity. RESULTS: At baseline, SEA patients exhibited a marked Treg/Th2 imbalance, with increased ICAM-1 and CD62L expression on effector T cells and reduced ICAM-3 on Tregs. Alarmin stimulation enhanced ICAM-1 and CD62L expression on Th2 and Treg subsets and increased T-cell proliferation and cytotoxicity. After benralizumab therapy, Treg levels increased, and effector T-cell expression of ICAM-1, ICAM-3, and CD62L was significantly downregulated upon alarmin stimulation, suggesting a restoration of immune homoeostasis. CONCLUSION: SEA is associated with alarmin-driven dysregulation of adhesion molecule expression on T cells. Treatment with benralizumab induces an at least partial immunological rebalancing by indirectly modulating T-cell responses to epithelial-derived signals.