bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Prospective, Multinational Study of Clinical and Biological Factors Associated with Short Overall Survival in Multiple Myeloma
Authors: Tang Andy , Kim Kihyun , Chen Fiona , McQuilten Zoe K , Mollee Peter , Rajagopal Rajeev , Quach Hang , Ho Phoebe Joy , Harrison Simon J. , Spencer Andrew , Chng Wee-Joo 
Published: December 2023

Introduction: Multiple myeloma (MM) is an incurable cancer, but a subset of patients can achieve long-term remission and overall survival (OS). We aimed to study the clinical and biological factors associated with short OS defined as less than 3 years.
Methods: A prospective, observational, multinational study was conducted by Australian and New Zealand (ANZ) and Asia-Pacific (APAC) Myeloma and Related Disease Registry (MRDR) from January 2013 to January 2023, across 5 countries (Australia, New Zealand, Korea, Singapore, Malaysia). Eligible patients were ≥18 years old, diagnosed with MM per International Myeloma Working Group (IMWG) criteria, received a bortezomib-containing triplet, and had at least 3 years of follow-up or had deceased within 3 years. Descriptive analysis was completed using chi-squared test for categorical variables and Wilcoxon rank-sum test for continuous variables. The Kaplan-Meier method was used for analysing OS and follow-up data. The ‘stepwise’ function in Stata was used for the forward stepwise logistic regression, with the p-value set to 0.1. All analyses were completed using Stata 16.
Results: Of the 1539 patients enrolled, majority were from ANZ (1071 and 359, respectively), with male preponderance (61.0%). Half were above 65 years old. High risk cytogenetic abnormalities, a criterion of the Revised International Staging System (R-ISS), was unknown for half of the patients (49.4%). 45.3% patients presented as ISS stage 1, 21.9% stage II, and 32.8% stage III, respectively at study entry . The most frequent front-line agent used in combination with bortezomib-based triplet was cyclophosphamide [VCd, 1380 (89.7%)], followed by thalidomide [VTd, 92(6.0%)], lenalidomide [VRd, 63 (4.1%)] and daratumumab [DVd, 4 (0.3%)]. The median follow-up was 29.9 months (95%CI: 28.3-31.8) and the median OS was 87.7 months (95%CI: 80.9-93.2). Thirty percent patients had OS&lt;3 years. Clinical and biological factors associated with long OS (≥3 years) were compared with those &lt;3 years (Table 1). Baseline factors associated with higher odds of short OS included age≥65, Eastern Cooperative Oncology Group performance status (ECOG PS)≥2, ISS III, lower creatinine clearance and platelet count, high LDH and poor cytogenetic abnormalities (Table 1). In a multivariate analysis, age≥65 (OR:2.50; p&lt;0.001), ECOG≥2 (OR:2.08; p&lt;0.001), ISS III (OR:2.48; p&lt;0.001), t(4;14)[OR:2.04; p=0.004], t(14;16)[OR:6.33; p=0.004] and 17p deletion (OR:2.77; p =0.001) were associated with a significantly shorter OS.
Conclusion: From clinician perspective, identifying patients with an increased likelihood of shorter OS through the determination of patient- and disease-specific risk factors might be clinically relevant to facilitate better treatment decisions.
Acute Abdominal and Pelvic Complications in Patients with Non-Promyelocytic Acute Myeloid Leukaemia Undergoing Intensive Induction Chemotherapy Are Associated with Favorable Prognosis
Authors: Murphy Philip T , Alsaleh Mohammed , Cheema Harris , John Quinn , Glavey Siobhan , Sargent Jeremy , Swan Dawn Jennifer 
Published: December 2023

Acute abdominal abnormalities are relatively uncommon during the treatment of acute leukaemia but, historically, have been associated with high mortality rates (Hawkins JA, Mower WR, Nelson EW. Acute abdominal conditions in patients with leukaemia. Am J Surgery 1985;150:739-742). Given the improvement in diagnostic and supportive measures for patients with acute myeloid leukaemia (AML) over time, we aimed to determine the rate and outcomes of acute abdominal and pelvic complications in a cohort of AML patients at our hospital.
We retrospectively reviewed the medical records, radiology reports and laboratory test results of 70 consecutive newly diagnosed, non-promyelocytic AML patients undergoing intensive induction chemotherapy between January 2012 and December 2019. Seventeen patients developed 22 episodes of acute abdominal or pelvic pathology and were investigated by radiology (abdominal X ray, CT scan and/or MRI). Table 1 summarises the underlying causes for these complications, as well as neutrophil count and platelet count at time of presentation. Colitis was the most common complication, occurring 6 times. The neutrophil count was &lt;1x10 9/L in 15 of the 22 episodes. Platelet count &lt;20x10 9/L occurred in 8 of the episodes, including the 2 cases of ureteric obstruction by clot. All complications resolved completely with conservative management, except for 1 patient who required surgical drainage of an intraperitoneal and psoas muscle abscess in addition to intravenous broad spectrum antibiotics.
In conclusion, acute abdominal and pelvic complications were relatively rare in our cohort of patients. All but 1 of these episodes resolved with conservative management alone. These results suggest that, with current diagnostic and therapeutic measures, the prognosis for non-promyelocytic AML patients who develop such complications is favorable.
DNA Vaccines Against GPRC5D in Myeloma
Authors: Li Yong 
Published: December 2023

Introduction:
Myeloma is an incurable disease despite improved survival from the ongoing immunotherapy revolution. Virtually all myeloma cases are preceded by MGUS, a condition affecting over one million Americans. Smoldering myeloma is an asymptomatic clonal plasma cell disorder between MGUS and myeloma. Smoldering myeloma is distinguished from MGUS primarily for clinical reasons because the risk of progression to malignancy in the first five years after diagnosis is different: 10% per year in smoldering myeloma vs. 1% per year in MGUS. Yet the risk of progression is not constant, and in a subset of MGUS patients, the risk evolves from a low chance of progression to a high degree of probability of progression to MM. Therefore, patients with smoldering myeloma and MGUS are potential subjects for myeloma prevention. GPRC5D is an emerging novel immunotherapeutic target for myeloma, with several ongoing clinical trials using CAR T cells and antibodies directed against GPRC5D.
Methods:
Nanoplasmid is a next-generation plasmid technology that bypasses the antibiotic selection when amplified in E. coli by expressing a 150 bp RNA-OUT antisense RNA and uses the highly productive heat-inducible R6K origins for DNA replication. With a &lt;500 bp backbone, Nanoplasmids achieve significantly higher expression levels than pVAX1, the most widely used plasmid in DNA vaccine development. We used Nanoplasmid to express human GPRC5D and introduced it into mice via electroporation xenografted with mouse cancer cells that express the human GPRC5D gene. We examined the animals and determined whether the prophylactic vaccines prevented myeloma development and progression.
Results:
We found that mice vaccinated with the human GPRC5D Nanoplasmids had both humoral and cellular responses against the GPRC5D protein. The DNA vaccines were active in reducing tumor development from human GPRC5D-expressing tumors.
Conclusions:
GPRC5D-targeting DNA vaccines are a cost-effective prevention agent for MGUS and smoldering myeloma.
Gsdme Promotes PAD4 Activation and DNA Externalization from Apoptotic Neutrophils
Authors: Zhu Yanfang Peipei , Speir Mary Helen , Tan ZheHao G , Hoffman Harold M , Wong Lai Ping , Sadreyev Ruslan , Jeffrey Kate L , Croker Ben A 
Published: December 2023

Introduction
Neutrophil extracellular traps (NETs) neutralize bacterial and fungal pathogens but can also promote thrombosis, autoimmunity, and sterile inflammation. The presence of citrullinated histones, generated by the peptidylarginine deiminase 4 (PAD4), is synonymous with NETosis and is considered independent of apoptosis. However, non-apoptotic cell death signaling pathways mediated by MLKL and GSDMD can also engage PAD4 in neutrophils to trigger NET formation. Additionally, while PAD4 is hypothesized to neutralize charge on histones to facilitate chromatin decondensation, a genetic deficiency in Padi4 fails to prevent chromatin decondensation but does prevent NET formation following MLKL activation. Together, these data suggest more complex roles for PAD4 in the extrusion of nuclear DNA. Here we explored the role of GSDME - another pore-forming protein activated by apoptotic caspases - in controlling PAD4 activation, DNA externalization, and NET formation in apoptotic neutrophils.
Methods
Cell viability was quantified by flow cytometry and live-cell imaging using Hoechst, Cell Tracker Green, Annexin V, and propidium iodide. Histone citrullination was studied at the population level by immunoblot, at the single cell level by lattice SIM super-resolution microscopy, and at the molecular level by an in-situ ChIP-Seq methodology CUT&Tag. Calcium signaling linked to PAD4 activation was monitored by flow cytometry. Ultrastructural changes occurring in the absence of PAD4 and GSDME were investigated by transmission electron microscopy and super-resolution microscopy.
Results
Intrinsic and extrinsic apoptosis promote GSDME-dependent calcium mobilization and membrane permeabilization, leading to histone H3 citrullination (H3Cit), nuclear DNA extrusion, and cytoplast formation. H3Cit distribution on chromatin is developmentally controlled by PAD4 in neutrophils, with H3Cit found concentrated at promoter regions during neutrophil development. Lattice SIM super-resolution microscopy revealed clustered distribution of H3Cit in the nuclei of neutrophils, reflecting a unique spatial organization and coordination of multiple promoter elements in neutrophils. Following apoptotic stimulation, H3Cit redistributes in a coordinated process from promoter to intergenic and intronic regions. Loss of GSDME prevents nuclear and plasma membrane disruption of apoptotic neutrophils, but also blocks calcium signaling that activates PAD4, ultimately preventing NET formation. During apoptosis in GSDME-deficient neutrophils, early-apoptotic cellular changes to the chromatin and cytoplasmic granules are prolonged, generating highly atypical cellular states that fail to extrude nuclear DNA.
Conclusion
Apoptotic signaling engages PAD4 in neutrophils, establishing a cellular state that is primed for NETosis, but that occurs only upon membrane disruption by GSDME, thereby redefining the end-of-life for neutrophils.
The Clinical Complexity of Langherans Cell Histiocytosis in Adult Patients: Experience of the Institute of Hematology of Bologna
Authors: Broccoli Alessandro , Bagnato Gianmarco , Argnani Lisa , Cantelli Martina , Casadei Beatrice , Pellegrini Cinzia , Zoli Sabrina , Sutto Emanuele , Coppola Paolo Elia , Gentilini Marianna , Morigi Alice , Carella Matteo , Gugliotta Gabriele , Nanni Laura , Stefoni Vittorio , Zinzani Pier Luigi 
Published: December 2023

Langerhans cell histiocytosis (LCH) in adult patients is a rare disease with protean manifestations, including single system unifocal (SSU) or multifocal (SSM) presentation or multisystemic (MS) involvement. Clinical care of adult patients is based on case series and reports. Regimens applied in pediatric patients show unacceptable toxicity in the adult setting.
Our single-center experience with LCH is presented. Data on 30 patients diagnosed between 1997 and 2022 have been reviewed. Patients with isolated pulmonary histiocytosis were excluded. Responses to any treatment were classified according to the acknowledged criteria. Progression-free survival (PFS) after frontline treatment was calculated on all treated patients. Overall survival (OS) was determined on the whole cohort irrespective of any treatment received.
Eighteen male and 12 female patients received a diagnosis of LCH at a median age of 46 years (range 20-75). Sixteen patients had single system (SS) disease, with SSU involvement in 12 cases and SSM involvement in 4 cases. The skeleton was the mostly involved system (Figure), while SSU extra-skeletal disease was detected in 25% of cases. Fourteen patients had MS disease: axial skeleton, lungs, hypophysis, skull, skin and appendicular skeleton were the predominantly involved sites, in this order. Ten patients with SS disease received chemotherapy because of symptoms (mostly bone pain) or due to multifocal dissemination. Two patients underwent radiotherapy (RT), 2 had their disease completely excised and 1 received systemic steroids. One patient was observed. A complete response (CR) was obtained in 60% of treated cases, while a partial response (PR) in 27%. Four patients relapsed after frontline therapy and were rescued with RT or autologous transplant. Among patients with MS disease, chemotherapy (MACOP/VNCOP-B, cladribine, vinblastine) was applied in 6 cases; 2 patients received RT and 1 systemic steroids. One patient underwent surgery and 4 were observed because of asymptomatic disease. A CR was obtained in 70% of treated patients and a PR in 10%. Five patients relapsed, with symptomatic disease requiring treatment (chemotherapy and RT) in 3 cases. Median PFS among all treated patients was 177 months. OS was 91% at 20 years.
Appropriate treatment based on disease extension, site involvement and clinical manifestations yields high remission rates and long term PFS and OS. The optimal approach to relapsed patients remains undefined.
A Prognostic Nomogram Survival Model for Newly Diagnosed Patients with AIDS-Related Diffuse Large B-Cell Lymphoma: A Multicenter Cohort Study in China
Authors: Yang Tao , Liang Yang , Wang Chaoyu , Liu Jun , Wu Yan , Min Haiyan , Huang Yunhong , Wei Guo , Zhang Wei , Wang Min , Tang Xiaoqiong , Yang Zailin , Jun Li , Zhou Hui , Liu Yao 
Published: December 2023

BACKGROUND
The prognosis of patients with AIDS-related diffuse large B-cell lymphoma(AR-DLBCL) becomes very poor when the lymphoma relapses or is refractory to first line immunochemotherapy. We aimed to develop a novel ARDPI nomogram prognostic model for risk stratification so as to guide individualized treatment to achieve sustained remission and improve the overall prognosis for newly-diagnosed AR-DLBCL patients.
METHODS
We interrogated data from 306 patients with newly-diagnosed AR-DLBCL. We filtered variables using LASSO regression and Cox regression to identify prognostic co-variates and develop a survival model, we termed AR-DLBCL Prognostic Index (ARDPI). We evaluated model discrimination, calibration and clinical benefit by Area Under the Receiver-Operator Characteristic (AUROC), calibration plots and decision curve analysis (DCA). Next, we compared the ARDPI model discrimination, calibration and clinical benefit with the IPI and NCCN-IPI models using the same methods. Lastly, we stratified patients into three survival risk cohorts based on ARDPI model by X-tile selecting cutoff point.
RESULTS
7 co-variates were independently correlated with survival and were used to develop the ARDPI model including age, lymphocyte monocyte ratio (LMR), CD5 expression on lymphoma cells, blood EBV-DNA copy number, CD4/CD8 ratio, central nervous system (CNS) involvement and anti-HIV therapy (ART). AUROCs of ARDPI model for 1-, 3-, and 5-year were 0.80 (95% Confidence Interval [CI], 0.72, 0.88), 0.78 (0.69, 0.87) and 0.77 (0.63, 0.91). Predicted and calibrated values were concordant. The DCA curve had higher net benefit using the ARDPI model. Prediction accuracy of the ARDPI model was better compared with the IPI and NCCN-IPI models. For example, 3-year survival AUROC in the ARDPI model was 0.78 (0.69, 0.87) compared with the IPI (0.53 [0.43, 0.63] P&lt; 0.001) and the NCCN-IPI (0.52 [0.42, 0.62] P&lt; 0.001). Using the ARDPI model, we identified 3 survival risk cohorts with 3-year survivals of 0.80 , 0.38 and 0.09 ( P&lt;0.001).
CONCLUSION
The ARDPI has good survival prediction accuracy in newly-diagnosed persons with AIDS-related DLBCL and using it has clinical benefit.Accuracy is better than the IPI and NCCN-IPI models. Validation of our conclusions is needed.
Influenza Training of Granulopoiesis Promotes Long-Term Anti-Leukemia Activity
Authors: Liu Yi , Chen Nianci , Zhou Yile , Zhu Li , Lv Zuopo , Li Chenying , Huang Jiansong , Tong Yanhong , Meng Haitao , Jin Jie , You Liangshun 
Published: December 2023

Abstract
Influenza viral infections have the ability to reprogram the immune system of the host and alter its functions to fight infections. However, the exact mechanisms and functions of virus-induced innate immunity in the context of leukemia are not yet fully understood. Our previous research has shown that a patient with refractory acute myeloid leukemia (AML) achieved complete remission (CR) after being infected with the Influenza A virus (IAV, H1N1 subtype), and this was functionally validated in two different animal disease relevant models. Our recent study demonstrates that mice pre-trained with the IAV promotes a long-term anti-leukemia effect. The anti-leukemia activity of IAV-induced trained immunity is due to the transcriptomic rewiring of hematopoietic stem and progenitor cells (HSPCs), resulting in a sustained enhancement of myeloid cells reprogramming toward an antitumor phenotype. This mechanism involves the upregulation of type I interferons (IFNs) and subsequent downregulation of inflammatory proteins. Our findings shed light on the dynamic changes in innate immune cells following viral infections and indicate a novel anti-leukemia facet of appropriate rewiring of granulopoiesis via upregulation of type I IFNs.
Statement of significance
The study profiles the dynamic changes in immune cells during exposure to the Influenza virus and sheds light on the role of Influenza trained innate immunity in anti-leukemia effect. The study also explores a novel anti-leukemia facet of appropriate rewiring of granulopoiesis via upregulation of the type I IFN pathway. These findings suggest that innate immune training could be a promising adjuvant therapy for cancer and warrant further investigation.
Legend for Figure 5 . H1N1 reprogrammed granulopoiesis via up-regulation of type I interferon pathway.
(A-C) FCM analyses and absolute counts of BM progenitor cells on day 7 after training with H1N1 or PBS. FCM, flow cytometry; BM, bone marrow; LK, Lin-c-kit+Sac1-; LSK, Lin-c-kit+Sac1+; GMP, granulocyte-monocyte progenitors (Lin-c-kit+Sac1-CD16/32 hiCD34+); CMP, common myeloid progenitors (Lin-c-kit+Sac1-CD16/32 intCD34+); MEP, megakaryocyte-erythroid progenitor cell (Lin-c-kit+Sac1-CD16/32-CD34-).
(D) T-SNE plot of top 7 progenitor cells population changes. t-SNE, t-distributed stochastic neighbor embedding.
(E) Heatmap visualization of the expression of different genes in HSPCs. The upregulated genes related to the type I IFNs pathway are listed on the right. HSPCs and hematopoietic stem/progenitor cells.
(F) The top enriched GO terms of biological processes for upregulated genes in H1N1 trained group. GO, gene ontology.
(G-H) Heatmap and t-SNE plot of type I IFN-associated upregulation genes in progenitor cells of HSPCs, GMP, CMP, and MEP. t-SNE, t-distributed stochastic neighbor embedding.
Inaccuracy of Initial Clinical Mobility Assessment in Venous Thromboembolism Risk Stratification
Authors: Hoyer Erik , Brotman Daniel J. , Streiff Michael 
Published: December 2023

Background: The risk of Venous Thromboembolism (VTE) often escalates in hospital settings in part due to reduced patient mobility. However, mobility assessment for VTE risk determination is often clouded by lack of clear definitions and standards. This vagueness can result in erroneous evaluations, especially near the time of admission, particularly since a patient's mobility is not static but fluctuates throughout the hospital stay.
Methods: We conducted a retrospective cohort analysis of patients who were discharged from medicine services in a large academic hospital. For each of these patients, daily nurse-collected Johns Hopkins-Highest Level of Mobility (JH-HLM) scores were used to calculate an objective measure of mobility. Reduced mobility was defined as an JH-HLM score of ≤3 on three consecutive days during hospitalization. We compared this definition of reduced mobility with clinician reported immobility as reflected by Padua scores entered on admission as part of mandatory VTE risk stratification. We also assessed the association between immobility and VTE using an adjusted odds ratio controlling for other VTE risk factors.
Results: Out of 1715 included patients, clinicians identified only 111 (6.5%) as having reduced mobility compared with 328 patients (19.1%) using the JH-HLM calculated approach. If the JH-HLM calculated measure of reduced mobility had been utilized, it would have led to the reclassification of 37 patients from a low-risk category to a high-risk category for VTE. In the cohort, 33 of 1715 (1.9%) patients developed VTE. Among these patients, JH-HLM calculated reduced mobility was identified in 12/33 (36%) of patients, whereas clinicians identified reduced mobility in 3/33 (9%) of patients. Presence of JH-HLM calculated reduced mobility was significantly associated with VTE events (aOR: 2.53, 95% CI: 1.23 - 5.22, P = 0.012). Clinician assessed reduced mobility at the time of admission was not associated with VTE events.
Conclusion: The initial clinician's assessment of mobility during VTE risk assessment did not accurately capture the extent of reduced mobility during the patient's hospitalization. These findings highlight the importance of employing objective measures of patient mobility for assessing and reassessing VTE risk throughout the hospital stay. Healthcare organizations should consider implementing objective measures of mobility like the JH-HLM to improve VTE risk assessment and potentially reduce the occurrence of VTE.
Extravascular Factor IX Pool Fed By Prophylaxis Is a True Hemostatic Barrier Against Bleeding
Authors: Leuci Alexandre , Enjolras Nathalie , Marano Muriel , Daniel Melanie , Brevet Marie , Connes Philippe , Dargaud Yesim G. 
Published: December 2023

Factor IX (FIX) can bind to type-IV collagen in the endothelial basement membrane and diffuse into extravascular spaces. Previous studies in rodents have reported a large biodistribution of FIX. However, the potential hemostatic activity of extravascular FIX and its role in protecting against joint bleeds have not been demonstrated. The capacity of 4 different FIX molecules (plasma derived [pd] and recombinants) to bind type I and type IV collagen was studied here. FIX molecules were also administered intravenously at doses of 50 to 3000 IU/kg in FIX knock-out (KO) mice. A specific FIX signal was detected in immunohistochemistry in the liver as well as in muscles and knee joints with recombinant FIX molecules injected at 1000 and 3000 IU/kg but not at the usual clinical doses of 50-100 IU/kg, while pdFIX generated a FIX signal at all doses including 50 IU/kg. After five 100 IU/kg daily infusions of rFIX, a clear accumulation of FIX was seen in the liver and joints of animals having received 5-day daily FIX infusions with all FIX molecules, with a higher FIX labelling intensity compared to that observed after a single infusion of FIX 100 IU/kg or a single infusion of FIX 500 IU/kg.
The extravascular procoagulant activity of FIX was assessed in saphenous vein bleeding assays performed 7 days after a single infusion of FIX 100 IU/kg. An additional group of FIX KO mice received intravenously for 5 days a single daily dose of 100 IU/Kg of one the four types of FIX concentrate in order to mimic prophylaxis. The number of clots formed in 15 minutes was significantly greater in mice having received prophylaxis during 5 days with 100 IU/kg FIX compared to untreated FIX KO mice (p=0.009) and to mice having received a single infusion of FIX 100 IU/kg (p&lt;0.0001) (Figure 1).
Taken together, these results show that in individuals with severe hemophilia B receiving regular prophylaxis with FIX, extravascular accumulation of FIX over time may have a significant impact on the coagulation capacity and protection towards bleeding.