bluuebunny/crossref_metadata_2025_split huggingface dataset:
Final Results of a Phase II Study of Brentuximab Vedotin and Lenalidomide in Relapsed and Refractory T-Cell Lymphomas
Authors: Reneau John C. , Huang Ying , Hanel Walter , Brammer Jonathan E. , Chung Catherine , William Basem 
Published: December 2024

Brentuximab vedotin (BV) and lenalidomide (Len) demonstrate independent activity in peripheral T cell lymphoma (PTCL) and cutaneous T cell lymphoma (CTCL). This study evaluated the efficacy and safety of this combination at reduced doses.
This phase II trial enrolled 26 patients (table 1) with relapsed/refractory PTCL/CTCL. CD30 positivity was not required, and prior BV treatment was not exclusionary. Patients were treated with BV 1.2 mg/kg IV q3weeks and Len 20 mg PO daily. Len was reduced to 10 mg due to tolerability. The primary endpoint was overall response rate (ORR).
Enrolled patients had a median age of 60 (37-90), 18 were male (69%), and had a median of 4.5 prior lines of therapy (1-9). Thirteen patients (50%) were diagnosed with mycosis fungoides, 8 with PTCL (31%), 3 with Sezary syndrome (12%), and 2 with CD30+ lymphoproliferative disorder (8%). The mean CD30 percent positivity was 7.5% (1-75%); CD30 was negative in 4 patients (18%).
Five patients achieved complete response (2 CTCL, 3 PTCL), four achieved partial response (3 CTCL, 1 PTCL), and ten had stable disease (all CTCL). The ORR was 27.8% (5/18) for CTCL and 50% (4/8) for PTCL. Nineteen patients experienced grade 3 or higher adverse events, the most common of which were neutropenia (19.2%), lymphopenia, rash, fatigue, and abdominal pain (11.5% each) Patients came off treatment most commonly for progression (54%) and adverse events (23%).
This combination demonstrated efficacy that was comparable to each agent when used as monotherapy. After reducing the Len dose to 10 mg, the combination had toxicity similar when compared to monotherapy at FDA approved dosing, although hematologic toxicity may be slightly higher. Including patients who were CD30 negative (4 patients, 18%) and having a relatively low median CD30 positivity at 7.5% may explain the lack of substantial improvement in efficacy over monotherapy with either agent. The trial was terminated early because of poor accrual.
Automated Rapid CAR-T Cell Manufacturing Process, Starting from Whole Blood, on a Novel Closed Platform
Authors: Sa Silin , Yu Liping 
Published: December 2024

Background: Autologous CAR-T (Chimeric Antigen Receptor T) cell therapy has been a great success in treating hematological cancers and making progress in treating autoimmune diseases as well as solid tumors. However, the high manufacturing cost and complicated logistics have prevented the therapy from being accessible by general patients. Recently, there are discoveries and developments in the manufacturing process to reduce cost, including reduction of manufacturing time from 7-14 days to one day by elimination of in vitro cell expansion. Researchers have learned that the “rapid” manufacturing process maintains stemness of the CAR-T cells that achieved a higher potency after infusion. Additionally, changing the cell source from leukapheresis products to peripheral whole blood also helps reduce processing time and overall cost. Finally, having CAR-T cells manufactured at “point-of-care” facilities that are closer to patients will greatly reduce logistical overhead. An automated closed platform that achieves: (1) “point-of-care” manufacturing, (2) starting from whole blood, and (3) completes CAR-T cell manufacturing within 1~2 days would be ideal to reduce the CAR-T therapy cost to 10% of its current cost, and potentially further to 1% when becoming a generally practiced method with volume.
Method: We have developed a novel cell manufacturing platform (MARS Atlas), which integrates T cell isolation, viral transduction and cell washing/formulation processes on one platform. We demonstrated the CAR-T manufacturing process starting from whole blood can be completed within 24 hours. Using healthy donor's peripheral blood, we isolated T cells with CD4 and CD8 directly conjugated magnetic beads. The T cells were then activated and transduced with lentiviral vector containing CAR-19 gene. After overnight incubation, product cells were washed and harvested in either the medium that is suitable for injection or medium for cryopreservation. As a comparison, we also performed a standard 7-day expansion of transduced T cells in culture.
Results: CAR-T cell count, CAR-T cell phenotype, and CAR-T cell cytotoxic activity were monitored and compared of the 24-hour process and 7-day process. In the rapid process we harvested an average of 20million T cells after 24 hours from 30mL of blood with purity &gt;94%. The product T cells have twice more naïve population (CD45RA+CCR7+) than the T cells harvested after 7- day process. Transduction efficiency was 60%-70% (CAR expression was stable after day 2). The function of CAR-T cells manufactured in 24 hours were verified by in vitro killing assay. By repeated stimulation with target cells CAR-T cells was observed to kill target cells in day 7.
Conclusion: In this study, we demonstrated an automated 24-hour LV-based CAR-T cell manufacturing workflow produced functioning CAR-T cells and this process has great potential for high potency and extreme low-cost CAR-T therapy.
Impact of Kidney Transplantation on Hospitalization Outcomes in Patients with Multiple Myeloma
Authors: Iqbal Rabia , Bajwa Ahmad Taimoor , Bazaz Aemen Shafqat , Gaddam Mrunanjali , Khan Fiqe , Htet Nyan Linn , Mumtaz Aqsa , Anwer Faiz 
Published: December 2024

Introduction:
Despite the advancement in the treatment of Multiple Myeloma, most of the patients still develop end-stage renal disease, requiring hemodialysis. Kidney transplant is rarely performed due to risks of graft rejection and other complications, and data is limited to only a few case reports.
Objective:
In this study, we aimed to determine the impact of kidney transplants' impact on all-cause mortality and other outcomes in multiple myeloma patients who were hospitalized.
Methods:
We conducted a retrospective analysis using the National Inpatient Sample Database (NIS) from 2016 to 2020. We used ICD-10 codes to diagnose patients with a primary diagnosis of Multiple Myeloma (MM). The database was further used to classify the MM patients who underwent kidney transplants due to irreversible kidney damage. We calculated the multivariate regression analysis after adjusting for confounding variables.
Results:
A total of 580,544 patients were detected with a primary diagnosis of multiple myeloma between 2016 and 2020. Out of them, 1741 patients had a history of kidney transplant. The mean age of the patients was 64 years (P-value &lt;0.001). Out of them, 62% (n=359,937) of the patients were male, while 38% (n=220,606) of them were female (p-value 0.03). The majority of the patients who underwent kidney transplants were white (62%, n=1079), while the black population constituted 23% (n=400), and Hispanics were almost 7% (n=122) of the patients. Most patients (78%) had medicare insurance, 18% had private insurance, and 3% had Medicaid (p-value 0.2). Our analysis showed that multiple myeloma patients who underwent kidney transplants had a decrease in mortality (aOR 0.9, p-value 0.09). However, it revealed that kidney transplant was associated with an increased risk of organ rejection (2%, aOR 49 [95% CI: 10- 235], p-value &lt;0.01), organ infection (0.2%, aOR 11 [95% CI: 1.5-84], p-value 0.01), organ failure (4%, aOR 23 [95% CI: 6-82], p-value &lt;0.001) and sepsis (11.6%, AOR 1.2 [95% CI: 0.6-2.3], p-value 0.5).
Conclusion:
Our study concludes that for renal damage caused by multiple myeloma, kidney transplants if performed, are associated with a decrease in all-cause mortality. However, it is also found to be associated with an increase in worse outcomes, including organ infection, rejection, and failure. Hence, although it has mortality benefits, kidney transplant comes with substantial risks leading to rejection and wasting of the organ. More research is needed to understand these associations better and improve patient selection for possible transplants.
Deep Learning the Cis-Regulatory Code of Epigenomic Rewiring By Fusion Transcription Factors in Pediatric Leukemia
Authors: Mani Shouvik , Grubert Fabian , Gratzinger Dita , Kundaje Anshul , Kasowski Maya 
Published: December 2024

Pediatric leukemias are commonly driven by chromosomal translocations which create gene fusions involving hematopoietic transcription factors (TFs) in progenitor lymphoid and myeloid cell populations. Although driver gene fusions and altered signaling pathways across leukemia subtypes have been extensively cataloged, the regulatory mechanisms enabling TF fusions to reprogram the epigenome and arrest hematopoietic differentiation remain unclear.
In this study, we generated a single nucleus multiomic atlas from pediatric leukemia patient samples and leveraged deep learning models of regulatory DNA sequence to decipher the regulatory logic linking mutant TFs and regulatory elements to downstream genes and pathways in a sample and cell type-specific manner.
We profiled 22 bone marrow specimens from major diagnostic categories (T-ALL, B-ALL, AML) and including recurrent gene fusions such as ETV6-RUNX1 and RUNX1-RUNX1T1. Using whole genome sequencing (WGS) and multiplexed 10X multiome profiling (single-nucleus RNA+ATAC-seq), we simultaneously profiled gene expression and chromatin accessibility for over 70,000 cells. Unsupervised clustering and cell type annotation revealed 21 distinct clusters, including leukemic and healthy cell populations. Demultiplexing using SNPs from WGS allowed us to recover sample identities and distinguish between malignant and healthy cell populations.
To determine the sequence basis and downstream functional effects of TF rewiring in leukemia, we trained and interpreted ChromBPNet, a fully convolutional neural network, on ATAC-seq data from healthy and malignant B cell clusters. The model discovered enriched motifs for hematopoietic transcription factors, including RUNX1, ETV6, PAX5, and ERG, in ATAC peak regions of ETV6-RUNX1 B-ALL samples.
This integrative approach provides new insights into how oncogenic fusions confer blocked differentiation, survival, and proliferation to leukemia cells. Future work will leverage these models to identify novel motifs for TF fusions and fine-map germline variants to identify functional mutations that perturb TF binding and accessibility through motif disruption.
Platelet RIG-I Promotes Flu-Induced Severe Lung Injury in Sickle Cell Disease
Authors: Kaminski Tomasz , Swendrowski Nicholas , Katoch Omika , Sundd Prithu 
Published: December 2024

Background: Sickle cell disease (SCD) affects over ~8 million people world-wide. Acute chest syndrome, a type of acute lung injury (ALI) is a major cause of mortality among SCD patients. Flu typically causes a self-resolving upper airway inflammation, however, it may progress for unknown reasons into a highly morbid ALI. Epidemiological evidence suggests that flu results in severe outcomes in SCD patients and associates with a 50-fold higher risk of hospitalization among SCD compared to non-SCD humans. However, the mechanisms underlying the flu severity and subsequent severe lung injury in SCD remains largely unknown.
Methods: We have developed a new model of A/PR/8/34 (H1N1) influenza A virus (IAV) induced respiratory infection in knock-in, humanized Townes SCD (SS) mice. SCD or control (Townes AS) mice were inoculated intranasally with a mild dose of IAV, and severity of lung injury was evaluated 14 days post infection using histological scoring, oxygen saturation was measured every other day and body weight was assessed every day. Real-time intravital (in vivo) multi-photon-excitation fluorescence microscopy (MPE) was used to assess thrombo-inflammation and vascular leakage in the lung of mice at 10 days post IAV-infection. Platelets were isolated for western blotting and co-immunoprecipitation to assess the activation of anti-viral pathways in platelets.
Results: SCD+Flu mice manifested significant drop in oxygen saturation (&lt;90%), body weight (³ 20%) and developed severe lung injury indicated by the presence of hemorrhage, vascular congestion and edema in the lung histopathological analysis. Severe ALI in SCD+Flu mice at day 10 post infection was associated with pulmonary thrombo-inflammation leading to microvasculature occlusion by platelet-rich neutrophil-platelets aggregates (NPAs), resulting in pulmonary ischemia and loss of blood-air barrier. In contrast to SCD mice, control mice inoculated with mild dose of flu did not develop ALI and neutrophil-platelet aggregates were absent in the lung microcirculation of Control+Flu mice at day 10th post infection. Co-immunoprecipitation showed assembly of viral-RNA sensing RIG-I-MAVS complex in SCD+Flu but not Control+Flu mice platelets, suggestive of the activation of anti-viral response in SCD+Flu but not Control+Flu mice platelets 10-days post infection.
Conclusions: These findings suggest for the first time a potential role for platelet-dependent anti-viral RIG-I signaling in promoting thrombo-inflammation and severe lung injury following flu infection in SCD. Currently, studies are in progress to identify the innate immune signaling downstream to platelet RIG-I-MAVS complex formation, and how it can be therapeutically manipulated to reduce the flu morbidity in SCD.
Interim Results of a New Examination Protocol for Women and Girls with Inherited Bleeding Disorders (WGBD)
Authors: Halimeh Susan , Daoud Mohamad Ayman , Schmitz Derya , Habermann Bjoern 
Published: December 2024

Women and girls with haemophilia (WGBD), including those who are symptomatic carriers (F VIII/IX plasma levels ≥ 40 IU/ml1), experience joint haemarthrosis similar in nature to that experienced by men with mild haemophilia.2 However, WGBD are often overlooked in both clinical and research settings.3,4 Current ultrasound techniques are primarily able to detect synovitis, which is a later stage of haemarthrosis.5 Inflammatory processes may lead to joint dysfunction even in the absence of structural damage.6 Early detection of subclinical joint bleeding is of paramount importance.7
We are therefore developing a new assessment protocol for WGBD that combines biomechanical analysis and our new psychometric quality of life questionnaire with the existing diagnostic toolset of the Pictorial Blood Loss Assessment Chart (PBAC), Haemophilia Joint Health Score, ISTH Bleeding Score, Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US).
In collecting the interim results described in this second abstract, we aimed to determine whether the Noraxon system, using validated inertial measurement units (IMUs) and electromyography (EMG), can facilitate the early detection of joint damage in WGBD using non-invasive gait analysis. A comparison was made between the results of the Noraxon biomechanical analysis and those obtained from PBAC, ISTH bleeding scores, HEAD-US and HJHS measurements in a group of 26 WGWH. Symptomatic participants were asked about any joint complaints.
The mean age of the participants was 38.8 years (range 14-71). Of the participants, 23 had haemophilia A and three had haemophilia B, including seven individuals with combined VWD. As expected, the PBAC score for heavy menstrual bleeding was above 150 (mean 161). There was a positive correlation between HJHS and HEAD-US scores (Pearson correlation coefficient r = 0.595). Interestingly, there is a positive and moderately significant correlation between the ISTH Bleeding Score and HJHS (r = 0.5), but not with HEAD-US.
When patients were asked about joint complaints, a strong correlation was found in bilateral EMG measurements when the gastrocnemius muscle was considered in the stance phase (Pearson correlation coefficient (r = 0.446)). A very high significance was also observed when the recorded ankle complaints were correlated with kinematic measurements of hip abduction (0.002), hip rotation (0.034) and ankle abduction (0.011).
The strong correlations shown in the interim results convinced us that gait and movement analysis is a very powerful tool for early detection of incipient joint and ankle changes in WGBD. Therefore, we are encouraged to a) further develop our new WGBD-Examination-Protocol b) test it on more patients and c) propose to collect and analyze more data nationally and internationally.
Bone biochemical markers, bone mineral density, and the risk of osteonecrosis of the femoral head: a Mendelian randomization study
Authors: Jia Hai-feng , Tian Ze-ming , Liang Xue-zhen , Li Han-zheng , Lu Bo-wen , Zhang Jian , Li Gang 
Published: December 2024

Abstract
Background
Alterations in bone metabolism may play a significant role in the early stages of femoral head necrosis, yet the causal relationship remains unclear. This study utilizes a two-sample Mendelian randomization (MR) approach to explore the genetic causal links between biochemical markers of bone metabolism, bone mineral density, and the risk of femoral head necrosis.

Methods
This study utilizes publicly available genome-wide association study (GWAS) datasets, with exposure factors including biochemical bone markers (25OHD, calcium, and alkaline phosphatase) and bone mineral density (measured at the lumbar spine, heel, femoral neck, and total body). The outcome of interest is osteonecrosis of the femoral head. We selected validated single nucleotide polymorphisms that are strongly associated with the exposure factors as instrumental variables. Mendelian randomization analysis was conducted using inverse variance weighting(IVW), MR-Egger regression, and weighted median estimation. Additionally, we performed analyses for horizontal pleiotropy, heterogeneity, and sensitivity.

Results
A total of 934 SNPs were included in this study. The MR analysis results indicate that the IVW analysis of 25OHD, Ca, and ALP did not reach statistical significance (25OHD OR = 1.006, 95%CI: 0.69–1.47, P = 0.975; Ca OR = 0.856, 95%CI: 0.43–1.70, P = 0.657; ALP OR = 1.022, 95%CI: 0.86–1.21, P = 0.801). However, bone density, including heel, lumbar spine, and total body bone density, showed a protective causal relationship with the onset of ONFH, while the results for femoral neck bone density did not reach statistical significance (lumbar spine BMD OR = 0.662, 95%CI: 0.48–0.91, P = 0.010; heel BMD OR = 0.726, 95%CI: 0.62–0.85, P < 0.001; total body BMD OR = 0.726, 95%CI: 0.62–0.85, P < 0.001; femoral neck BMD OR = 0.748, 95%CI: 0.53–1.05, P = 0.096). Cochran’s Q statistic for IVW and MR-Egger methods indicated no intergenic heterogeneity for all exposure outcomes’ SNPs, and the tests for pleiotropy suggested a low likelihood of pleiotropy in all causal analyses.

Conclusions
The results of this study indicate that there is no genetically mediated causal relationship between serum levels of 25-hydroxyvitamin D, calcium, and alkaline phosphatase and osteonecrosis of the femoral head. However, heel, lumbar spine, and total body bone mineral density can be considered protective factors for the occurrence of ONFH. There is no genetic causality between femoral neck bone mineral density and ONFH development.
The role of the public health service in the implementation of heat health action plans for climate change adaptation in Germany: A qualitative study
Authors: Geffert Karin , Voss Stephan , Rehfuess Eva , Rechel Bernd 
Published: December 2024

Abstract
Background
In response to climate change-induced increases in heat periods, the WHO recommends the implementation of heat health action plans (HHAPs). In Germany, HHAPs are implemented neither comprehensively nor nationwide. Several recommendations have identified the public health service (PHS) at municipal and federal state levels as a key actor regarding to heat and health. Therefore, this study aimed at assessing the role of the PHS in implementing HHAPs at municipal and federal state levels in Germany.

Methods
We conducted a policy document analysis to assess the legal basis for the work of the PHS in the 16 federal states in Germany. Furthermore, we conducted semi-structured interviews with 16 experts from within and outside the PHS to explore their perceptions of the PHS in the implementation of HHAPs. The interviews were analysed using reflective thematic analysis.

Results
The policy document analysis revealed that heat is not mentioned in any of the federal states’ regulatory frameworks for the PHS, while tasks related to environment and health are addressed, but tend to remain vague. The interviews confirmed that there is currently no clearly defined role for the PHS in implementing HHAPs in Germany and that the actual role primarily depends on the local setting. Main barriers and facilitators could be assigned to three levels (individual, organizational and political), and two overarching contextual factors (awareness of the need for adaptation and existence of other public health emergencies) influenced the implementation of HHAPs across all levels. At the individual level, motivation, knowledge and competencies, and previous experience were possible barriers or enablers. At the organizational level, administrative structures, financial and human resources, leadership and networks were barriers or facilitators, while at the political level they included legislation and political decisions.

Conclusions
The PHS could and should be a relevant actor for implementing measures addressing health and climate change locally, in particular because of its focus on vulnerable populations. However, our findings suggest that the legal basis in the federal states of Germany is insufficient. Tailored approaches are needed to overcome barriers such as rigid, non-agile administrative structures and competing priorities, while taking advantage of facilitators such as awareness of relevant actors.