bluuebunny/crossref_metadata_2025 huggingface dataset:
First record of Silene oliveriana (Caryophyllaceae) in Iran with nomenclatural and taxonomic notes
Authors: JAFARI FARZANEH , RABELER RICHARD K.
Published: December 2024

Specimens from Kermanshah Province (western Iran), which were identified as Silene vivianii in Flora Iranica, are reviewed and identified as S. oliveriana. A description and geographical distribution are presented. The name is lectotypified with a specimen preserved at G (Candolle’s collection).
Ilex malayana, a replacement name for Ilex macrophylla Wall. ex Hook.f., and its lectotypification (Aquifoliaceae)
Authors: MALEK ALIAA ATHIRAH ADAM , PRUESAPAN KANCHANA , CORLETT RICHARD T.
Published: December 2024

N/A
CAT-ty Gossip and Rumor: An Integrative Framework
Authors: Emler Nicholas , Giles Howard
Published: December 2024

Despite the power and extensive applications of communication accommodation theory (CAT), it has yet to be linked to the most common of conversational activities, gossip. We examine both the ways in which gossip plays a role as a communicative adjustment and the influence of accommodative behaviors upon gossip. The latter are relevant to strategic uses of gossip to influence others’ reputations, particularly others regarded as sexual rivals. We consider how gossip can operate as a form of norm talk, reinforcing ingroup norms. Gossip is conceptually and colloquially close to rumor and we explore how manipulation of ambiguity between the two may operate as an accommodative move while attacking others. The penultimate section concerns gossip and rumor on the internet and the forms of accommodation that promote conspiracy theories and allow abuse and trolling. Finally, theoretical implications for CAT and future directions for research on gossip and rumor are proposed.
Risk of Reading Difficulties in School-age Children Treated for Non-syndromic Craniosynostosis
Authors: Weinfeld Justin , Havstam Christina , Kölby Lars , Tarnow Peter , Persson Christina
Published: December 2024

Objective

We assessed the prevalence of guardian-reported reading difficulties in children treated for non-syndromic craniosynostosis (NSC) and in relation to the location of the closed suture. Additionally, we determined correlations with guardian-reported neurodevelopmental disorders (NDDs) and associations between reported reading ability, sex, timing of surgical intervention, parental education, and heredity of reading difficulties in guardians.

Design

Cross-sectional, prospective, population-based study.

Setting

Tertiary hospital.

Participants

The cohort included 127 participants (aged 9-10 years) treated for NSC (76 sagittal, 38 metopic, 9 unicoronal, and 1 each of bicoronal, lambdoid, frontosphenoidal, and multisuture NSC).

Main outcome measures

The prevalence of guardian-reported reading difficulties was defined as a score ≥8 out of 14 points on the Short Dyslexia Scale. We determined associations between reported reading ability and reported NDDs through binomial regression analysis.

Results

The cohort demonstrated a 14.2% risk of of guardian-reported reading difficulties, with sagittal, metopic, and unicoronal NSCs exhibiting respective prevalences of 10.5%, 18.4%, and 23.1%. NDDs were reported in 22% of participants and significantly associated with reading difficulties.

Conclusions

The results indicated that participants with sagittal NSC showed the lowest risk of reading difficulties. Additionally, we found that NDDs represent significant risk factors for guardian-reported reading difficulties across the patient cohort. These findings underscore the need for targeted screening and support, especially for patients with metopic and unicoronal NSC, to guide clinical and educational decisions.
Citizen Oversight of Public Spaces: Evaluating Public Participation in Managing Privately Owned Public Spaces
Authors: Jung Sungju , Lee Jae Seung , Kim Saehoon
Published: December 2024

Privately owned public spaces (POPS) are intended for public use but are owned and maintained by building owners. Many POPS in Seoul fail to offer a welcoming environment due to inadequate maintenance and illegal private use. In this study, we explored whether citizen participation can effectively enhance the management of POPS and reinforce the general public’s determination to reform public spaces. We involved nonprofessional citizens and local architects in simulated inspections and qualitative assessments of Seoul’s POPS. The citizens were able to effectively identify violations in POPS and provide more rigorous qualitative evaluations from a user perspective than experts. Following the inspection, the citizens developed a new sense of responsibility as stakeholders in urban public spaces. These findings reveal that citizen participation could make POPS more public and empower citizens to become active agents in improving public spaces.
Role of Supplementation with Selenium and Myo-Inositol Versus Selenium Alone in Patients of Autoimmune Thyroiditis: A Systematic Review and Meta-Analysis
Authors: Zuhair Varisha , Sheikh Areeba Tufail , Shafi Nimra , Babar Areesha , Khan Areeb , Sadiq Arooba , Ashraf Muhammad Afnan , Nihan Khuld , Hamza Muhammad , Khalid Burhan , Haya Fatima Syeda , Arshad Mirza Ammar , Ali Eman
Published: December 2024

Objective:

The main objective was to assess the therapeutic efficacy of selenium alone versus a combination of myo-inositol and selenium (MI + Se) in treating patients with autoimmune thyroiditis (AIT). The study aims to determine which treatment option is more effective in restoring euthyroid state, as indicated by changes in thyroid-stimulating hormone (TSH), T3, T4, thyroid peroxidase antibodies (TPOAb), and thyroglobulin antibodies (TgAb)

Methods:

Google Scholar and PubMed databases were searched for randomized controlled trials (RCTs) and observational studies that reported outcomes of combined treatment (MI + Se) in restoring a euthyroid state, specifically comparing it with selenium-only (Se-only) treatment. Changes in TSH, T3, T4, TPOAb, and TgAb levels from baseline were defined as indicators to compare the effect of combined versus selenium-only treatment in restoring euthyroid levels. The Cochrane risk of bias tool and Newcastle Ottawa Scale were used to assess the quality of the randomized control trials included in the study. Review Manager (version 5.4, Nordic Cochrane Centre, Copenhagen, Denmark) was used for statistical analysis.

Result:

We pooled three studies, enrolling 151 participants in the MI + Se group and 137 participants in the Se group. Supplementation of Se with MI demonstrated a significant reduction in TSH levels compared to Se alone (SMD = −1.15, 95% CI: −1.60 to −0.69, P < .00001). MI + Se treatment also significantly reduced TgAb levels compared to Se (SMD = −0.51, 95% CI: −0.78 to −0.24, P = .0002). In contrast, TPOAB, T3 and T4 levels were non-significantly reduced from baseline in patients treated with MI + Se when compared to Se alone (SMD = −0.81, 95% CI: −0.44 to 0.09, P = .20), (SMD = 0.16, 95% CI: −0.09 to 0.42, P = .22), and (SMD = 0.30, 95% CI: −0.23 to 0.83, P = .26) respectively.

Conclusion:

Supplementation of Se with MI showed a significant reduction in TSH and TgAb levels compared to selenium-only treatment, with a non-significant reduction in TPOAB, T3, and T4 levels. This entails the need for powered clinical trials and observational studies with longer follow-ups to critically assess the role of combined therapy in restoring euthyroid state in patients with AIT.
Life Satisfaction and Work–Life Balance: The Complexities of Gender Patterning
Authors: Brooks Rachel , Fu Jun , Maire Quentin
Published: December 2024

Conventionally, issues connected to work–life balance have been thought to concern women more than men – not least through the promotion of a strongly gendered discourse about the imperative to become a ‘balanced woman’. In this article, however, we draw on interview data from both men and women (in Australia, occupying broadly middle-class social positions) to show the complexities of gender patterning. Specifically, we demonstrate that the cultural imaginary of a ‘balanced life’ as route to life satisfaction was shared equally by the men and women in our sample. Moreover, men were as likely as women to point to the arrival of children as a key ‘fateful moment’ for re-evaluating their own work–life balance. However, gender disparities were evident in both the nature of change that was effected to achieve ‘balance’ and the associated expectations of partners. The article contributes to the gendered theorisation of work–life balance as a cultural norm in contemporary society.
A case study of a sports school scholarship programme: Student-athlete dual career competency development and perceptions of the talent development environment
Authors: Earle James , Till Kevin , Cowburn Ian
Published: December 2024

Purpose: Sports scholarship programmes are a common feature internationally for schools to attract and retain sporting student-athletes. Thus, it is important to understand how a sports scholarship programme supports holistic athlete development. The current study presents student-athlete perspectives of the talent development environment (TDE) and the development of dual career (DC) competencies in a sports school scholarship programme and examines the relationships between TDE and DC competencies. Methods: A case-study design was adopted to analyse student-athlete perspectives of a sports scholarship programme using the talent development environment questionnaire (TDEQ-5) and dual career competency questionnaire (DCCQ-A). Results: The TDE was perceived positively (1 = strongly disagree and 6 = strongly agree), with long-term development (5.0 ± 0.3) and alignment of expectations (4.6 ± 0.5) the highest subscales. Support network (4.3 ± 0.4) was the lowest perceived subscale. All DC competencies were considered important by student-athletes. However, student-athletes had a significantly lower perceived possession than importance in 88% of DC competencies. Emotional awareness was the subscale that required the most development. Significant relationships were found between the TDE and DC competencies, including long-term development vs. DC management ( r = 0.41) and emotional awareness ( r = 0.32), alignment of expectations vs. DC management ( r = 0.39), communication vs. emotional awareness ( r = 0.36), holistic quality preparation vs. DC management ( r = 0.48) and support network vs. DC management ( r = 0.38). Conclusion: Student-athletes perceived the TDE positively yet felt the sports scholarship programme could develop their DC competencies further. Perceptions of the TDE relate to DC competencies, especially DC management. Organisations offering sports scholarships should ensure stakeholders recognise the demands of a DC by monitoring the value of such programmes.
Angiotensin receptor neprilysin inhibitor in chronic heart failure and comorbidity management: Indian consensus statement
Authors: Mittal Sanjay , Harikrishnan Sivadasanpillai , Gupta Anoop , Bansal Sandeep , Koshy George A. , Mohanan Padhinhare P. , Bhattacharya Debdatta , Kerkar Prafulla , Swamy Ajay , Aggarwal Vinayak , Srivastava Sameer , Mahajan Ajay , Mehta Ashwani , Sharma Kamal , Shetty Sadanand
Published: December 2024

Heart failure (HF) is a significant public health concern characterized by notable rates of morbidity and mortality. Multimorbidity, ranging from 43% to 98% among HF patients, significantly impacts prognosis and treatment response. HF management requires a holistic approach, including guideline-directed medical therapy. Sacubitril/valsartan (angiotensin receptor neprilysin inhibitor [ARNI]) is a cornerstone of HF treatment, supported by robust evidence from large-scale clinical trials across different levels of left ventricular ejection fraction. The recommendations presented in this paper have been developed by a group of cardiologists in India who convened in expert opinion meetings to discuss the utilization of ARNI in chronic HF patients with five different comorbid conditions like type 2 diabetes mellitus (T2DM), chronic kidney disease, myocardial infarction (MI), obesity, and hypertension. Key focus areas include initiation, dose titration, and management across different HF phenotypes and comorbidities. Emphasis is placed on the efficacy of ARNI irrespective of glycemic status in the T2DM population, its role in HF patients with obesity, and addressing challenges related to renal function decline and hyperkalemia. Additionally, the document highlights ARNI’s potential benefits in hypertensive and post-MI HF patients, alongside observations on the obesity paradox in HF prognosis. Overall, these recommendations aim to optimize ARNI therapy in HF patient populations with different comorbidities, addressing specific challenges and considerations to improve outcomes and quality of life.
Aspirin Nonresponsiveness in Congenital Heart Disease—Prevalence, Risk Factors, and Management
Authors: Stauber Catherine E. , Well Andrew , Dawson-Gore Catherine , Mizrahi Michelle , Fraser Charles D. , Mery Carlos M. , Stromberg Daniel
Published: December 2024

Background

Aspirin is frequently utilized for antiplatelet therapy in children with congenital heart disease (CHD). Patients who are unresponsive to aspirin, as measured by aspirin reaction units (ARU), are at higher risk for thrombotic events. It is undetermined if dose modification of aspirin results in adequate responsiveness in these patients. This study evaluates the prevalence and risk factors for aspirin nonresponsiveness and the results of dose escalation in this population.

Methods

This is a retrospective review of patients cared for in the cardiac care unit at a quaternary care academic congenital heart center who received aspirin and had responsiveness evaluated between January 2018 and January 2023. Patient demographics and clinical characteristics were extracted from the medical record. Descriptive, parametric, and nonparametric univariate analysis were employed.

Results

A total of 142 patients (69 [49%] female, 45 [32%]Non-Hispanic White, and 63 [44%] Hispanic]) were identified. Median age at first aspirin responsiveness assessment was 54 [interquartile range, IQR: 23.3-411.5] days with a median weight of 5.2 [IQR: 3.64-9.29] kg. Of these, 32/142 (22.5%) were nonresponsive on their initial testing. Of these patients, 23/32 (72%) had follow-up testing with 19/23 (83%) subsequently becoming therapeutic. This was achieved with an increased dose in 12/19 (63%) patients and increased duration of therapy in 7/19 (37%) patients. Seventeen of 142 (12%) patients experienced a thrombotic event, 13/17 (77%) of which were therapeutic on initial responsiveness assessment.

Conclusions

It is common for CHD patients to be aspirin nonresponsive with initial weight-based dosing. If aspirin is used in this population, it is necessary to evaluate ARUs on all patients as underdosing is not uncommon with current weight-based dosing methods.
Single-Cell Whole Genome Sequencing Reveals the Evolution and Migration of Lymphoma
Authors: Steemers Alexander S. , Poort Vera M , Van Boxtel Ruben , Meyer-Wentrup Friederike , Hagelaar Rico , Groenen Niels M
Published: December 2024

In contrast to RNA expression, which captures the current state of a cell, DNA is the only biomolecule in a cell that is not constantly replaced but copied and passed on during cell divisions. As a result, mutations that occur in the DNA code are fixed and gradually accumulate forming an archive of the life history of cells. DNA from pediatric cancers usually do not have high mutational loads. However, this is not the case with pediatric lymphomas which tend to harbor many mutations. This makes pediatric lymphomas an ideal model disease to study mutation accumulation. Here, we have applied state-of-the-art single-cell whole genome sequencing on pediatric Burkitt, T-lymphoblastic and Hodgkin lymphoma using the Primary Template-directed Amplification technique. Using this method, we have compared the genomes of malignant and non-malignant cells from the same tumors. We have also included patients in our cohort which have multiple-site involvement to investigate clonal dynamics across tissues. Using in-depth mutational analyses, we have generated detailed phylogenetic trees of each patient, identified processes unique to tumorigenesis and timed the occurrence of driver mutations and mutagenic processes. This type of analysis has not been applied to lymphoma before. Outcome of lymphoma in children is excellent (>90% survival), whereas survival in adults is much lower (~50%), because children can be treated with higher doses of chemotherapy. Consequently, treatment is extremely toxic, and relapses are mostly lethal. We envision that our research will contribute to improved diagnostics and ultimately the development of more targeted, less toxic treatment and a strongly improved quality of life.
Mixed Type Autoimmune Hemolytic Anemia: A Single Center Observational Study
Authors: Versino Francesco , Pedone Giacinto Luca , Bortolotti Marta , Barcellini Wilma , Fattizzo Bruno
Published: December 2024

Mixed type autoimmune hemolytic anemia (mAIHA) is a rare form of AIHA, marked by the combined positivity of warm reacting IgG autoantibodies (Ab) and cold agglutinins. The diagnosis requires second level direct antiglobulin test (DAT) with monospecific antisera, autoagglutination at 20°C and cold agglutinin titer. Treatment of mAIHA is not standardized, patients are mainly managed case by case and no trials are ongoing for this disease.

Here we present a retrospective observational study of 63 mAIHA patients evaluated from Sep. 1999 until June 2024, belonging to a series of 299 AIHA patients followed at a tertiary Hematologic Center in Milan, Italy. We sistematically collected clinical and hematological features at diagnosis, therapy lines with relative responses (overall response rate (ORR) Hb > 10g/dL and increase > 2 g/dL from baseline), complications and outcome. Adverse events were graded according to CTCAE v5.0.

Patients were mainly females (92%), with a median age of 54 years (9-83) and were followed for a median of 54 months (1-217) . Most patients had a severe presentation with median Hb of 7.1 g/dL (2.9-11), notably 43/63 (68%) had Hb levels < 8g/dL, and 20/63 (32%) < 6g/dL; 43% of cases required transfusion, and median LDH levels were 4.1 x ULN (1.2 - 12). Furthermore, 55% of patients displayed inadequate reticulocyte compensatory response as per Bone Marrow Responsivness Index < 121 and 11% of cases had a concomitant immune thrombocytopenia (Evans Syndrome). Patients recieved a median of 2 (1-6) therapy lines, 44/63 (70%) required more than one treatment, and 22/63 (35%) more than two. These included steroids in 58 (92%, ORR 83%), rixutimab frontline in 8 (13%, ORR 100%), rituximab further lines in 21 (33%, ORR 90%). Cytotoxic immunosuppressants were used in 26 (41%, ORR 77%) in second or further therapy lines. Finally, 11 patients (17%) undwerwent splenectomy with good response rate (ORR 91%) and 4 patients (6%) recieved erythropoietin stimulating agents. During the follow up, an infectious complication occurred in 16 of patients (25%), mainly grade 2 and thrombosis in 4 (6%). Overall, 9 patients died, 2 of which due to AIHA complications (one multiorgan failure and one sepsis in a splenectomized patient).

In conclusion, mAIHAs mainly show a very severe clinical presentation, require high transfusions need, several therapy lines and display frequent infections and thrombotic complications. New therapies are under investigation for wAIHA or CAD, while therapy of relapsed/refractory mAIHA represent an unmet need.
Excess Risk of Monoclonal Gammopathy of Undetermined Significance (MGUS) in a Screened Cohort of Patients with Gaucher Disease (GD)
Authors: Istaiti Majdolen Joleen , Thoren Katie , Revel-Vilk Shoshana , Zimran Ari , Landgren Ola
Published: December 2024

BACKGROUND

Prior retrospective studies and smaller case series have proposed that patients with Gaucher Disease are more likely to of be diagnosed with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). To our knowledge, we have performed the first systematic screening study to define the prevalence of MGUS in a large cohort of patients with Gaucher Disease.

METHODS

We included consecutive adult (>20 years) Gaucher Disease patients who have been followed at the Gaucher Unit, Shaare Zedek Medical Center, Israel since 2016 and who signed consent for biomarker testing. All assays were performed at the Sylvester Myeloma Institute at the University of Miami. Similar to prior large screening studies, all samples were tested with serum protein electrophoresis (SPEP) and free light-chain (FLC) assays, with reflex immunofixation for positive cases. All analyses were conducted in a blind manner, and results were independently evaluated by two experts. Demographics data, Gaucher Disease genotype, treatment status, and laboratory data, including platelet count, hemoglobin, creatinine, C-reactive protein, immunoglobulin, triglyceride, and glucosylsphingosine (Lyso-Gb1), a downstream metabolic product of glucosylceramide, levels were extracted for the Gaucher Unit database. Variables were evaluated across MGUS subtypes (M-spike MGUS and light-chain MGUS).

RESULTS

The cohort included a total of 411 patients;182 (44%) were males and the median age was 46.5 years (range:20-92). The majority of patients (n=258, 62%) had mild GD genotype and 282 (68.2%) patients had received Gaucher Disease-specific treatment. M-spike MGUS and light-chain MGUS were found in 43 (10.5%) and 83 (20.2%) patients, respectively. In univariate analysis, factors associated with M-spike MGUS were increasing age (OR=1.08, 95% CI: 1.05-1.10), mild genotypes (OR=3.48, 1.49-8.08), and elevated creatinine levels (OR=9.36, 2.2-39.4). Hemoglobin and lyso-Gb1 levels were lower in patients with M-spike MGUS, but this did not reach statistical significance. In multivariate analysis, only older age was associated with excess risk of M-spike MGUS. Similarly, older age was associated with increased risk (OR=1.02, 1.01-1.04) of light-chain MGUS. Gaucher Disease-specific treatment status did not significantly alter the risk of having M-spike or light-chain MGUS.

CONCLUSIONS

In this first systematic screening study of 411 Gaucher Disease patients and with a median age of less than 50 years, the prevalence of M-spike MGUS and light-chain MGUS were 10.5% and 20.2%, respectively, which is significantly higher than rates in the general population. These novel findings are expected to shape future therapeutic strategies and improve patient care, potentially influencing genetic counseling practices in the management of Gaucher Disease.
Blood Cell Homeostasis Is Maintained in the Absence of Resident Mononuclear Phagocytes in Fetal Liver and Bone Marrow in CSF1R Knockout Rats
Authors: Roberts Megan , Carter-Cusack Dylan , Huang Stephen , Maxwell Emma , Summers Kim Z , Irvine Katharine M , Hume David A
Published: December 2024

Erythrocytes are produced through a highly regulated process that requires an adequate supply of iron to develop properly. The constant production of red blood cells occurs in erythroblastic island (EBI) niches, which exist in the fetal liver during embryonic development and move to the bone marrow. The macrophages within this niche are thought to be essential regulators of erythropoiesis via recycling iron for haemoglobin synthesis and phagocytosing the extruded nuclei generated during terminal erythroid maturation. The proliferation, differentiation and survival of many resident tissue macrophages depends upon signals from the macrophage colony-stimulating factor receptor (CSF1R), including macrophages within haematopoietic tissues. Homozygous loss of function mutation in Csf1r in the rat produces a near complete loss of tissue resident macrophages, which is associated with severe postnatal growth retardation and osteopetrosis.

CSF1R signalling is also implicated in maintaining erythropoiesis in a model of anaemia. We aimed to determine the role of CSF1R-dependent macrophages in steady-state erythropoiesis and iron homeostasis. RNA-Sequencing of fetal liver from late gestation embryos showed no dysregulation of erythropoiesis or iron homeostasis in CSF1R knockout rats, despite loss of macrophage associated genes and reduced staining of the key iron recycling receptor CD163. Reduced CD163 was also observed in the liver and spleen in 3-week-old knockout rats. At three weeks of age, RNA-Sequencing of bone marrow revealed a significant reduction tissue resident macrophage associated genes. Despite the loss of bone marrow, liver and spleen macrophages and altered phenotype of the few remaining macrophages, CSF1R knockout rats have normal haematological parameters and show no indication of iron deficiency or overload. Altogether these results indicate that CSF1R-dependent macrophages are not absolutely required for early-life steady-state erythropoiesis and iron homeostasis in rats. Ongoing studies focus on the mechanism of erythrocyte development, erythrocyte recycling and iron homeostasis in the absence of CSF1R-dependent macrophages.
Patient-Derived Follicular Lymphoma Tumoroids: A Tool to Recapitulate Biological Features of Low and High-Grade Lymphoma
Authors: Gimenez Ruben , Serrat Neus , Castellote-Borrell Miquel , Jiménez-Martínez Victor , Pérez del Río Eduardo , Bachiller Mireia , Araujo-Ayala Ferran , Pérez Raul F , Martínez-Farran Ares , Robles Jose Ángel , Lopez-Guillermo Armando , Campo Elias , Villanueva Josep , Guedan Sonia , Martin-Subero Jose Ignacio , Guasch Judith , Hodson Daniel J , Colomer Dolors , Pérez Galán Patricia
Published: December 2024

Follicular lymphoma (FL), the most common indolent non-Hodgkin lymphoma, is a paradigm of the contribution of the immune tumor microenvironment (TME) to disease onset, progression, and therapy resistance. To recreate the cellular components, signaling cues, and the physical environment, we have optimized the generation of Patient Derived Lymphoma Tumoroids (PDLT) embedded in collagen I, highly present in the reticular network of the lymphoma lymph node (LN) where FL originates. PDLTs are composed of tumor B cells and autologous T cells. In addition, a supportive follicular dendritic cell line (FDC), or a modified variant expressing specific cytokines and factors (CD40 ligand and interleukin 21) present in FL germinal center (GC) microenvironment (FDC-GC), was integrated. These components rendered a compact tumoroid, rheologically relevant to the lymphoma LN. Our model is capable of sustaining viability for up to 10 days and promote proliferation in the presence of GC cues. Through single-cell RNA sequencing (scRNAseq), we observed that, after culture in PDLTs, both tumor cells and TME maintained a FL-LN gene expression signature. However, coculture with FDCs yielded a profile more closely related to the original biopsy sample, whereas when FDC-GC stimuli were included instead, features of a high-grade FL were recapitulated. In this regard, mass spectrometry analysis of the secretome compartment revealed that high-grade PDLTs are also able to remodel their initial extracellular matrix (ECM) and refine it with newly secreted collagens (I, IV, V and VI), fibronectin, and tenascin C (all of them present in FL-LN), together with vimentin, known to be associated with FL transformation. Finally, we used PDLTs as a preclinical tool for cell therapy. The anti-CD19 CAR-T product ARI-0001 was able to adhere to the tumoroid's surface but shows moderate infiltration and e'icacy, compared to CART activity in Patient- Derived Lymphoma Spheroids lacking ECM. This indicates that ECM may be a crucial player in cell therapy evasion in lymphoma by preventing CAR-T cells from reaching their target cells, which is a common hindrance in solid tumors.

In summary, we have developed a patient-derived model that can recapitulate both indolent and aggressive FL features, providing an in vitro model suitable to study disease biology and personalized therapy testing in the context of structural and cellular elements of the TME, while reducing animal usage.
A Specific Coagulation Factor X Activator for on-Demand Treatment in Hemophilia with Inhibitors
Authors: Liu Wei , Zhou Hu , Huang Ruibin , Du Xin , Zhou ZePing , Zheng Changcheng , Lou Shifeng , Dai Xinyue , Yang Renchi , Zhang Lei
Published: December 2024

Background

Bemiltenase alfa targeting factor X (FX), purified from Daboia russelii siamensis venom, is developed as a hemostatic agent for hemophilia A or B with inhibitors (HAwI and HBwI).

Methods

This is a prospective, multicenter, open-label, phase Ib/II trial evaluating the safety and efficacy of bemiltenase alfa for on-demand treatment in HAwI and HBwI patients (Clinicaltrials.gov NCT05027230). Adults (18-65 years) male HAwI and HBwI patients were enrolled to achieve multiple doses of bemiltenase alfa in stage 1 (0.10 U/kg dose cohort) and stage 2 (0.10 U/kg cohort and 0.16 U/kg dose cohort). The primary endpoints were safety and hemostatic efficacy. The secondary endpoints were pharmacokinetic (PK) and pharmacodynamic (PD) profiles, alleviation of clinical symptoms of bleeding events, and the dosage of bemiltenase alfa needed to achieve hemostasis.

Results

Between October 2021 and July 2023, 80 patients were assessed for eligibility and 70 were enrolled. The 0.16 U/kg dose group (n=37) achieved an effective hemostasis rate of 96.48% (95% confidence interval: 92.89% to 98.57%) in 199 bleeding events, while the 0.10 U/kg dose group (n=20) showed a comparable rate of 94.07% (88.66% to 97.41%) in 135 bleeding events. The clinical remission rate also showed the same trend. For bleeding events, the 0.16 U/kg cohort required fewer number of injections (1.7±0.9 vs. 2.1±1.1, respectively P<0.001). Four patients in 0.16U/kg cohorts experienced grade one asymptomatic venous thromboembolisms. No drug-related serious adverse events or anti-drug antibodies were observed. PK findings showed that plasma drug concentrations increased with consecutive doses. The PD results indicated bemiltenase alfa can dramatically improve the activated partial thromboplastin time, peak height and endogenous thrombin-generating potential of thrombin generation assay.

Conclusion

Our study indicates that FX as a novel target in treating bleedings showed good efficacy. We also demonstrated for the first time that FX activator from snake venom showed good safety and strong therapeutic effect which supports its potential as a hemostatic treatment for HAwI and HBwI patients.
Generation of FcRH5xCD28 Bispecific Antibodies Synergizing with T-Cell Engagers for Enhanced Multiple Myeloma Treatment
Authors: Majocchi Sara , Moine Valéry , Magistrelli Giovanni , Gueneau Franck , Fischer Nicolas , Shang Limin , Masternak Krzysztof , Ferlin Walter Giovanni
Published: December 2024

The approval of several bispecific T-cell engagers (TCEs) in recent years has contributed to revolutionizing the treatment of multiple myeloma (MM). However, not all patients benefit from these new treatments and acquired resistance eventually occurs. Consequently, strategies to deepen the extent of the response to TCEs in MM patients are needed.

Here we describe the generation of FcRH5-targeted CD28 bispecific antibodies (bsAbs) designed to co-stimulate T cells specifically in presence of FcRH5-positive MM cells. FcRH5 is a B-cell lineage marker whose extracellular domain (ECD) consists of 9 Ig-like domains (D1 to D9) that is often overexpressed by MM cells. Importantly, MM patients display high levels of soluble FcRH5 (consisting of ECD D1 to D8) and preferential binding of the bsAbs to membrane-bound FcRH5 via domain 9 (D9) is highly desirable to minimize the potential loss of efficacy due to the sink effect. However, the amino acid sequence of D9 shares a high degree of similarity with some of the other FcRH5 ECD domains (intramolecular similarity) and with some of the Ig-like domains present in the ECD of the other FcRH family members (intermolecular similarity). Consequently, the generation of FcRH5-specific antibodies that bind uniquely to membrane-bound FcRH5 is a challenging process.

Using our proprietary fully human κλ body antibody platform, which relies on a common heavy chain and on two distinct light chains driving specificity and affinity (i.e., one kappa and one lambda), we have identified a panel of cyno cross-reactive, FcRH5 specific (i.e., not binding to other FcRH family members) antibody arms that preferentially bind to membrane-bound FcRH5. Binding experiments using PEAK cells expressing at the cell surface the different FcRH family members or truncated version of the FcRH5 protein confirmed the desired features of the identified antibody arms. These arms were paired to an agonist (but not superagonist) anti-CD28 arm to generate FcRH5-CD28 κλ bodies capable of bridging T cells to MM cells to deliver signal 2. In the absence of signal 1, FcRH5xCD28 κλ bodies showed no sign of T cell activation, potentially limiting peripheral toxicity. FcRH5xCD28 κλ bodies strongly synergized with TCEs such as Teclistamab (BCMAxCD3 bsAb) and Talquetamab (GPRC5DxCD3 bsAb) resulting in enhanced killing of MM cell lines in in vitro T-cell dependent cellular cytotoxicity assays. Of note, in some cases, the bsAbs could even rescue the activity of TCEs (i.e. in settings where the TCEs alone displayed limited or no activity). Importantly, significant activity is retained in the presence of soluble FcRH5 in vitro. Therefore, FcRH5xCD28 bispecific antibodies have the potential to expand the number of patients who benefit from TCE-based therapies, possibly leading to deeper and more durable responses.
Tissue-Resident Double Negative T Cells Mediate Salivary Gland Damage in Chronic Oral Graft-Versus-Host Disease
Authors: Hu Ziyi , Xu Yuxi , He Yuxuan , Xu Qing , Zhou Ya , Wang Qi , Xie Xiaodong , Wang Rui , Wang Xiaoqi , Yang Shijie , Song Qingxiao , Zhang Xi
Published: December 2024

Chronic graft-versus-host disease (cGVHD) is the most significant long-term complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). The oral cavity is frequently affected, second only to the skin, with the majority of cGVHD patients complaining of xerostomia. This condition significantly diminishes patients' quality of life. The manifestations of salivary gland damage in oral cGVHD are similar to classic Sjögren Syndrome, though its pathogenesis remains poorly understood.

Our study examined the pathological features within the salivary glands of cGVHD individuals, identifying periductal infiltration, gland atrophy, and fibrosis. In three murine cGVHD models, categorized as major MHC mismatched, haplo-HSCT and miHA-mismatched GVHD models, immune cell infiltration was mainly comprised of CD8+ T cells and double-negative T cells (DNTs). Notably, these DNTs expressed various cytotoxic molecules (e.g., KLRG1, Granzyme B) and inflammatory cytokines. Furthermore, higher levels of GITR, CXCR6, PD-1, and TIM-3 were observed in DNTs compared to CD8+ T cells, suggesting a TEM/TEMRA-like phenotype with pathogenic roles in cGVHD lesion formation. The DNTs in the major MHC mismatched model exhibited Th1/Tc1 signatures with increased IFN-γ and T-bet expression, while those in the haplo-HSCT model showed Th17/Tc17 signatures with higher IL-17 expression.

We found that the development of DNTs in the salivary gland is thymus independent. Lineage tracing, single-cell RNA, and TCR-CDR3 sequencing in mice showed that GITR+ DNTs originated from Tcf-1+CD8+ T cell progenitors. Moreover, the attraction of these cytotoxic DNTs by GITR ligand (GITRL) expressed on salivary epithelial cells led to glandular damage. Triggering mGITR with anti-mGITR antibodies (DTA-1) promoted the proliferation of DNTs in a CD8+ T cell-dependent GVHD model (C3HSW to B6/SJL)

Our findings reveal that the interplay between salivary epithelial cells and donor-derived DNTs is central to the pathogenesis of salivary gland damage in oral cGVHD. Moreover, these data indicate that the mechanism of salivary gland damage in oral cGVHD differs from that of oral mucosal cGVHD, which is driven by cytotoxic CD8+ T cells.

In conclusion, targeting the GITR/GITRL signaling pathways emerges as a potential therapeutic strategy for addressing salivary gland dysfunction in oral cGVHD. This finding opens new avenues for more specific and effective treatments for patients suffering from this debilitating condition.
Endothelial Protein C Receptor CD201 Enables Identification of Transplantable Mouse Hematopoietic Stem Cells in Inflammatory Conditions Unlike SCA1
Authors: Bisht Kavita , Shatunova Svetlana , Barbier Valerie , Winkler Ingrid G , Levesque Jean-Pierre
Published: December 2024

Stem cell antigen-1 (SCA1) is widely used to identify mouse hematopoietic stem cells (HSC) and multipotent progenitors (MPP) among lineage-negative KIT+ (LK) cells. However, SCA1 is not expressed by HSCs and MPPs from Ly6A.1 haplotype inbred strains such as BALB/c, C3H, CBA and nonobese diabetic (NOD), precluding proper HSC isolation and characterization in these mice. Furthermore, SCA1 is strongly induced on lineage-committed progenitor cells even in Ly6A.1 haplotype strains following treatment with type 1 and type 2 interferons, lipopolysaccharide (LPS) or after bacterial infection or sepsis which further compromises the ability SCA1 to correctly distinguish HSC/MPP from lineage-committed progenitors in inflammatory conditions. The endothelial protein C receptor CD201 has been suggested as an alternative marker for mouse and human HSC. However, whether CD201 expression changes during inflammation has not been investigated. Here we show in a mouse model of acute sepsis that LPS dramatically upregulates SCA1 expression in LK cells with 3-fold increase in mean fluorescence intensity and frequency. In sharp contrast, CD201 expression remains invariant on mouse bone LK cells in response to in vivo challenge with LPS, suggesting that CD201 is more suitable than SCA1 to identify HSC and MPP during inflammation. We then performed long-term competitive transplantations assays to assess the engraftment potential of LK201+ versus LK201- versus LK SCA1+ (LKS+) cells. Following LPS treatment, HSC from LK201+ engrafted 4.4-fold better than LKS+ and 75-fold better than LK201- cells suggesting that during inflammation, true HSCs are within the LK201+ population. Based upon CD201+ gating, LPS increased HSC and MPP cell proliferation but reduced their numbers in the BM. Also based on CD201+ gating, LPS suppressed myeloid and erythroid progenitors, decreased expression of HSC retention factors in the BM, and increased HSC mobilization. Finally using knock-out mice, LPS upregulated SCA1 expression on HSC and MPP via both MYD88 and TRIF signaling. Likewise, LPS increased HSPC mobilization via both TRIF and MYD88 pathway. However, LPS induced suppression of myeloid and erythroid progenitors required MYD88 but not TRIF signaling. In conclusion, CD201 enables a more accurate analysis of mouse HSC and MPP in all inbred strains under inflammatory conditions unlike SCA1. Activation of TLR4-TRIF and TLR4-MYD88 pathways play a distinct role on BM myeloid and erythroid progenitors and HSPC mobilization.
Clinicopathological and Gene Expression Analysis of Hyaline Vascular Castleman Disease
Authors: Nishimura Midori Filiz , Nishimura Yoshito , Iwamoto Yuika , Haratake Tomoka , Ujiie Hideki , Nishikori Asami , Habermann Thomas M. , Dispenzieri Angela , Sato Yasuharu
Published: December 2024

Introduction:

Hyaline-vascular type unicentric Castleman disease (HV-UCD) is a classic variant of Castleman disease, characterized by localized lymph node hyperplasia. Due to its rarity, there have been few systematic reports summarizing its clinicopathological features globally. Also, its pathogenesis remains unelucidated. The present study aims to provide a detailed clinicopathological and transcriptomic analysis of HV-UCD to enhance the understanding of its underlying mechanisms at a molecular level.

Methods:

We conducted a clinicopathological analysis of 51 HV-UCD cases and performed whole transcriptome analysis on frozen lymph node specimens from four cases. Differentially expressed genes (DEGs) and Gene Ontology (GO) analyses were performed to identify significant pathways and biological processes involved in HV-UCD, with reactive lymphoid hyperplasia as control.

Results:

The mean age of HV-UCD patients was 42.8 years, with no significant gender differences. The most common sites involved were the abdominal cavity (n = 18, 35.3%), mediastinum (n = 11, 21.6%), and retroperitoneum (n = 9, 17.6%), with an average size of the lesions being 4.8 cm. Histologically, 33.3% of cases exhibited “dysplastic follicular dendritic cells (dFDCs)” characterized by multinucleation or large nuclei within and outside follicles, positive for follicular dendritic cells (FDC) markers. DEGs analysis compared to reactive lymphoid hyperplasia revealed significant upregulation of genes related to FDCs and angiogenesis. Notably, the placental growth factor (PGF), a proangiogenic factor and a member of the VEGF family, demonstrated significant overexpression. GO analysis identified significant enrichment of genes involved in angiogenesis, cell adhesion, tissue architecture, and humoral immunity.

Discussion:

This large cohort of HV-UCD cohort provides potentially novel clinicopathological insights. Gene expression analysis demonstrated increased expression of FDC-related genes, suggesting a pivotal role of FDCs in HV-UCD pathogenesis. The differences in the gene profiles related to angiogenesis may contribute to the distinct mechanisms and histological features of HV-UCD and iMCD-TAFRO, where HV-UCD is associated with hyalinization of vascular walls and iMCD-TAFRO is characterized by angiogenesis with endothelial cell swelling.

Conclusion:

The present results suggest the crucial role of FDCs in HV-UCD pathogenesis from the molecular features. Currently, there are no objective diagnostic markers for HV-UCD. Identifying these markers may lead to a clearer understanding of the disease pathophysiology and improve diagnostic accuracy for HV-UCD. Further investigation is warranted to verify the findings.
Clinical and Laboratory Characteristics of Pediatric Patients with ACKR1/Darc-Associated Neutropenia
Authors: Oz-Alcalay Lital , Steinberg-Shemer Orna , Elitzur Sarah , Brik Simon Dafna , Tamary Hannah , Izraeli Shai , Yacobovich Joanne , Gilad Oded
Published: December 2024

Background: ACKR1/DARC-associated neutropenia (ADAN), resulting from homozygosity for a single nucleotide polymorphism (SNP) in the ACKR1/DARC gene (rs2814778), is a common cause of benign neutropenia that primarily affects individuals of African and Jewish Yemenite descent. We aimed to characterize ADAN in pediatric patients in Israel, given its ethnically diverse population.

Procedure: We assessed children with isolated neutropenia treated during 2018-2023 at one pediatric center, for the ACKR1/DARC polymorphism, using Sanger sequencing or targeted next-generation sequencing.

Results: Of 115 patients evaluated, 55 (47.8%) were diagnosed with ADAN; of these, 27 (49%) were in the severe range (neutrophil count 0-0.5X109/L). The allele distribution revealed 40.0% of Muslim Arab and 58.2% of Jewish origin. The diverse geographical range included Yemenite, Ethiopian, Mediterranean, Asian, and European ancestry. Fifty-one percent had a family history of neutropenia. The median age at the first neutropenia detection was 1.1 years; nearly 90% were identified during routine blood counts. The median absolute neutrophil count at diagnosis was 0.5X109/L (interquartile range 0.3). Patients did not show an increased susceptibility to infections either before or during the median follow-up period of 2.5 years (interquartile range 1.54) after the diagnosis of ADAN. In 42 patients (75.0%), neutrophil counts increased during febrile illnesses.

Conclusions: We identified ADAN in individuals of variable ethnicities, almost half with severe neutropenia. We recommend testing for ADAN in all children with isolated neutropenia without severe infections. This suggests that homozygosity for the ACKR1/DARC rs2814778 SNP eliminates the need for further investigation, follow-up, or treatment in this clinical scenario.
A Survival Prognostic Model for Gastro-Intestinal Non-Hodgkin Lymphoma
Authors: Wu Shaojie , Du Junru , Ma Jie , Huang Li , Peng Zhiqiang , Ling Yiwen , Deng Xiaofang , Zhu Weijian , Li Hongliang , Wang Hua , Li Yuhua
Published: December 2024

Primary gastro-intestinal lymphoma is the most common extra-nodal lymphoma. There is no widely-accepted survival prognostic model. We interrogated data from 1, 023 consecutive newly-diagnosed subjects. The most common site was stomach (n = 560, 54.74%) followed by the large intestine (excluding the ileocecal region) (n = 177, 17.30%), small intestine (n = 134, 13.10%), ileocecal region (n = 85, 8.31%). Most were of B-cell origin (n = 973, 95.1%). Diffuse large B-cell lymphoma (DLBCL) was the most common diagnosis (n = 668, 65.30%). Subjects with B-cell non-Hodgkin lymphoma had better survival compared with those with T-cell non-Hodgkin lymphoma (3.99 [2.55-6.25], P<0.001). According to the principle of non-randomized, non-intervention analysis, Survival of subjects with stomach or large intestine sites was better compared with other single (HR 1.73,95%CI,1.25-2.41,P<0.001). Subjects receiving chemotherapy with surgery had better survival compared with surgery only(HR 2.22,95%CI,1.09-4.52,P=0.023). Receiving R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) was associated with better survival compared with CHOP. A total of 668 patients with PGI-DLBCL were divided into the training(465 patients from 6 centers in Guangdong) and validation (203 patients from the other 3 non-Guangdong centers) sets. In multi-variable Cox regression analyses: age (HR 2.60,95%CI,1.50-4.51, P<0.001), albumin concentration (HR 0.94,95%CI,0.89-0.99, P=0.047), Lugano stage (HR 1.35,95%CI,1.03-1.77, P=0.030), and lactic dehydrogenase (LDH) (HR 2.36,95%CI,1.30-4.30, P=0.005) were independently correlated with survival. These co-variates were used to develop a survival prognosis nomogram model with C-statistics of 0.82 (95%CI,0.77-0.86) and 0.80 (95%CI,0.74 - 0.85) in the training and validation cohortst. Our model, if validated, may be useful to predict survival of patients with primary gastro-intestinal lymphomas.