bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hijacking of the Fibrinolytic System By B-Cell Acute Lymphoblastic Leukaemia and Its Therapeutic Targeting
Authors: Minciacchi Valentina , Karantanou Christina , Zanetti Costanza , Kumar Rahul , Krack Theresa , Thomasberger Nathalie , Llavona Pablo , Hartmann Sylvia , Maguer-Satta Veronique , Lefort Sylvain , Putyrski Mateusz , Ernst Andreas , Meduri Eshwar , Huntly Brian , Ruf Wolfram , Krause Daniela S. 
Published: December 2023

The fibrinolytic system plays a role in the mobilization of hematopoietic stem cells from their bone marrow microenvironment (BMM), but its function in leukemias is not well understood. The fibrinolytic system consists of the proenzyme plasminogen and its active form, plasmin, a serine protease. The activation of plasmin is tightly regulated by activators such as tissue plasminogen activator (tPA) and various inhibitors. A role of this plasminogen activation system in the microenvironment of solid tumors is being unravelled, but a function of this pathway in the BMM, where hematological cancers usually originate, has so far been elusive.
Transcriptome analysis of mesenchymal cells in the BMM of mice with different leukemias had revealed annexin A2 ( Anxa2), an initiator of fibrinolysis, to be differentially expressed. Using an ANXA2-deficient BMM as a model for impaired fibrinolysis, we showed that ANXA2 promotes the activation of plasmin, leading to decreased levels of the extracellular matrix (ECM) protein fibronectin in the BMM and accelerating the progression of BCR-ABL1 + B-cell acute lymphoblastic (B-ALL), but not MLL-AF9 + acute myeloid leukemia. Consistently, induction of B-ALL in tPA-deficient mice led to fibronectin accumulation in the BMM and significant survival prolongation.
The dense ECM in an ANXA2-deficient BMM is shown to entrap insulin-like growth factor (IGF) and to specifically reduce mTORC2-dependent signalling and proliferation in B-ALL cells. Conversely, B-ALL cell-derived interleukin (IL)-6 conditions hepatic generation of plasminogen, the precursor of plasmin, perpetuating this circuit. Treatment with -aminocaproic acid (EACA), an anti-hemorrhagic drug, which inhibits plasmin activation, reduces tumor burden and prolongs survival in syngeneic and xenogeneic murine models via increased fibronectin in the BMM. Human data confirm that IGF1 and fibronectin staining in trephine biopsies are correlated and that the mTORC2 pathway is distinctly activated in B-ALL. Higher expression of SERPINF2 (α2-antiplasmin), an inhibitor of plasmin, in human B-ALL cells leads to superior outcome. In summary, B-ALL-derived IL-6 impacts hepatic generation of fibrinolytic agents influencing B-ALL progression via ECM remodeling and regulation of the availability of B-ALL-supportive growth factors. Inhibition of plasmin-mediated degradation of the ECM by EACA may be beneficial as adjunct therapy in B-ALL.
A Phase 1 Study to Evaluate the Pharmacokinetics of Single High Doses of Iptacopan
Authors: Schmouder Robert , Kaetterer Noemi , Kulmatycki Kenneth , Nidamarthy Prasanna Kumar 
Published: December 2023

Introduction: Iptacopan is a first-in-class, oral, selective inhibitor of factor B, a key component of the complement system alternative pathway. Inhibition of the complement system represents a potential mechanism for treatment of several diseases including paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. At the current clinical dose of 200 mg twice daily, the steady-state area under the concentration curve (AUC) and peak concentration (C max) are 25,600 ng•hr/L and 4,120 ng/mL, respectively. In this randomized, participant-blinded, placebo-controlled phase 1 study, we evaluated the pharmacokinetics (PK) of single high doses of iptacopan.
Methods: Iptacopan single doses of 400 mg (n=6), 800 mg (n=9), and 1200 mg (n=9) were included in this study, representing ≤6-fold higher doses than the clinical dose of 200 mg twice daily. The study population included healthy men and women aged 18-55 years. The log-transformed PK parameters AUC and C max were analyzed separately using a linear model with treatment as fixed effect.
Results: Twenty-four patients received iptacopan and 8 received placebo. The median age of participants in the 400-, 800-, and 1200-mg groups was 51.5, 35, and 36 years, respectively. Following a single oral administration, iptacopan was rapidly absorbed with C max at 1.06, 2.00, and 2.52 hours for 400-mg, 800-mg, and 1200-mg doses, respectively ( Table). Variability (CV% geometric-mean) in iptacopan plasma concentrations were low to moderate (16.6%-30.6%) at C max. After administration, iptacopan plasma concentration-time profiles increased over the dose range of 400 to 1200 mg and were biphasic, with an inflection point at approximately 12 hours ( Figure). Compared to the 200-mg twice daily steady-state PK, the 1200-mg single dose resulted in C max and AUC exposure multiples of 4.0- and 6.5-fold, respectively. The mean apparent elimination half-life was similar across all doses, ranging from 20 to 21 hours. Iptacopan was well tolerated with no moderate or severe treatment-emergent adverse events reported.
Conclusion: Iptacopan was rapidly absorbed after administration of single oral doses ranging from 400 to 1200 mg. Variability in iptacopan plasma concentrations were low to moderate over the dose range studied and half-lives were similar. Supratherapeutic, single doses up to 1200 mg were well tolerated and resulted in substantial multiples of iptacopan systemic exposure.
Lbl-034, a Highly Differentiated T-Cell Engaging Bispecific Antibody Targeting GPRC5D for the Treatment of Relapsed or Refractory Multiple Myeloma
Authors: Wang Baohui , Huang Xiao , Sun Jianming , Qin Yurong , Shang Hongyan , Li Tingting , Wu Guojin , Chen Min , Wang Hailin , Zhang Peng , Jiang Duqing , Liu Tongjun , Ye Mi , Cai Shengli , Lai Shoupeng , Kang Xiaoqiang , Ling Hong 
Published: December 2023

G protein-coupled receptor, class C group 5 member D (GPRC5D) is a type-C 7-pass transmembrane receptor protein that selectively overexpresses on malignant plasma cells in multiple myeloma (MM). The expression of GPRC5D is rarely seen in normal tissues or cells, and is not detectable on other hematopoietic derived cells, therefore indicating that GPRC5D may be a novel target for anti-multiple myeloma therapy.
LBL-034, a novel T-cell engaging bispecific antibody targeting GPRC5D, is developed with a specifically designed molecular format and unique 2:1 structure. It showed a potent binding on cell lines with various levels of GPRC5D expression, while its binding to CD3 on Jurkat cells was much lower examined by flow cytometry. Furthermore, LBL-034 re-directed engagement of GPRC5D+ cells and T cells was validated by gating engaged cell population with flow cytometry and confirmed visually with laser scanning confocal microscopy.
LBL-034 induced potent T cell dependent cell killing (TDCC) of various types of GPRC5D expressing cells (high to low expression: MM.1R, NCI-H929, MOLP-8 and RPMI 8226 cells), and elevated activation marker (CD25, CD69) expression and cytokine release (IFN-γ, TNF-α, IL-6). LBL-034 demonstrated weak binding to CD3 and minimal effects on cytokine release in the absence of GPRC5D expressing cells and it indicates that LBL-034 activates T cells only in the presence of GPRC5D target cells. LBL-034 was further examined in the MC38-GPRC5D syngeneic model and NCI-H929 xenograft model. Robust antitumor efficacy was observed at the low dose of LBL-034 at 1 mg/kg and 0.3mg/kg respectively.
LBL-034 GLP toxicology study with repeated doses was conducted in cynomolgus monkeys. 5, 15 and 50 mg/kg of LBL-034 was given intravenously with Q1W for up to 5 doses. LBL-034 was well tolerated with a good safety profile as determined by pharmacology, pathology and biochemistry analysis. The NOAEL of LBL-034 in cynomolgus monkeys was confirmed at 50 mg/kg.
In summary, LBL-034 is a novel T cell engaging bispecific antibody targeting GPRC5D expressing R/R MM with well differentiated binding of GPRC5D and CD3 to enhance anti-tumor activity, while mitigate the risk of CD3-induced CRS, showing a great in vitro potency and in vivo anti-tumor efficacy. LBL-034 IND has been approved by both FDA and NMPA and a FIH study in patients with R/R MM will begin in the 2 nd half of 2023.
Evaluating Chatgpt As an Adjunct for Analyzing Challenging Case
Authors: Liu Xiaoni , Song Ying , Lin Hai , Xu Yiying , Chen Chao , Yan Changjian , Yuan Xiaoliang , Bao Fang , Jing Hongmei , Wu Chaoling , Zhang Weilong 
Published: December 2023

Introduction
Despite the rapid development of medicine, clinicians still faced with many challenging cases in practice. For challenging cases, most inexperienced doctors are unable to make a clear diagnosis in the first place, resulting in misdiagnosis and delayed disease. Recently, OpenAI released a new Chatbot model, called ChatGPT (Generation Pre training Converter), which is an artificial intelligence (AI) system that uses reinforcement learning model based on human feedback for training. There have been many research reports on the application of ChatGPT in the medical field, and it has been proven to have a wide range of clinical applications. In our study, we aimed to assess the accuracy and reliability of ChatGPT in diagnosing and treating challenging case.
Methods
We provided 2 challenging cases. Case 1 provided a medical history and auxiliary test results for ChatGPT, and then ChatGPT answered the possible diagnosis, diagnostic basis, further auxiliary examination and treatment. Case 2 provides negative symptoms and auxiliary test results for ChatGPT, which answers all possible diagnoses. Conduct a comprehensive evaluation and scoring of the results of ChatGPT responses by 5 senior physicians. A score of 10 is the perfect score.
Results
The analysis results of 2 challenging cases by ChatGPT were comprehensively evaluated by senior experienced professional doctors and scored 9 points. We found that ChatGPT's analysis of challenging case is comprehensive. Especially for the diagnosis and treatment of diseases, ChatGPT analyzes all possible diagnoses and provides accurate treatment plans through the provided medical history, auxiliary examination results, and treatment processes. ChatGPT can directly interpret the auxiliary examination results, such as high level of procalcitonin (PCT), abnormal kidney function, and with negative results can rule out certain diseases, such as ANA, ENA, and ANCA negative, ruling out the possibility of autoimmune diseases. ChatGPT can summarize all the diagnoses including rare diseases, based on the results of an auxiliary test, and explain the cause of the disease and the pathogenesis in detail.
Conclusions
Our study shows that ChatGPT can provide important reference value as an adjunct to clinicians in challenging case analysis. In particular, it can assist inexperienced doctors in remote areas and underdeveloped medical conditions to make clear diagnosis and treatment as soon as possible, avoid unnecessary referral to higher-level hospitals, reduce medical burden, and reduce waste of medical resources. In the medical field, ChatGPT needs more research to evaluate in clinical applications and become a better adjunct tool in clinical work.
Comprehensive Geriatric Assessment and Geriatric Intervention in Older Patients with Newly Diagnosed Lymphoma: A Prospective Study
Authors: Lopez Garcia Alberto , Hormigo Ana Isabel , Mahillo Ignacio , Askari Elham , Morillo Daniel , Perez Saez Maria Angeles , Prieto Elena , Riesco Miriam , Urrutia Celia , Martinez Peromingo Francisco Javier , Gonzalez Montalvo Juan Ignacio , Cordoba Raul 
Published: December 2023

Introduction: Aggressive and indolent non-Hodgkin lymphomas have a median age at diagnosis of 70 years. Above this age, this population is very heterogeneous and clinical outcomes may be worsened due to patient's frailty phenotype. Very few studies of comprehensive geriatric assessment (CGA) guided approach to care have been published.
Methods: A prospective follow-up with baseline CGA were performed in a cohort of consecutive patients older than 70 years with newly diagnosed Hodgkin and non-Hodgkin lymphoma as standard of care. CGA tools are described in Table 1. Clinical outcome has been analyzed in patients diagnosed between May 2016 and March 2021.
Results: Ninety-three consecutive patients (55.9% of them were women) were included in this analysis, with a median age of 81.1 years (+/- 5.7). 23 patients (24.7%) were classified as robust (type I), 30 patients (32.3%) as pre-frail (type II) with potentially reversable impairments, 38 patients (40.9%) as frail (type III), and only 2 patients (2.2%) as unfit (type IV). Patients' characteristics are shown in Table 1. All patients received antineoplastic therapy. Treatment modifications were carried out in 64.5% of patients based on CGA results. In the follow-up, with a median follow-up 27.3 months (range 18-74 months), the relapse rate was of 25.8%, with no differences between groups. Overall survival was around 2-fold higher among the fit patients (type I) (42.5 ±19.6 months) than in the disabled patient's group (types III-IV) (23.7 ±20.5 months) (p 0.002) Statistically significant differences in overall survival (p 0.002), response to treatment (p&lt;0.001) and likelihood of increased frailty at the end of treatment (p 0.024) were observed among groups, with type III-IV patients showing worse overall survival (Figure 1), lower response rates, and higher incidence of frailty.
Conclusion: Systematic CGA allows physicians to address the functional reserve or resilience in older patients with lymphoma in the need of antineoplastic treatment. A frailty-guide approach to care may allow to improve clinical outcomes in this group of high-risk patients.
Bio-Orthogonally Redirected Bispecific Lentiviral Vectors for In Vivo CAR-T Cell Generation
Authors: Mei Heng , Chen Zhaozhao , Hu Yu , Mei Heng 
Published: December 2023

Background: Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a remarkably efficacious treatment modality in recent years for refractory and relapsed hematopoietic malignancies. However, the exorbitant cost and intricate manufacturing procedure of ex vivo CAR-T cell generation have impeded its broader application. In vivo induced CAR-T therapy offers the potential to circumvent cumbersome manufacturing logistics, thereby providing novel insights into the field of CAR-T treatment. In this study, we have developed a bio-orthogonally redirected bispecific lentiviral vector platform for the reprogramming of circulating T lymphocytes into CAR-T cells and subsequent elimination of tumor cells in vivo.
Methods: To engineer dual-targeting lentiviral vectors (D-LVs), the packing cell lines 293T was labelled with azide groups by glycometabolic bio-orthogonal chemistry (designated N 3-293T) firstly, and a CD3 promoter (CD3p) was fused to CAR transfer plasmid. Secondly, azide groups modified LVs were further surface engineered with anti-CD3 antibody (OKT3) via click chemistry. The conjunction of OKT3 and was analyzed using dot immunobinding assay, confocal microscopy and the in vitro transduction efficiency was evaluated using flow cytometry. To demonstrate the ability of targeted transduction and specific cytotoxicity in vivo, D-LVs were intravenously infused into humanized NOD-scid-IL2Rγnull (huNSG) mice engrafted with Nalm6-luc cells. Subsequently, the tumor burden was monitored using a noninvasive bioluminescence imaging system and the in-vivo CD19 -CAR-T cells existence were detected by flow cytometry.
Results: By displaying OKT3 on the single lentiviral surface and fused CD3p into the key construct, we could achieve targeted delivery of CD19-CAR genes to T cells both in vitro and in vivo.
Conclusion: These results demonstrate the great potential applications of this engineered lentiviral system as a new strategy for inducing CAR-T immunotherapy in vivo and a promising approach for leading personalized treatment.
Homoharringtonine Enhances the Anti-Leukemia Effect of Venetoclax in Acute Myeloid Leukemia with t(8;21)(q22;q22) Via Regulation of c-Myc/Bim Axis
Authors: Yu Guopan , Yin Zhao , Yao Zurong , Nie Xiaqi , Jin Hua , Zhang Yu , Xu Dan , Jiang Xuejie , Ping Baohong 
Published: December 2023

Purpose: Recently, small cases reports showed that acute myeloid leukemia (AML) with translocation (8;21)(q22;q22) [t(8;21) AML] responded poorly to venetoclax (VEN) plus azacitidine (AZA) (VA) regimen. Our previous study revealed homoharringtonine (HHT) enhanced the the killing effect of VA in AML. This study went further to explore the mechanism of VEN-resistance and the synergetic effect of VEN and HHT (VH) in overcoming resistance in t(8;21) AML.
Methods: Patients with/without t(8;21) AML, being treated with VA with/without HHT were included for response assessment. Synergetic effect and mechanism of VEN combined with HHT or AZA was studied in cell lines, primary cells and mice.
Results: Patients with t(8;21) AML acquired significantly lower CR/CRi rate than those without, with VA regimen as frontline (1/5 vs. 56/82, P=0.027) or salvage treatment (1/10 vs. 60/127, P=0.023), while the CR/CRi rate was comparable between the two cohorts with VA plus HHT (VAH) as salvage treatment (9/13 vs. 102/152, P&gt;0.05). Synergetic effect in anti-leukemia was observed in VH but not VA in t(8;21) AML cell lines, primary cells and cell line-derived xenograft mice. Transcriptome RNA-sequencing and western blot detection found c-Myc and its downstring signialing were significantly decreased with the treatment of VH but not VA as compared to the controls. In addition, VEN induced accumulation of c-Myc in t(8;21) cells. Genetic silencing or pharmacological inhibition of c-Myc restored VEN sensitivity in t(8;21) cells. Co-immunoprecipitation assay found Bim, the crucial BH3-only protein, participated in the course of VH-inducing apoptosis. Direct or indirect inhibition of c-Myc increased expression of Bim, while overexpression of c-Myc significantly inhibited the transcription of Bim in t(8;21) cells. CUT&RUN assay revealed two functional sites of c-Myc binded to the promoter of Bim gene.
Conclusion: Abnormal activation of c-Myc might contribute to the resistance of VEN via suppression of Bim in t(8;21) AML. HHT might enhance the killing effect of VEN by regulation of c-Myc/Bim axis.
Key words: acute myeloid leukemia, t(8;21), homoharringtonine, venetoclax, c-Myc
Myopathy with Lactic Acidosis and Sideroblastic Anemia Caused By a Novel PUS1mutation
Authors: Xiong Youzhen , Yang Wenrui , Fan Huihui , Zhang Li , Zhao Xin , Jing Liping , Zhang Fengkui 
Published: December 2023

Mutations in the mitochondrial aminoacyl tRNA synthetases (ARSs) are associated with various clinical phenotypes, including myopathy, lactic acidosis, and sideroblastic anemia (MLASA), which is a rare autosomal recessive disorder. Due to oxidative phosphorylation disorder and abnormal iron metabolism in the skeletal muscle and erythroid bone marrow lines, patients show progressive muscle weakness, exercise intolerance, lactic acidosis, siderocyte anemia, and growth retardation, etc. Herein, we report a case of MLASA caused by a novel homozygous missense mutation (c.597G&gt;T p.R199S) in the pseudouridine synthase 1 ( PUS1) gene, causing the loss of protein function. The patient's parents had a consanguineous marriage, with a grandmother in common. All mutations were heterozygous without disease. While the patient was homozygous for the mutation and developed symptoms of anemia, no specific treatment exists for this genetic disease. Deferrization therapy can reduce iron overload, which leads to reduced heme synthesis in such patients but cannot treat the disease. Consanguineous marriage often causes autosomal recessive genetic diseases and prohibiting it can reduce the incidence of these diseases.
The present patient's condition was caused by a mutation in nuclear PUS1, which manifested as SA, hyperlactatemia, iron overload, and muscle damage. PUS1 mutations can be missense, nonsense, or frameshift. We identified a novel missense mutation type in PUS1 in this patient, located on chromosome 12, c.597G&gt;T (p.R199S), which is a homozygous mutation. This was confirmed by the PUS1 analysis revealing homozygosity for the novel mutation. Both the parents and grandmothers were heterozygous for the mutation, but none of them had a clinical manifestation. Combining the patient's family history, medical history, laboratory examination, and genetic characteristics of the disease, the mutation was identified as a pathogenic variant, and the clinical manifestations and genetic findings of the patient expanded the genotype-phenotype spectrum of MLASA.
The possibility of MLASA should be suspected in cases of progressive muscle weakness, growth retardation, exercise intolerance in childhood, SA, and lactic acidosis before or after puberty. With the recognition of MLASA and the advent of NGS, identifying patients with PUS1 mutations characterizing incomplete MLASA syndrome became easier, thus further expanding the phenotypic and genotypic heterogeneities of these mitochondrial disorders. Targeting NGS may also significantly improve the prenatal and preimplantation genetic diagnosis of MLASA, providing better genetic counseling for parents. Genetic diseases lack effective treatment measures, and the curative effect is unsatisfactory. Therefore, prevention is more important. Prevention strategies include avoiding consanguineous marriage, genetic counseling, genetic testing for carriers, and a prenatal diagnosis.
Retrospective Analysis of Clofarabine Salvage Therapy in Refractory Multifocal Langerhans Cell Histiocytosis (LCH)
Authors: Parekh Deevyashali , Lin Howard , McClain Kenneth L. , Gulati Nitya , Eckstein Olive S. , El-Mallawany Nader Kim , Agrusa Jennifer Elise , Allen Carl E 
Published: December 2023

Purpose: LCH is a neoplastic inflammatory disorder driven by recurrent somatic mutations in the MAPK pathway in myeloid precursors. Over 50% of patients with systemic LCH are not cured with front-line therapies and data to guide salvage options are limited. In this study, we describe 58 patients with relapsed/refractory LCH who were treated with clofarabine.
Methods: Data were extracted from clinical records of patients treated with clofarabine for LCH by Texas Children's Hospital physicians or collaborators between May 2011 and 2023.
Results: Patients were treated with a median of two chemotherapeutic regimens prior to receiving clofarabine; median age was 3.49 (4 months to 61 years). The typical treatment course was 25mg/m2 daily for 5 consecutive days per month; 19%(11/58) received treatment for less than 6 months; 26%(15/58) for 6-9 months; and 55%(32/58) for 9-24 months. OS in this cohort was 100%(58/58) and PFS was 75% with median 2-year follow-up (range: 5 months to 11 years); The objective response rate (ORR) for all patients was 84% with 9%(5/58) maintaining stable disease and 7%(4/58) developing progressive disease during the study period. Patients treated for LCH-associated neurodegeneration had relatively worse outcomes (ORR: 63%) compared to patients with systemic disease without LCH-ND (ORR: 88%). Patients treated with clofarabine showed significant decreases in the amount of detectable BRAFV600E alleles in their circulating peripheral blood mononuclear cells. Toxicities included cytopenia, vomiting, and bacterial infections, but the majority tolerated chemotherapy in the outpatient setting.
Conclusion: Clofarabine monotherapy has activity against LCH in heavily pretreated patients, the majority of whom achieved durable remission. Prospective multi-center trials are warranted to determine optimal dosing as well as long-term efficacy, late toxicities, relative cost and patient reported outcomes of clofarabine compared to alternative salvage therapy strategies (e.g. MAPK inhibitors) in patients with relapsed/refractory LCH.