bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aberrant Mitochondrial Iκbα/NF-Κb-Signaling in Lung Cancer Cells Mediates Endothelial Cell Activation and Platelets Aggregation, Facilitating Lung Cancer Metastasis and Cancer-Associated Thrombosis
Authors: Carra' Giovanna , Vacca Rita , Basile Roberta , Menga Alessio , Morotti Alessandro 
Published: December 2024

Cancer presents a significant risk of blood clot formation in cancer patients, impacting patient outcomes. The intricate relationship between cancer-associated thrombosis and metastasis involves multifaceted mechanisms, including a hypercoagulable state, endothelial dysfunction, platelet activation, and interaction with the coagulation system, alongside inflammatory and immune responses. Here, we aim to unveil the non-cell autonomous pathways driving endothelial activation, platelet aggregation, and pro-thrombotic terrain for metastatic fomentation in a murine model of lung cancer.
The inhibitor IκBα, a regulator of the p65-NF-κB signaling pathway, plays a pivotal role in cancer metastasis. Our previous research identified IκBα overexpression in lung cancer, highlighting its potential role in the tumor's pathogenesis. To delve deeper into the role of mitochondrial IκBα, we engineered a construct specifically targeting it to the mitochondria (IκBα-MTS) of cancer cells. Intriguingly, lung cancer cells expressing IκBα-MTS displayed increased aggressiveness, as measured by their capability to increase proliferation, reducing apoptotic response and inducing migration.
Additionally, mitochondrial IκBα led lung cancer cells to activate endothelial cells (ECs), promoting an inflammatory and adhesive state, ultimately priming ECs at the metastatic site to facilitate cancer cells intravasation. This mechanism may be attributed to the metabolic shift observed in lung cancer cells with IκBα-MTS compared to those with wild-type IκBα, related to the induction of mitochondrial dysfunction.
In response to this environment, ECs were conducive to cancer-associated thrombosis, characterized by a hypercoagulable state resulting from the release of the procoagulant factors vWF, and favoring platelet activation and aggregation. Simultaneously, this facilitated cancer cell intravasation and metastasis.
Therefore, our findings offer crucial insights into “thrombo-oncotic” mechanisms and underscore the significance of ECs activation, microthrombi and metastasis formation as potential therapeutic targets in cancer treatment.
A Simple Pathway to Identify Duffy-Null Associated Neutrophil Count (DANC) Early on Hematology Consult Process
Authors: Ribeiro Maria-Jose 
Published: December 2024

Introduction: The normal range for neutrophil counts in individuals with Duffy-null RBCs is often lower than commonly used laboratory reference ranges. This is a genetically determined baseline neutrophil count. The Duffy-null phenotype is caused by a variant in the ACKR1 promoter that results in loss of expression of Duffy antigens (Fy) on RBCs.
Method: Primary care submits electronic consults for patient who have white blood cell count below the laboratory normal range. The hematology service consultant recommends peripheral blood smear review, differential count, B12, folate, copper, HIV screen and HCV screen the last two according to CDC guidelines. The hospital blood bank committee created a process that include the routine type and screen with a comment that Duffy a and Duffy b report required.
Results: Forty-five patients have been tested on this pathway from November 2023 to July 2024 because the hematologist suspected DANC, from those 43 had the confirmation of Fy(a) and Fy(b) negative. Two were Fy(a) negative but Fy(b) positive. All had normal B12, folate, copper, negative HIV, and hepatitis c screening. On the referral for those patients, several have been told that they were being referred for possible myelodysplastic syndrome and for bone marrow biopsy. Once the test results were available, the patients who wanted to have a meeting to discuss the results were either scheduled on a clinic with medical students or residents with purpose of educating trainees and expand the knowledge of this normal variant. The individuals who wanted included their self-identified race. The incidence on different races were discussed only when the patients inquired.
Conclusion: This test is simple, produces rapid results, is relatively inexpensive and is easily incorporated on day-to-day practice. An education material was submitted to primary care providers, hematology fellows, residents, and students. Future direction is to develop education material for patients. Test consideration will be discussed at our center for patients who initiate chemotherapy with counts lower than the reference range or who have prolonged neutropenia during treatment to avoid unnecessarily holding therapy. Plan to develop studies and guidelines specific for patients with DANC based in developing literature.
Senescence of Mesenchymal Stromal Cells in Myelofibrosis Tumor Microenvironemnt Is Mediated By Glutamate-Induced Intracellular Fumarate Accumulation
Authors: Giallongo Sebastiano , Giallongo Cesarina , Longhitano Lucia , Ferrigno Jessica , Amorini Angela Maria , Calvo Deborah , Li Volti Giovanni , Romano Alessandra , Di Raimondo Francesco , Palumbo Giuseppe Alberto , Tibullo Daniele 
Published: December 2024

Primary myelofibrosis (PMF) is a type of myeloproliferative neoplasm characterized by ineffective blood cell production. The growth of malignant cells is influenced by their interaction with the tumor microenvironment (TME), which is marked by significant fibrosis and inflammation. In this setting, mesenchymal stromal cells (MSCs) are reprogrammed to become senescent, releasing proinflammatory cytokines as part of the senescence-associated secretory phenotype (SASP), thereby worsening the inflammatory state of the PMF-TME. Additionally, the PMF-TME is rich in various metabolites that reshape the microenvironment to support the growth of malignant cells.
To investigate the metabolic changes in PMF, we analyzed several metabolites in peripheral blood using HPLC and found an accumulation of Glutamate (Glu) and its byproduct fumarate. Both Glu and fumarate are known to induce cell senescence. To explore their impact on the mesenchymal compartment, we used an in vitro model of healthy MSCs. Treatment with Glu and fumarate led to increased accumulation of reactive oxygen species (ROS), causing elevated DNA damage and fumarate-associated epigenetic modification H3K36me2. Moreover, fumarate inhibited cell proliferation, as shown by clonogenic assays and triphosphate accumulation. Importantly, supplementation with Glu and fumarate induced cell senescence, as evidenced by increased β-Galactosidase activity. This senescent phenotype was further supported by the accumulation of phospho-p53 and increased expression of SASP-associated genes IL6, TNF, and TGFβ. Senescent cells also showed increased 5mC levels, similar to those observed in primary PMF-MSCs. Additionally, fumarate supplementation led to enhanced expression of Col1a1, highlighting its role in promoting the characteristic fibrotic environment of the PMF-TME.
In conclusion, our findings reveal that Glu metabolism plays a critical role in the onset of PMF. The conversion of Glu to fumarate induces a senescent profile in MSCs, contributing to the fibrotic TME typical of PMF. Future studies aiming to inhibit Glu uptake could lead to novel therapeutic strategies against PMF.
Enhanced Potency of BCMA/CD19 Dual-Targeting Allogeneic CAR-T Cells for Relapsed/ Refractory Multiple Myeloma with 4-1BB/TACI Intracellular Domains
Authors: Wang Steven , Pang Iris , Chang Claudia , Burrascano Michelle , DeMarco Nick , Mendoza Danny , Reyes Sonia , Barcenas Arturo , Nieto Pastor , Diaz Jose , Arauz Garrett , Lynn Chris , Nguyen Tony , Reed Connor , Connerney Jeannette , LE Quy , Coronella Julia , Shedlock Devon J 
Published: December 2024

B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cell therapy has shown high initial response rates in relapsed/refractory multiple myeloma (RRMM), but a majority of patients eventually relapse with progressive disease. Previous studies have identified a less differentiated, CD19-positive progenitor subpopulation of MM cells that contributes to resistance and poor survival. Furthermore, it has been reported that anti-CD19 CAR-T cells given after high-dose melphalan and stem cell transplant improve patient survival and can eliminate MM progenitor cells that are resistant to BCMA-directed CAR-T cells in ex vivo assays.
P-BCMACD19-ALLO1 is a fully allogeneic CAR-T therapy expressing two full-length CARs targeting BCMA and CD19, each with an optimized intracellular domain (ICD) for enhanced potency. P-BCMACD19-ALLO1 is a T stem cell (TSCM)-rich product derived from healthy donor pan-T cells using a nonviral transposon-based system for transgene delivery, with knockout of TRBC1/2 and B2M. Clinical data from Poseida and others have demonstrated safety and efficacy advantages associated with TSCM CAR-T, including for P-BCMA-ALLO1, our BCMA-targeting allogeneic CAR-T for RRMM (NCT04960579).
We show that replacing the standard 4-1BB co-stimulatory domain with an ICD derived from the tumor necrosis factor (TNF) receptor family member transmembrane activator and CAML interactor (TACI) enhances in vivo potency against a CD19 +/BCMA+ xenograft model when TACI is placed in the CD19 CAR. In contrast, the configuration of CD19 CAR with 41BB + BCMA CAR with TACI underperformed compared to the dual 4-1BB configuration.
The BCMA CAR was constructed using two unique fully human single-domain heavy-chain variable domains (VHs) against BCMA joined by a GS4 linker in tandem, independently binding BCMA. The binding of two unique BCMA epitopes may prevent the emergence of BCMA escape mutants. The anti-CD19 CAR binder comprises a fully human single-domain heavy-chain VH against CD19. Both CARs are expressed from a single transgene containing BCMA and CD19 CARs, an inducible Caspase-9 safety switch, and a dihydrofolate reductase mutein, separated by T2A sequences for independent expression. P-BCMACD19-ALLO1 CAR-T cells demonstrated potent in vitro cytotoxicity against tumor cells expressing BCMA, CD19, or both antigens, while single BCMA and CD19 CAR-T cells only recognized tumor cells that are BCMA and CD19 positive, respectively.
In this study, we report the enhanced in vivo activity of P-BCMACD19-ALLO1 CAR-T cells using 4-1BB/TACI ICD combination. These findings underscore the therapeutic potential of P-BCMACD19-ALLO1 CAR-T cells to be evaluated in clinical trials.
Comparing BAT and Beighton Scores in Patients with ITP: A Retrospective Observational Cohort Study
Authors: Gaston Farrah N. , Barclay Dominique , Kreitzer Sarah , Tarantino Michael D 
Published: December 2024

Introduction
Immune thrombocytopenic purpura (ITP) is an acquired thrombocytopenia that leads to clinically significant bleeding in many. The Bleeding Assessment Tool (BAT) is a validated tool used to assess the degree of bleeding with scoring directly proportional to the severity of bleeding. Predicting the occurrence of bleeding is challenging in patients with ITP. Hypermobility syndromes have been associated with higher rates of clinically significant bleeding. Joint hypermobility, assessed by the Beighton Scoring System, has been shown to be associated with more severe bleeding phenotypes in persons with hemophilia, von Willebrand disease, and in some platelet function disorders, but has not been studied in patients with ITP.
Methods
We conducted a retrospective observational cohort study to investigate the relationship between joint hypermobility and the degree of bleeding by comparing BAT scores and age/sex-specific Beighton scores in patients with ITP at least 6 years age at the Bleeding and Clotting Disorders Institute. Correlations were determined using nonparametric analyses to test the difference between two groups: (a) abnormal BAT versus Beighton scores and (b) abnormal BAT versus degree of thrombocytopenia or sex. The Independent-Samples Kruskal-Wallis Test was used to determine the impact of age and platelet count on BAT and Beighton scores, if one existed.
Results
Data from 174 patients were obtained, though 122 were excluded due to a lack of BAT or Beighton score, or both. Of the 52 patients remaining, 34 (65.4%) were female and 18 (34.6%) were male, with ages ranging between 12-81 years. BAT scores ranged between 0-18 with a median of 5 and mean of 5.8+4.4, while Beighton scores ranged between 0-9 with a median of 3.5 and mean of 3.4+3.4. A moderate correlation (r values between 0.5-0.7) was found between overall BAT and Beighton scores (r=0.66), while an inverse correlation was found between Beighton scores and platelet counts (r= -0.89). All 12 patients with positive Beighton scores had abnormal (high) BAT scores (r=1.00) and were all female. Overall, there was no significant association (p=0.681) between gender, BAT, and Beighton scores. Further, there was no significant difference in BAT and Beighton scores across age and platelet count.
Conclusions
Hypermobility was associated with more bleeding based on higher BAT scores. The degree of bleeding was not predicted by the platelet count or age. Our data also suggest that females with ITP and hypermobility are more likely to have more clinically significant bleeding, however results comparing hypermobility and platelet count across the categories of age and sex were unrevealing. Broader investigation is needed to determine the full impact of the association of joint hypermobility and bleeding severity in patients with ITP.
Haploidentical Bone Marrow Transplantation for Wiskott-Aldrich Syndrome
Authors: Wang Yingjie , Zhang Mengmeng , Zhang Chengtao , Kang Zhijie , Liu Junli , Hu Jiong , Yan Jinsong 
Published: December 2024

Introduction: Wiskott-Aldrich syndrome (WAS) is an X-linked disorder caused by mutations in the WAS gene, which encodes the WAS protein involved in actin polymerization. WAS is a rare syndrome affecting approximately 1 in 100,000 live births. Hematopoietic stem cell transplantation is the mainly curative option for WAS. In this study, the outcome of Haplo-BMT in four patients with WAS was investigated.
Methods: Four patients with WAS, who were confirmed with frameshift mutation in the WAS gene, were treated with haploidentical bone marrow transplant (haplo BMT) in second hospital of Dalian Medical University (China) from May 2018 to July 2024. The follow-up period was up to July 31, 2024. Flu/Bu/Cy/ATG was used as conditioning regimen, containing fludarabine (Flu, 30 mg/m2) once a day for 4 consecutive days, Busulfan (Bu, 0.8 mg/kg) four times a day for 4 days, cyclophosphamide (Cy, 30 mg/kg) once a day for 2 days, and rabbit ATG (SangStat, France) of 2.5 mg/kg once a day for 4 days. G-CSF-primed HSCTs plus marrow grafts were infused into recipients. Father served as blood stem cell donor.
Results: Four patients with were retrospectively collected, who had median age of 1.8 (range, 0.4-14) years. They received a median mononuclear cell number of 18.7 (range, 14.2-24.0) × 108/kg of body weight, or median CD34+ cell number of 12.9 (range, 10.3-14.9) × 106/kg of body weight. They were all successfully engrafted with a median time for neutrophil or platelets of 12 (range, 11-16) days and 12 (range, 11-14) days, respectively. One developed limited chronic graft versus host disease, and he well recovered by treating with methylprednisolone (1 mg/kg/day) and tacrolimus. One patient died of transplantation associated thrombotic microangiopathy at 8 months post-transplantation. Four patients with overall survival is 75%, with a median follow-up time of 26 (range, 2.5-48) months.
Conclusion: This retrospective investigation indicated haplo-BMT is feasible for a long-term overall survival in pediatric patients with WAS.
Toward a circular economy in Italian agri-food: upstream partners in insect biorefineries
Authors: Cattaneo Arianna , Padula Cecilia , Meneguz Marco , Mileto Carola , Barbero Silvia , Dabbou Sihem 
Published: December 2024

AbstractThe insect biorefinery (IB) is central to recycling nutrients from food losses and waste (FLW) in an emerging circular bioeconomy approach. The sustainable leadership of the European insect industry and its integration into the bioeconomy depend on implementing symbiotic production models through site selection and partnerships. Only 8 studies, including 3 in the EU, have examined stakeholder acceptance. This pilot study is the first to focus on potential upstream symbiosis partners (USPs) in the EU, examining the factors that influence the willingness of potential USPs in suitable Italian locations to adopt IB. Preliminary analyses identified a final sample of 31 respondents who completed an online-survey divided into four sections. After data elaboration, a principal component analysis was conducted, considering 27 questions and their correlations with the first two principal components. The analysis revealed that the presence of internal research and development within the company, along with the company’s role in the supply chain and the seasonality of production, had a minor influence on explaining the variance of the data. Interestingly, company size was negatively correlated with the willingness to become part of the insect-rearing supply chain or receive information about this technology. On the contrary, interest in innovative production and self-management of by-products were strongly related. Finally, funding opportunities could positively influence both the Italian and EU contexts, encouraging innovative practices among small and medium-sized enterprises. In contrast, barriers to implementing insect farming include misinformation, anticipated negative media impacts on branding, and resistance to changing by-product management practices. This pilot study serves as a foundational exploration, providing insights into the acceptability of insect farming among potential USPs and offers valuable insights for future studies, thereby shaping the discourse on the acceptability and integration of insect farming within the circular bioeconomy.
The host genotype actively shapes its microbiome across generations in laboratory mice
Authors: Benga Laurentiu , Rehm Anna , Gougoula Christina , Westhoff Philipp , Wachtmeister Thorsten , Benten W. Peter M. , Engelhardt Eva , Weber Andreas P. M. , Köhrer Karl , Sager Martin , Janssen Stefan 
Published: December 2024

Abstract
Background
The microbiome greatly affects health and wellbeing. Evolutionarily, it is doubtful that a host would rely on chance alone to pass on microbial colonization to its offspring. However, the literature currently offers only limited evidence regarding two alternative hypotheses: active microbial shaping by host genetic factors or transmission of a microbial maternal legacy.

Results
To further dissect the influence of host genetics and maternal inheritance, we collected two-cell stage embryos from two representative wild types, C57BL6/J and BALB/c, and transferred a mixture of both genotype embryos into hybrid recipient mice to be inoculated by an identical microbiome at birth.

Conclusions
Observing the offspring for six generations unequivocally emphasizes the impact of host genetic factors over maternal legacy in constant environments, akin to murine laboratory experiments. Interestingly, maternal legacy solely controlled the microbiome in the first offspring generation. However, current evidence supporting maternal legacy has not extended beyond this initial generation, resolving the aforementioned debate.

Graphical Abstract
Jail-based interventions to reduce risk for opioid-related overdose deaths: Examples of implementation within Ohio counties participating in the HEALing Communities Study
Authors: Sprunger Joel , Brown Jennifer , Rubi Sofia , Papp Joan , Lyons Michael , Winhusen T. John 
Published: December 2024

Abstract
Background
Opioid-related overdose is a leading cause of death for criminal legal-involved individuals and, although naloxone distribution and medications for opioid use disorder (MOUD) are effective means for reducing post-release overdose death risk, jail-based availability is limited. This case report describes the challenges faced by three Ohio communities as they implemented evidence-based practices (EBPs) in jails to combat post-release opioid overdose deaths.

Method
We present case examples of how barriers were overcome to implement jail-based EBPs in three Ohio communities (two urban and one rural) as part of the HEALing Communities Study (UM1DA049417; ClinicalTrials.gov Identifier: NCT04111939). Of the 18 participating Ohio HEALing Communities Study counties, we highlight 3 communities for the novelty of their EBPs implemented, the challenges that they faced, and their rural/urban status. We present descriptive data regarding the EBPs that they implemented and discuss the challenges identified by HEALing Communities Study staff with first-hand experience facilitating their implementation.

Results
Newly implemented interventions included overdose education and direct provision of naloxone to incarcerated individuals upon release (2 of 3 communities), initiating MOUD prior to release (3 of 3), linkage to ongoing MOUD treatment in the community (2 of 3), peer support-facilitated treatment retention efforts (2 of 3) and emergency housing (1 of 3) in the immediate post-incarceration period. Common challenges that emerged included skepticism about the need and feasibility of implementing EBPs to reduce overdose and death, lack of knowledge about the options available and whether external agencies may assist, and difficulty engaging stakeholders to overcome inertia.

Conclusions
Creative flexibility, calm persistence, technical facilitation, and collaboration with community service providers were assets that helped these Ohio jails implement evidence-based strategies that combat the opioid epidemic and reduce the likelihood of post-incarceration overdose and death in a high risk, formerly incarcerated population.
Microfluidic biosensors for biomarker detection in body fluids: a key approach for early cancer diagnosis
Authors: Liu Zhiting , Zhou Yingyu , Lu Jia , Gong Ting , Ibáñez Elena , Cifuentes Alejandro , Lu Weihong 
Published: December 2024

AbstractEarly detection of cancer significantly improves patient outcomes, with biomarkers offering a promising avenue for earlier and more precise diagnoses. Microfluidic biosensors have emerged as a powerful tool for detecting these biomarkers in body fluids, providing enhanced sensitivity, specificity, and rapid analysis. This review focuses on recent advances in microfluidic biosensors from 2018 to 2024, detailing their operational principles, fabrication techniques, and integration with nanotechnology for cancer biomarker detection. Additionally, we have reviewed recent innovations in several aspects of microfluidic biosensors, such as novel detection technologies, nanomaterials and novel microfluidic chip structures, which significantly enhance detection capabilities. We highlight key biomarkers pertinent to early cancer detection and explore how these innovations in biosensor technology contribute to the evolving landscape of personalized medicine. We further explore how these technologies could be incorporated into clinical cancer diagnostic workflows to improve early detection and treatment outcomes. These innovations could help enable more precise and personalized cancer diagnostics. In addition, this review addresses several important issues such as enhancing the scalability and sensitivity of these biosensors in clinical settings and points out future possibilities of combining artificial intelligence diagnostics with microfluidic biosensors to optimize their practical applications. This overview aims to guide future research and clinical applications by addressing current challenges and identifying opportunities for further development in the field of biomarker research.