bluuebunny/crossref_metadata_2025 huggingface dataset:
Conversational Dynamics in Task Dialogue Between Interlocutors With and Without Hearing Impairment
Authors: Sørensen A. Josefine Munch , Lunner Thomas , MacDonald Ewen N.
Published: December 2024

This study investigated the effects of noise and hearing impairment on conversational dynamics between pairs of young normal-hearing and older hearing-impaired interlocutors. Twelve pairs of normal-hearing and hearing-impaired individuals completed a spot-the-difference task in quiet and in three levels of multitalker babble. To achieve the rapid response timing of turn taking that has been observed in normal conversations, people must simultaneously comprehend incoming speech, plan a response, and predict when their partners will end their turn. In difficult conditions, we hypothesized that the timing of turn taking by both normal-hearing and hearing-impaired interlocutors would be delayed and more variable. We found that the timing of turn starts by talkers with hearing impairment had higher variability than those with normal hearing, and participants with both normal hearing and hearing impairment started turns later and with more variability in the presence of noise. Overall, in the presence of noise, talkers spoke louder and slower, increased the duration of their pauses but decreased their rate of occurrence, and produced longer interpausal units, that is, units of connected speech surrounded by silence. However, when compared to previous studies of conversations between normal-hearing partners, the pattern of changes in conversational behavior by the normal-hearing participants was very different in the most challenging noise condition. The extent to which these adaptations are made to reduce the difficulty experienced by their partner with hearing impairment vs. the difficulty they experience themselves is not clear.
Engaging, Binding and Retaining Nurses: The Success Formula of an Exemplary Ward
Authors: Spoolder D.A.E. , van Duijn A.G. , Schreuder-Cats H.A. , de Bie-Timmer M.J.
Published: December 2024

Background

Nurse staffing remains an ongoing issue in healthcare worldwide. However, a Dutch urology ward has hardly any staffing difficulties. Nevertheless, it remains challenging to grasp what exactly is the success formula of the ward. Investigating a practical example of a successful ward will facilitate a deeper understanding of the application of current knowledge. Furthermore, novel concepts offer potential solutions to current problems. There is a need of putting the knowledge into practice.

Objective

The objective is to identify the factors that contribute to the success of the urology ward in engaging, binding, and retaining nurses, to provide practical insights and opportunities for other wards.

Methods

The Dutch Model for Excellent Care forms the basis of a prospective, qualitative research study with focus groups. Twelve nurses were divided into three focus groups, based on work experience. They were asked about why they love working on the ward. Analysis was performed using Braun and Clarke's method for thematic analysis. Emerged themes were presented, substantiated by quotes.

Results

Four themes and twelve subthemes became apparent: (a) Supportive structures: nursing governance, professional development, and quality of leadership. (b) Optimal work environment: working with skilled nurses, a professional relationship with physicians and professional autonomy. (c) Team culture: feeling seen, good ambiance, and equality. (d) Specialty of urology: variation in work, workload, and the type of patient.

Conclusions

Nurses are uniquely positioned to provide invaluable insight into their needs. They illuminated the crucial importance of fostering a work environment that prioritizes both professional as well as personal needs.
Pluralising the materiality of water: More-than-water, lively waters, water with, and the agency of hydro-social assemblages
Authors: Rusca Maria , Browne Alison L , Di Baldassarre Giuliano , Menga Filippo
Published: December 2024

This special issue combines insights from an array of theoretical perspectives, including political ecology, Indigenous studies, and more-than-human and feminist geographies to engage with a critical question for water studies: What are the theoretical, empirical and methodological implications of a closer engagement with the matter and properties of water and infrastructure? To answer this question, the contributions draw on a geographically and empirically diverse set of case studies that illuminate a range of articulations of materiality of water and infrastructures in hydro-social assemblages. Collectively, the papers highlight how the materiality of water is inherently plural, as it is co-constituted through its entanglement with other materialities ( water with), gives rise to emergent materialities through its intra-action with other elements and more than human natures ( more-than-water), and relies on the labour of living organisms to transform and maintain its function ( lively waters). Second, the papers show how apprehending and pluralising materiality of water and infrastructure extends conceptualisations of agency, justice and care in hydro-social assemblages. The third thread emerging from this collection of papers is that methods matter for interdisciplinary, community and more-than-human knowledges. We conclude by identifying potential areas of interdisciplinary practice and future research on the material matters of water/s and infrastructures that engage with the interplay between ecological, hydrological, technical and social processes.
Benefits of nuclear twin family models for estimating heritability: An investigation of 93 personality-relevant constructs using JASP
Authors: Instinske Jana , Kandler Christian
Published: December 2024

To disentangle genetic and environmental contributions to individual differences, classical twin models (CTMs) are predominantly used. Prior research revealed several conditions under which CTMs spawn biased heritability and environmentality estimates, including the simultaneous relevance of nonadditive genetic and shared environmental influences, the presence of assortative mating, and passive gene-environment covariance. Nuclear twin family models (NTFMs), adding information from parents of twins, can handle these conditions. Little is known, however, on the actual impact of such conditions considering the empirical properties displayed by various personality-related phenotypes. The present study therefore investigated differences between NTFMs and CTMs in terms of error-adjusted heritability and environmentality across 93 personality-relevant constructs based on data from 636 twin pairs and 320 parents. Overall, NTFMs resulted in significantly lower heritability and higher environmentality estimates, suggesting an overall overestimation of heritability in CTMs. These trends pertained to about two-thirds of the investigated constructs, but reversely directed changes were detectable under specific conditions. We discuss the extent to which the assumptions underlying CTMs might bias conclusions regarding genetic and environmental contributions to personality differences and demonstrate benefits of NTFMs. Furthermore, we provide user tutorials for implementing CTMs and NTFMs based on the open-source and user-friendly statistical program JASP.
Theory testing and the work-family interface
Authors: Allen Tammy D. , Shockley Kristen M. , Ohya Takaki , Schoffel Molly
Published: December 2024

In this editorial we examine theory testing within the work-family literature. We identified three highly cited theoretical articles ( Ashforth et al., 2000 ; Greenhaus & Beutell, 1985 ; Greenhaus & Powell, 2006 ) and examined the extent that the propositions posed in these articles had been tested. Results indicated that the majority of the propositions posed in these three influential theoretical articles have not been tested. We discuss possible reasons for the lack of testing and offer potential paths forward for improving work-family theory.
Sociology and spirituality: Toward an immanent-transcendent critique of modernity
Authors: Saito Hiro
Published: December 2024

In this paper, I set up three thought experiments that mobilize nonmodern ontologies and epistemologies to explore the possibility of spiritual sociology. These experiments engage with Pierre Bourdieu as a Buddhist quantum physicist, Emile Durkheim as a New Age transpersonal psychologist, and Michel Foucault as a daemon-inspired revolutionary. The three experiments illustrate that, while many worlds (consisting of objective and subjective structures) exist, they tend to collapse into a few through “echo effects” produced by the powerful; these powerful echo effects are counteracted by the evolution of Spirit or Collective Consciousness growing more enlightened; and the more individuals reconnect with Spirit, the more echo effects are transformed into resonances, pointing to the pluriversal future that permits many worlds to co-flourish. This spiritual–sociological experimentation not only articulates an immanent–transcendent critique of modernity (or any society), but also suggests that contemplative practice be incorporated into undergraduate and graduate education because the quality of sociological research depends fundamentally on that of the researcher's mind.
Quality of Life after Gene Therapy in Pediatric Patients with Transfusion-Dependent β-Thalassemia and Their Family Caregivers: A Prospective Cohort Study
Authors: Kuang Zhexiang , Wang Anni , Yu Xiao , Xu Jing , Wang Weiwei , Xu Chun , He Xintong , Yuan Weiping , Shi Jun , Xu Li , Xie Wenjun
Published: December 2024

Objectives To investigate the impact of gene therapy on the health-related quality of life (HRQoL) of pediatric patients with transfusion-dependent β-thalassemia (TDT), and to assess the changes in anxiety and depression levels among their family caregivers during the therapy.

Methods A total of 9 pediatric patients with TDT and their family caregivers were enrolled in this prospective cohort study from July 2020 to July 2023. The Chinese version of the Pediatric Quality of Life Inventory 4.0 (PedsQL 4.0) was used to compare changes in children's HRQoL before and 6 months after receiving gene therapy. The Hamilton Anxiety Rating Scale (HAMA) and Hamilton Depression Rating Scale (HAMD) were used to assess the anxiety and depression levels in the family caregivers before and after children's gene therapy.

Results The TDT patient cohort included 3 males and 6 females with a median age of 12 years (range: 5-16 years). The total PedsQL 4.0 score post-gene therapy was significantly higher than the pre-gene therapy score (post: 90.46±11.42, pre: 76.45±10.48, t=-7.79, P<0.001). Scores for both physical function and school performance at 6 months post-gene therapy were also higher than those pre-gene therapy (physical function: t=-7.17, school performance: t=-5.36, both P<0.001). Prior to gene therapy, 3 family caregivers had mild anxiety and 7 had mild to moderate depression. After gene therapy, 1 caregiver had mild anxiety and 1 had mild depression. There was a statistically significant difference in the HAMD score before and after gene therapy (t=3.98, P=0.004), with medians of 9 (range: 4-15) and 4 (range: 2-8), respectively.

Conclusions The HRQoL of pediatric TDT patients improved 6 months after gene therapy, and their family caregivers experienced decreased anxiety and depression. Gene therapy can effectively enhance the health outcomes of both TDT patients and their caregivers.
ARPC2 Targeting Inhibition Progress the Proliferation Suppression of Acute Myeloid Leukemia through PI3K-AKT Pathway
Authors: Chen Chunxiao , Li Fenglin , Lu Ying , Pei Renzhi , Jin Jie , Zhuang Haihui , Li Shuangyue
Published: December 2024

Background: Acute myeloid leukemia (AML) is a hematologic malignancy originating from the bone marrow, and its high degree of heterogeneity has led to differences in clinical treatment and prognosis. Therefore, there is an urgent need to find new potential biological targets to guide clinical treatment. Actin related protein 2/3 complex subunit 2 (ARPC2) is an actin-binding component involved in the regulation of actin polymerization. Benproperine phosphate and pimozide have been confirmed to be the target inhibitors of ARPC2. However, the role of ARPC2 and the target drugs, benproperine phosphate and pimozide, is poorly known. Therefore, this study intends to explore the expression characteristic and prognosis significance of ARPC2 in AML, as well as to explore the effect by target inhibition of ARPC2 by benproperine phosphate and pimozide in AML .

Methods: Threedataset of AML patients were obtained from TCGA, GTEx and GEO. The relationship between ARPC2 expression and survival of AML patients was analyzed by Kaplan-Meier curves and Cox regression. The main pathways of ARPC2 in AML were analyzed by Gene Set Enrichment Analysis (GSEA) . The toxic effects of benproperine phosphate and pimozide in AML cells were examined by MTS assay. The effects of target inhibition of ARPC2 by benproperine phosphate and pimozide in AML cells were analyzed by Real-time fluorescence quantitative PCR (RT-qPCR) . Cell proliferation was detected by MTS assay, apoptosis was detected by flow cytometry, and the expression of relevant proteins was detected by Western Blot (WB).

Results: Combining TCGA, GTEx and GEO databases, we found that ARPC2 was highly expressed in AML patients (P<0.001). Survival analysis showed that AML patients with high ARPC2 expression had poor prognosis (P<0.05). Univariate and multivariate Cox regression analyses showed that high expression of ARPC2 was an independent poor prognostic factor for AML (P<0.05). GSEA analyses showed that PI3K-AKT pathway, MTORC1 signaling pathway, oxidative phosphorylation and oxidative stress were significantly activated in ARPC2 high expression group. Targeting ARPC2 by benproperine phosphate and pimozide had a significant cytotoxic effect on AML cells with significant concentration and time dependence. Through WB analysis, we found that both benproperine phosphate and pimozide could suppress the apoptosis proteins, such as BCL-2. They could also suppress the PI3K and AKT proteins, which are the key proteins of PI3K/AKT pathway, and this consistent with GSEA analysis.

Conclusion: High expression of ARPC2 is an independent adverse prognostic factor for AML patients. Benproperine phosphate and pimozide can inhibit the proliferation and promote apoptosis of AML cells by targeting ARPC2 through PI3K-AKT pathway, which may provide a new idea for the future targeted therapy of AML.
Targeting p53 Improves Drug Resistance in Mantle Cell Lymphoma By Regulating Mitophagy-Dependent Ferroptosis
Authors: Chen Yingtong , Yang Ping , Zhang Weilong , Wang Jing , Gao Shuang , Yang Yuan , Liu Shuozi , Li Chunyuan , Jing Hongmei
Published: December 2024

Background: Drug resistance in mantle cell lymphoma (MCL) represents a critical challenge in clinical practice. Our preliminary findings indicated a high p53 mutation rate in drug-resistant MCL patients, accompanied by diminished expression of mitophagy-related markers PINK1 and Parkin, and elevated level of the ferroptosis-related marker GPX4 in these resistant cases. This study aimed to explore the regulatory relationship between p53, mitophagy, and ferroptosis in MCL.

Methods: The expression ofPINK1, Parkin and GPX4 was detected in MCL patients and MCL cell lines (Jeko, Mino, Rec1, Z138 and JVM2 cells).The correlation between p53 expression and the expression of PINK1, Parkin, and GPX4 in MCL patients was analyzed via GEO database. MCL cell lines were treated with APR-246, an agent targeting mutant p53, and then cell proliferation, gene expression and ROS level were determined by CCK-8, qPCR and flow cytometry. The regulatory mechanism between p53 and PINK1 was revealed by CUT&Tag technology.

Results: Compared with chemotherapy sensitive MCL patients, chemotherapy resistant MCL patients have lower expression of mitophagy-related genes PINK1 and Parkin, and higher expression of ferroptosis-related gene GPX4. Low expression of Parkin and high expression of GPX4 were associated with poor prognosis in MCL patients. Besides, p53 expression was positively correlated with PINK1 expression and negatively correlated with GPX4 expression in GSE93291 database. In p53-mutant MCL cells (Mino and Rec1), the expression of PINK1 and Parkin was lower than that of p53-deficient MCL cells (Jeko) and p53-wild type MCL cells (Z138 and JVM2), while the expression of GPX4 and SLC7A11 was higher than that of p53-deficient and p53-wild type MCL cells. APR-246 showed significant inhibitory effect on cell proliferation of p53-mutant MCL cells, while its inhibitory effect was not strong on p53-deficient and p53-wild type cells. After APR-246 intervention, the expression of PINK1 and Parkin was significantly increased, the expression of GPX4 and SLC7A11 was significantly decreased, and ROS accumulation was observed in p53-mutant cells. However, these phenomena were not occurred in p53-deficient and p53-wild type cells. CUT&Tag assay revealed mechanistically that PINK1 was transcriptionally activated by p53.

Conclusions: Our study elucidates the specific mechanism by which targeting mutant p53 could improve drug resistance in MCL by regulating mitophagy-dependent ferroptosis, and provides a new therapeutic strategy for chemotherapy resistant MCL patients.
Senescence Gene Senex May Regulate Apoptosis Signaling Pathway, Stem Cell Signaling Activation and Tumor Microenvironment to Promote Tumorigenicity and Invasiveness of Burkitt Lymphoma Cell
Authors: Zhai Zhimin , Li Qian , Tao Qianshan , Ren Xiyang , Guo Jinjing , Wang Huiping
Published: December 2024

Background: The SENEX gene, encoding the protein ARHGAP18, is thought to be involved in the development of various diseases. Previous studies have shown that the SENEX gene may trigger tumor cell senescence and is highly expressed in relapsed and refractory lymphoma. However, the mechanism of action of the SENEX gene in Burkitt's lymphoma remains unclear.

Methods: We verified the effect of SENEX gene-induced cellular senescence on RAJI cell through a series of functional experiments, including senescence-associated-β-galactosidase(SA-β-Gal) staining, cell proliferation, apoptosis and Transwell assays. The effects of SENEX gene-triggered senescence on the expression levels of senescence-related proteins, EMT-related proteins and WNT/β-catenin signaling pathway star proteins were detected by Western blot experiments. In addition, we established an immunodefic ient mice model of subcutaneous xenografts to observe the effects of SENEX gene-triggered tumor cell senescencehe biological characteristics and survival of lymphoma in vivo.

Results:Chemotherapy-induced SIPS significantly improves the SENEX gene and senescence-associated proteins, promoting resistance to apoptosis and leading to drug resistance. Through in vitro experiments, we found that SENEX gene-mediated SIPS affects the levels of senescence-associated proteins, enhances tumor cell apoptosis resistance, and increases tumor invasiveness via epithelial-mesenchymal transition (EMT) and the WNT/β-catenin pathway. In vivo experiments revealed that both chemotherapy-induced and SENEX gene-mediated SIPS promote malignant growth of mouse xenografts and reduce survival time. The mechanisms involve resistance to apoptosis through cellular senescence, tumor invasion and metastasis promotion via the WNT/β-catenin signaling pathway, and tumor progression through alterations in the tumor microenvironment.

Conclusion: Our study reveals that the SENEX gene can regulate the apoptosis signaling pathway, stem cell signaling activation and reprogram the tumor microenvironment to promote tumorigenicity and invasiveness of Burkitt's lymphoma cells both in vitro and in vivo. The SENEX gene may be a potential therapeutic target for Burkitt's lymphoma.
Large-Scale Metabolomic Mendelian Randomization Analysis Identifies Pyridoxate As a Key Factor in Graft-Versus-Host Disease
Authors: Yu Xinghao , Chen Yiyin , Lei Lei , Lin Dandan , Shen Ying , Hou Chang , Chen Jia , Fan Yi , Lu Huimin , Wu Depei , Xu Yang
Published: December 2024

Metabolites and their implications on prognosis following allogeneic hematopoietic stem cell transplantation (allo-HSCT), including graft-versus-host disease (GvHD) and relapse, remain largely unexplored. In discovery Mendelian randomization (MR) analysis, we used instrumental genetic variants identified from genome-wide association studies of 309 known metabolites to investigate potential causal associations. After multiple test corrections, four metabolites exhibited causal effects on allo-HSCT outcomes in a public cohort of 7,824 adults from two European population studies. Specifically, pyridoxate and 1-stearoylglycerophosphoethanolamine were associated with reduced GvHD risk, whereas glycochenodeoxycholate increased GvHD risk. Proline was linked to decreased relapse risk. Multiple sensitive methods, along with heterogeneity and horizontal pleiotropy tests, affirmed the robustness and stability of these findings. Multivariable MR analysis ruled out pleiotropic effects from potential confounders. Notably, the effects of pyridoxate remained robust upon further validation MR analysis from another independent dataset (N = 8,089 individuals), and pyridoxate levels consistently indicated its protective role against both acute and chronic GvHD, as well as relapse. Additionally, based on long-term follow-up cohort (NCT06143501), untargeted metabolomics study of 90 post-transplant patients over 4-6 weeks found that pyridoxine levels were maintained at higher levels in the non-GvHD group compared to the GvHD group (P= 0.019). Additional mediation MR analyses elucidated the direct and indirect effects of metabolites on GvHD through CD8+ T cells. Pathway analysis highlighted key biochemical processes and metabolic disturbances, including the regulatory roles of vitamin B6 derivatives. Our study offers novel insights into the pathogenesis and therapeutic strategies for GvHD and relapse after allo-HSCT, emphasizing the potential of pyridoxate and its metabolic pathways as therapeutic targets.
Molecular Characteristics of Bone Marrow Mesenchymal Cells in Ph+ Acute Lymphoblastic Leukemia and Their Protective Effects on Leukemia Cells
Authors: Mi Yingchang , Fang Qiuyun , Hao Qishan
Published: December 2024

Objective: The study aimed to compare the biological characteristics of bone marrow mesenchymal cells (MSCs) in patients with Ph-positive acute lymphoblastic leukemia (Ph+ ALL) with different disease states, to identify the differences in cyto-protective effects of MSCs with different disease states on leukemia cells and explore the possible mechanisms.

Methods: Bone marrow samples were collected from patients with Ph+ B-ALL and healthy donors, cultured to obtain primary MSCs, passaged and identified. The proliferation ability of MSCs in vitro and the impact on the migration ability of Ph+ ALL cell line SUP-B15 in each group were tested. MSCs from different groups were co-cultured with SUP-B15, and apoptosis of SUP-B15 cells after treated with drugs (imatinib, dasatinib, dexamethasone) was detected. Transcriptome sequencing was performed on MSC cells from different disease states. RT-PCR method was used to detect the expression level of target gene in MSCs.

Results: (1) Donor (DR) MSCs proliferated more strongly than ALL - MSCs in vitro (P < 0.01). Proliferation ability in vitro of MSCs from relapsed and refractory (RR-MSCs) ALL patients was stronger than that of MSCs from complete remission group (CR-MSCs) and MSCs in newly diagnosed ALL group (ND-MSCs) (P <0.05, P <0.05).

(2) After treatment with the drugs, proportion of apoptosis in SUP-B15 cells was significantly reduced in co-culture group. The protective ability of DR-MSCs and ND-MSCs were more marked than CR-MSCs (P < 0.001, P < 0.05, P < 0.01, P < 0.0001; P < 0.05, P < 0.05, P < 0.05, P < 0.001).(3) GO enrichment analysis of transcriptome sequencing results showed that BMP4 was significantly up-regulated in ND-MSCs compared with DR-MSCs (FC=3.311, P. adj=0.024). The expression levels of BMP4 in ND-MSCs and RR-MSCs were higher than those in DR- MSCs (P<0.05, P<0.01); RR-MSCs showed higher expression levels of BMP4 than CR-MSCs (P<0.05); CR-MSCs showed lower expression levels of BMP6 than ND-MSCs (P<0.05), CR- MSCs BMP6 expression was also lower in ND-CR matched MSCs than ND- MSCs (P<0.05).

Conclusion: Ph + ALL-MSCs showed weaker proliferative ability than DR-MSCs in vitro. MSCs derived from different disease states showed different protective effect of SUP-B15 cells from apoptosis (the protective effect of DR-MSCs and ND-MSCs are stronger than CR-MSCs). This protection was associated with the expression of genes involved in the BMP/SMADs signaling pathway.
Thrombopoietin Receptor Agonist Added to Standard Immunosuppressive Therapy for Hepatitis-Associated Aplastic Anemia
Authors: Wang Min , Ge Meili , Fang Liwei , Jing Liping , Mi Yingchang , Zhang Fengkui , Zheng Yizhou , Shi Jun
Published: December 2024

Background: Hepatitis-associated aplastic anemia (HAAA) is a rare variant of severe aplastic anemia (SAA) characterized with a syndrome of bone marrow failure that traditionally occurs within 6 months of an acute attack of hepatitis. HAAA is potentially lethal if left untreated. Management includes immunosuppression with antithymocyte globulin and cyclosporine and allogeneic hematopoietic stem cell transplantation. Addition of thrombopoietin receptor agonist (TPO-RA) improves both the overall response rate and complete response rate of SAA patients. Here, we tried to investigate the effect and adverse events of TPO-RA added to standard immunosuppressive therapy for HAAA.

Methods: A total of 17 HAAA patients who received ATG, cyclosporine and TPO-RA as first-line treatment between April 2019 and January 2024 were enrolled. 6 patients were SAA and 11 patients were very severe aplastic anemia (VSAA) according to the criteria of the International Aplastic Anemia Study Group. All TPO-RAs were added within 1 months after ATG initiation at dose of their standard administration respectively.

Results: Of all the patients, 8 received avatrombopag (2 with SAA and 6 with VSAA), 5 received eltrombopag (1 with SAA and 4 with VSAA), and 4 received hatrombopag (3 with SAA and 1 with VSAA). The median neutrophil count was 0.23 (range 0.01-0.78) ×109/L, median reticulocyte count was 11 (range 1-40) ×109/L, and median platelet count was 5 (range 1-12) ×109/L. All patients achieved the end-point of 3 months and 16 patients achieved the end-point of 6 months. The rate of complete response was 11.8% and rate of overall response was 52.9% at 3 months. The rate of complete response at 6 months was 41.2% and rate of overall response was 70.6%. The overall response rate of patients treated with avatrombopag, eltrombopag and hatrombopag were 37.5% vs 40% vs 100%, and 62.5% vs 60% vs 100% at 3, 6 months after IST, respectively. The overall response rate at 3 months and 6 months were both higher than historical results of standard IST (ATG and cyclosporine, 34.1% at 3 months and 56.1% at 6 months). All TPO-RAs were safe, and there was no drug-related liver dysfunction. No patient discontinued TPO-RA due to adverse events.

Conclusions: In conclusion, the addition of TPO-RA to IST was safe and associated with higher overall response rate among patients with HAAA.
Engineering Next-Generation CAR T Cells Via Genetic Screens
Authors: Datlinger Paul , Pankevich Eugenia , Arnold Cosmas D , Pranckevicius Nicole , Lin Jenny , Romanovskaia Daria , Schäfer Moritz , Orts Anne-Christine , Nemc Amelie , Biesaga Paulina , Chan Michelle , Neuwirth Theresa , Ladstaetter Sabrina , Piras Francesco , Li Wentao , Krausgruber Thomas , Bock Christoph
Published: December 2024

The successes of genetically engineered chimeric antigen receptor (CAR) T cells in B cell

leukemia and lymphomas have revolutionized the field of immunotherapy. However, durable

remission is only achieved in a subset of patients, and poor treatment efficacy has been

reported for solid tumors. These limitations often result from intrinsic dysfunctions of T cells,

such as poor proliferation, compromised effector function, or T cell exhaustion.

CRISPR-based functional genetic screens assess the impact of genetic modifications at the

genome-wide level and could greatly accelerate the design of improved T cell-based

therapies. We developed a new technology, CRISPR applied by mRNA electroporation and

lentivirus, to enable efficient genome editing and high-throughput screening in CAR T cells.

The simultaneous delivery of the CAR and a CRISPR guide RNA (gDNA) enabled single-

gene perturbation as well as genetic screens with libraries of target genes in CAR T cells

directed against various antigens. Our mRNA-based protocol for the delivery of CRISPR

modifiers extends the available tool kit for genome engineering in primary human T cells

from loss-of-function mutations to precise base editing and CRISPR activation.

We performed genome-scale fitness-based CRISPR screens in human T and CAR T cells. We

uncovered gene regulators specific to TCR-driven and CAR-driven proliferation. Moreover,

our screens robustly identified canonical immunotherapy targets such as CTLA4, along with

genes that have not been characterized in T cells. We have thus demonstrated the high

scalability and efficiency of our technology and created a comprehensive map of genetic

perturbations tuning CAR T cell performance.

Our platform is compatible with CROP-seq technology for single-cell CRISPR screens and

with pooled in vivo screening of CAR T cells in a mouse leukemia model. Thus, the

technology enables unbiased immunotherapy target discovery, and can be applied for high-

throughput characterization of functional regulators in primary human cells.
Association between Waist Circumference, Body Mass Index, High-Density Lipoprotein Cholesterol Level, and Risk of Chronic Myeloid Leukemia
Authors: Kim Ka Young , Han Kyung Do , Yoon Jae-Ho , Lee Sung-Eun
Published: December 2024

Advances in the treatment of chronic myeloid leukemia (CML) have resulted in increased prevalence. However, a more comprehensive understanding of its pathogenesis and epidemiology is necessary. Recent studies suggested the association between altered lipid metabolism and carcinogenesis, prompting an investigation of the relationship between metabolic disorders and incidence of CML. Thus, we conducted a study to examine the association between waist circumference, body mass index (BMI), high-density lipoprotein cholesterol (HDL-C), and the incidence of CML.

Using data from the Korean National Health Insurance Service from 2009 to 2017, a competing risks regression was conducted to examine the hazard ratios of CML in 3,879,560 individuals aged 20 years and above.

During a mean of 10.13±1.24 years of follow-up, there were a total of 848 cases of CML, including 539 male and 309 female patients.

1) Individuals in the group with a waist circumference equal to or greater than 100cm had the greatest risk of CML (adjusted hazard ratio [aHR], 95% CI = 1.593, 1.058-2.398), compared to those with a waist circumference from 80 to less than 85cm.

2) Those with a BMI less than 18.5 showed the lowest incidence of CML ([aHR], 95% CI = 0.509, 0.278-0.931) in comparison to the reference population with a BMI between 18.5 and 22.9.

3) Individuals in the highest quartile of HDL-C had the lowest risk of CML ([aHR], 95% CI = 0.795, 0.657-0.961) compared to those in the lowest HDL-C quartile.

A large waist circumference was significantly associated with increased risk of CML, whereas a low BMI and high HDL-C were associated with a reduced risk of CML. This suggests that a large waist circumference may be an independent risk factor of CML, whereas a low BMI and high HDL-C may be association with a protective effect against CML.
Predicting Vaso-Occlusion in Sickle Cell Disease By Microfluidics and Modeling
Authors: Ji Catherine , Chen Yi-Hua , Peng Zhangli
Published: December 2024

Sickle cell disease (SCD) affects approximately 100,000 Americans and occurs in 1 out of every 365 African-American births. One of the most debilitating symptoms of SCD is pain crisis caused by sickled red blood cells clotting microvasculature, which is termed vaso-occlusion. There are currently no methods to monitor or predict pain crises. This study aims to design a method by applying a microfluidic device and modeling system to predict vaso-occlusion events in SCD.

The study was designed to incorporate experimental and modeling approaches to predict the clotting of the microvasculature. The microfluidic device monitors and records the passage of healthy and sickled red blood cells through pores that mimic the smallest human microvasculature. Blood samples were obtained from the sickle cell patients. Using this approach, the migration of normal and sickled red blood cells through the pores of the microfluidic device was monitored, and the passage time was recorded.

The recorded data was integrated with a mathematical model of the passage of sickle cells through microvasculature to predict the clotting under various conditions. Specifically, the images of blood smear from the blood samples were used to calculate the statistical distributions of different types of sickle cells and construct computational model. The cells were modeled using a multiscale cell model based on the finite element method coupled with a boundary integral model of the surrounding flows. Pressures at the physiological conditions in various microvasculatures were applied to push the cells to pass through the pores. The altered cell shape and mechanical properties of different types of sickle cells were incorporated into the multiscale model to distinct them from normal red blood cells. After calibrating the passage time against measurements in the microfluidic experiments, the probability of vaso-occlusions was predicted based on the measured statistical distributions of sickle cells and dimensions of microvasculatures.

We found that sickled red blood cells could pass through the pores in the microfluidics. However, the dynamic and quantity of the migration were significantly compromised. This is closely related to the percentages of different types of sickled red cells, reflecting the severity of patients' disease. Through the changes in the size of the microvasculatures, the possibility of clotting of various vasculature in the body can be predicted using this model with patient-specific blood smear images. In this respect, we analyzed 72 blood smears from 24 patients with sickle cell disease. The percentage of the sickle cells out of total red blood cells were quantified in each smear using a computational approach. Indeed, the frequency of sickled red cells is positively correlated with the frequency of vaso-occlusion events in these patients. We conclude that this novel design of the vaso-occlusion prediction system could be useful in predicting the clotting and pain crisis of SCD patients.
The Real-World Data of Emicizumab in Previously Untreated and Minimally Treated Patients with Hemophilia a Infants from China
Authors: Yin Qixaun , Mao Qianqian , Li Zhengping , Li Gang , Chen Zhenping , Wu Runhui
Published: December 2024

Introduction

Emicizumab (EMI) is safe and efficient in pediatric patients with hemophilia A (HA). However, real-world data regarding immune response, pharmacokinetics (PK) and pharmacodynamics (PD) during EMI for previously untreated (PUP) and minimally treated (MTP) patients with HA infants(<3y) are limited in China. This study investigated the immune response and PK/PD of EMI in PUP and MTP with HA infants in China.

Methods

We performed a retrospective analysis of pediatric HA patients to collect data on PUPs and MTPs at our Comprehensive Hemophilia Care Center. Data included patients' baseline characteristics, therapy details, bleeding episode of pre- and post-EMI, and adverse events. Immune response included anti-emicizumab antibodies (ADAs) and factor VIII (FVIII) inhibitors. Laboratory analyses included FVIII-like activity and EMI concentration measurements.

Results

Sixteen PUPs and MTPs with HA had received EMI prophylaxis for a median (range) duration of 21.8 (4.9-47.0) months by July 2024. The median age at the beginning of EMI was 11.8 (5.8-33.3) months. At the initiation of EMI, all patients were inhibitor-negative.

While on EMI, EMI showed effectively prevented bleeding even: the median annualized bleeding rate (ABR) of 0.6 (0.0-1.9), annualized joint bleeding rate (AJBR) of 0.0 (0.0-0.3), and annualized spontaneous bleeding rate (ASBR) of 0.0 (0.0-1.59). Seven(43.8%) patients reached zero-bleeding rate (ZBR).

No drug-related serious adverse events were observed.

In the loading phase, patients with median age of 10.8 (5.8-32.9) months and body mass index (BMI) of 17.8 (15.6-21.6) received a median EMI loading dose of 3.0 (2.4-3.5) mg/kg. Their median EMI concentration was 65.9 (36.2-79.9) μg/mL and FVIII-like activity was 27.0 (13.5-35.4) IU/dL. Even though the mdian EMI 4-weekly maintenance dosage [4.8 (4.0-5.6)mg/kg] was below the internationally recommended dosage (6mg/kg), patients reached EMI concentration of 50.2 (36.0-76.8) μg/mL, and FVIII-like activity of 14.9 (10.4-30.4) IU/dL. EMI concentration was correlated with FVIII-like activity (rs=0.858，p＜0.001).

Four (25%) patients received a total of 9 administrations of factor-based therapy. During the long-term follow-up period, the median number of exposure days (EDs) was only 0 (0-3) days. No patients tested positive for ADAs or FVIII inhibitors.

Conclusion

EMI has demonstrated favorable tolerability and efficacy in PUPs and MTPs with HA in infants. Using EMI at substandard doses can still achieve relatively high maintenance concentrations. Furthermore, the concentration of EMI correlates well with their FVIII-like activity. No patients developed ADAs or FVIII inhibitors.
Efficacy and Safety of Different TPO-RAs Combined with Cyclosporine in the Treatment of NSAA
Authors: Wang Ting , Liu Donglan , Li Nianbin , Gao Shuai , Li Lijuan , Song Jia , Wang Huaquan , Fu Rong
Published: December 2024

TPO-RA has significantly improved the outcomes of patients with aplastic anemia. Currently, three small-molecule TPO-RAs, eltrombopag, hetrombopag, and avatrombopag are available for clinical use and work very well. This article compares the efficacy and safety of these TPO-RAs in the treatment of non-severe aplastic anemia (NSAA).Out of 67 NSAA patients, 31were male and 36 female, with a median age of 50 years (9-81 years). All patients received CsA combined with TPO-RAs (10 patients received avatrombopag, 15 patients received hetrombopag, and 42 patients received eltrombopag). The 3-month efficacy of CsA combined with TPO-RAs: the ORR of the avatrombopag group was 90.00% (CR 20.00%, PR 70.00%), the hetrombopag group was 73.33% (CR 13.33%, PR 60.00%), and the eltrombopag group was 66.67% (CR 4.76%, PR 61.90%); the 6-month efficacy, the ORR of the avatrombopag group was 90.00% (CR 20.00%, PR 70.00%), the hetrombopag group was 80.00% (CR 26.67%, PR 53.33%), and the eltrombopag group was 80.95% (CR 9.52%, PR 71.43%), with no significant difference among the three groups. There was no significant difference in the incidence of new liver damage, infection, and mortality among the three groups during treatment. Age(r=0.258, P=0.038) and infection(r=0.253,P=0.042) were independent factors affecting the length of the first hospitalization. In conclusion, eltrombopag, hetrombopag, and avatrombopag combined with CsA have comparable efficacy in the treatment of NSAA. Avatrombopag has advantages in patients with underlying liver diseases. Bone marrow residual hematopoiesis and adequate TPO-RAs dosage are independent factors for achieving good efficacy at 6 months.
Evans Syndrome: A Systematic Review
Authors: Gouli Sugam , KC Ojbindra , Mostafa Mariam , Shrestha Asis , Niraula Sujan , Dulal Aliza
Published: December 2024

Introduction:

Evans syndrome is a rare autoimmune disease that consists of autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia(ITP) with or without neutropenia. Evans syndrome can be classified as primary(idiopathic) vs secondary (presence of underlying causes). The presence of AIHA and ITP might not occur concomitantly and might precede one another. Treatment options in evans syndrome are variable but mostly involves corticosteroid, rituximab and splenectomy in refractory cases.

Methods:

Two independent investigators searched databases PUBMED, MEDLINE, EMBASE with key word “evans syndrome” and included articles containing 5 or more cases of Evans syndrome in adults, excluding articles on pregnant , infants and children. Further data about patient characteristics, clinical features and treatment were extracted for analysis.

Results:

10 studies (9 retrospective and 1 prospective studies) fulfilled our inclusion criteria.The number of female patients was 52.2% (275/527) vs 47.8% (252/527) male patients. Among them 68.4%(335/490) had primary Evans syndrome compared to 31.6%(155/490) had secondary evans syndrome due to underlying causes. ITP and AIHA occurred simultaneously in 52.4%(276/527) cases, ITP before AIHA in 34.2%(180/527) cases, AIHA before ITP in 23.1%(122/527) cases. Among the patients with positive Direct Antiglobulin Test(DAT), 46.6%(116/249) had positive IgG , 33.3%(83/249) had positive IgG +C3d and 6.4%(16/249) had positive C3d . Only 6 studies had data on neutropenia that was present in 8.2% (18/219) cases. All patients were treated with corticosteroids, 18.4% (47/256) were received rituximab and 16.3%(76/466) refractory cases received splenectomy. We had mortality data from six studies which showed that 40.87% (188/460) cases had died.

Conclusion:

Our review showed that the clinical presentation of Evans syndrome can be variable and quite challenging. Most cases are primary Evans syndrome however looking for underlying causes in secondary Evans syndrome and other differentials is also important. Evans syndrome though rare has high mortality.
Impact of Intravenous Immunoglobulin (IVIG) on Venous Thromboembolism/Pulmonary Embolism in Immune Thrombocytopenic Purpura- an NIS 2020 Database Analysis
Authors: Sanjeevi Aditya , Bhandari Samikchhya Keshary , Kharel Himal , Jose Domench Daniel Idoate , Vijay Rao Aniket
Published: December 2024

Background: The current study probed into the interplay between intravenous immunoglobulin administration and immune thrombocytopenic purpura on risk for venous thromboembolism (VTE) and pulmonary embolism (PE). Both ITP and IVIG have been independently reported to be associated with an increased risk for thrombosis. We aimed to investigate how IVIG administration influences the incidence of VTE/PE in the setting of ITP and to clarify if IVIG modulates the thrombotic risk inherent to ITP.

Methods: We conducted a retrospective analysis of the NIS database 2020 with an International Classification of Diseases (ICD)-10 diagnosis code for ITP, comorbidities, risk factors for VTE/PE along with the proportion of patients receiving IVIG and a diagnosis of VTE/PE. All statistical analyses were done by using STATA version SE18.0. The multivariate regression analysis was done after adjusting for demographic variables and comorbidities to estimate the adjusted odds ratio (aOR) of developing VTE/PE in those suffering from ITP that received IVIG

Results: There were 56,530 hospitalizations with a diagnosis of ITP. The median patient age was 58.9 (95% CI 58.3-59.5), and 56.55% of the patients were females. 26.9% of the patients have a Charlson Comorbidity Index (CCI) score of 0, while 16.5% scored 1 and 13.55% scored 2; 43.05% scored 3. The proportion of the patients who had IVIG out of the 56,530 hospitalizations for ITP is 4265.605 of the 56,530 who suffered VTE/PE. In this regard, a subgroup analysis among patients with ITP receiving IVIG was performed after adjusting for age, gender, race, CCI, and the risk factors of VTE/PE such as smoking, oral contraceptive intake, obesity, history of thrombosis, thrombophilia, cancer, myeloproliferative neoplasms, fracture, COPD, and varicose veins using multivariate regression analysis. This revealed that ITP patients who received IVIG had significantly decreased odds of developing VTE/PE with an aOR of 0.23 (95% CI of 0.05-0.91, p=0.037). This lowering of the thrombotic events in IVIG recipients may indicate a protective effect of IVIG in ITP.

Conclusion: Despite the intrinsic prothrombotic state associated with ITP, our results showed that intravenous immunoglobulin therapy in ITP was associated with a significantly reduced odds of VTE/PE. This would indicate that IVIG could reduce some of the thrombotic risks associated with ITP. These results are encouraging and need replication on larger prospective studies to clearly elucidate the mechanisms behind such an observed protective effect.
Continuous Positive Airway Pressure and Mandibular Advancement Splints: The CHOICE Multi-center Open-Label Randomized Clinical Trial
Authors: Hamoda Mona M , Huynh Nelly , Ayas Najib T. , Rompre Pierre , Bansback Nick , Masse Jean-François , Arcache Patrick , Lavigne Gilles , Series Frederic , Fleetham John A , Almeida Fernanda R.
Published: December 2024

RATIONALE

Adherence to Continuous Positive Airway Pressure (CPAP) for Obstructive Sleep Apnoea (OSA) continues to be low with high termination rates. Alternative therapies to CPAP are needed.

OBJECTIVES

To compare objective adherence to CPAP and Mandibular Advancement Splints (MAS) and to evaluate their effectiveness. Additionally, to identify treatment usage patterns and the clinical effectiveness of having both therapies.

METHODS

This multi-center, double-randomized, three-phase trial (titration/cross-over/observation) was conducted at three Canadian universities. Eligible participants were treatment-naïve with mild to severe OSA.

MEASUREMENTS AND MAIN RESULTS

Primary outcome was objectively measured adherence (hours/night) during cross-over phase. Secondary outcomes included efficacy during cross-over phase; adherence during observational phase; patient-centered outcomes, blood pressure and side-effects during cross-over and observational phases. Duration of cross-over and observational phases were 2.5 and 6 months respectively.

Eighty-one participants were enrolled in the first randomization. Seventy-nine entered the adaptation/titration phase [mean age (sd); 52·3 (10·8) years, 58 males], 73 entered the cross-over phase (included in the intention-to-treat analysis) and 64 completed the observation phase. Mean objective adherence over 1-month, MAS showed higher adherence than CPAP, 6·0versus5·3 h/night (difference= 0·7 h/night, 95% CI: 0·3–1·2 h, p<0·001). Mean CPAP-MAS difference (95% CI) in efficacy of 10·4 (7·8–13) events/hour, p<0·001. During the observation phase 55% (35/64) of participants chose to alternate therapies. All treatments led to substantial improvement in patient-centered outcomes.

CONCLUSIONS

Despite the higher efficacy of CPAP and higher adherence to MAS, both demonstrate comparable clinical effectiveness on patient-centered outcomes. Having both CPAP and MAS can improve long-term management of OSA.