bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Variable Heavy Chain Antibody Syn-VWFA1 Inhibits the Interaction of Platelets to Von Willebrand Factor in Solution but Not to Immobilized Von Willebrand Factor Thereby Inhibiting 3-Dimensional but Not 2-Dimensional Thrombus Formation
Authors: Huskens Dana , Van Der Vorm Lisa Nynke , Konings Joke , Arce Nicholas , Roest Mark , De Groot Philip G. , Li Renhao , Remijn Jasper A. , De Laat Bas 
Published: December 2023

Neutralizing the interaction between GP1bα and von Willebrand Factor (VWF) is an attractive strategy for treatment and prevention of platelet-VWF agglutinate formation in von Willebrand disease type 2B and thrombotic thrombocytopenic purpura.
The aim of this study was to characterize a llama-derived variable heavy chain antibody (VHH) targeting the A1 domain of active VWF (Syn-VWFA1), in terms of its interference with platelet VWF interaction.
Syn-VWFA1 (1.5 µM) abolished platelet binding to ristocetin-activated VWF (native and Haemate® P VWF) and R1306W VWF (VWF type 2B) in a flow-cytometric platelet function assay (Figure 1). Moreover, Syn-VWFA1 dose-dependently inhibited ristocetin-activated VWF and R1306W VWF platelet agglutination, but not collagen- and ADP-induced platelet aggregation. Under flow conditions, Syn-VWFA1 (1.8 µM) did not affect adhesion of platelets to collagen at high shear. In the shear- and collagen-dependent PFA-200, Syn-VWFA1 prolonged the closure time, but only at high concentrations (&gt;3 µM), while GPIba binding to immobilized VWF remained unaffected by Syn-VWFA1. Syn-VWFA1 increased the cleavage of VWF multimers by ADAMTS13. Furthermore, by applying deuterium exchange, we found a small region in the β1 to α1 loop (1288-1293) in the A1 domain of VWF, which is likely to constitute the nanobody binding site (Figure 2) and binding of Syn-VWFA1 to the A1 domain results in a conformational change exposing regions in the α2 and α3 helices.
In conclusion, Syn-VWFA1 dose-dependently blocks platelet-binding to activated VWF in solution, but not to (collagen-) immobilized active VWF. This implies that immobilization of VWF to collagen affects VWF conformation in such a way (1) that access of Syn-VWFA1 to its epitope in the A1 domain is hindered or (2) that conformational changes following Syn-VWFA1 binding are blocked, while allowing platelet binding. This implies that Syn-VWFA1 has potential treatment opportunities for patients with increased circulating active VWF, to prevent 3-dimensional thrombus formation (pathological platelet-VWF aggregate formation) but not 2-dimensional thrombus formation (leaving physiological hemostasis at sites of vascular injury intact).
Impact of COVID-19 Epidemics on Paediatric and Adult Patients with Haemophilia Treated in a Haemophilia Therapeutic Centre
Authors: Zhang Shuxia , Li Xiaofan , Yang Feng'e 
Published: December 2023

Abstract
Introduction: The pandemic of coronavirus disease 2019 (COVID-19) has posed an unprecedented health crisis for all humans, including people with haemophilia.
Aim: To investigate the impacts of COVID-19 pandemic on the infection, symptoms, drug use, and social intercourses of patients with haemophilia.
Methods: 265 adults or children with haemophilia followed up in the Haemophilia Diagnosis and Treatment Center of Fujian Medical University Union Hospital during the COVID-19 pandemic were collected and analyzed between January 2022 and January 2023.
Results: A total of 265 patients participated in this survey, 30.2% were children and 69.8% were adults. During the COVID-19 pandemic, coagulation factors were not associated with the type and severity of haemophilia, residence, or infection. Compared with adult patients, more children reduced social intercourses and outdoor activities due to the fear of COVID-19 (85.0% vs 66.5%; p = 0.002). The bleeding events were also significantly lower in children than in adult patients (61.2% vs 81.1%; p = 0.001). The SARS-CoV-2 infection rate was significantly higher in patients living in urban areas than in rural areas (74.3% vs 53.6%; p &lt; 0.001). The lasting time of symptoms after infection was not significantly associated with hemorrhage, type and classification of haemophilia, presence of inhibitors, complications, and vaccination.
Conclusions: The accompaniment of COVID-19 did not significantly influence the symptoms and treatments in patients with haemophilia. Compared with adults, the number of pediatric patients with bleeding events was significantly lower .
Keyword: COVID-19, haemophilia, hemorrhage, infection, symptoms
Rituximab Plus Bortezomib for Refractory and Relapsed Warm Autoimmune Hemolytic Anemia：a Prospective, Single-Arm, Phase Ⅱ Trial
Authors: Lin Xijuan , Yang Chen , Zhuang Junling , Zhou Daobin , Chen Miao , Han Bing 
Published: December 2023

Background Treatment of refractory and relapsed warm autoimmune hemolytic anemia （RR wAIHA） is challenging, especially for those who are in emergency with severe anemia and crossmatching incompatibility. Rituximab is now the preferred second-line treatment for RR wAIHA with unsatisfactory onset speed and sustained efficacy. Bortezomib induces apoptosis of plasma cells that produce autoantibodies and has multiple immunoregulatory functions. In this study, we report the results of rituximab plus bortezomib for the treatment of RR wAIHA in a prospective phase 2 trial.
Methods A prospective single arm trial to investigate the activity and safety of the combination of rituximab and bortezomib (RB regimen) in RR wAIHA patients were conducted. Eligible patients were aged 18 years or older, had a diagnosis of primary or secondary wAIHA or EVANS syndrome, refractory or dependent to glucocorticoids. Patients were given a single dose of 500 mg rituximab infusion on day 0 and a subcutaneous injection of 1.3 mg/m 2 bortezomib twice a week for two weeks on days 1, 4, 8, and 11. A same course was repeated after 3 months, with response assessment after 3 and 6 months. Patients with response were given rituximab 500mg every three months for 6 cycles. The primary endpoint was overall response rate (ORR) after 6 months; the co-primary endpoint was the days to hemoglobin (HGB) increase &gt;20 g/L and transfusion independence.
Findings Between Sep 2, 2019 and Jan 15, 2023, a total of 33 patients were enrolled, with 27 females (81.8%) and a median age of 56.5[interquartile range (IQR) 42.75 - 65.75]. There were 30 (91%) relapsed patients and 3 (9%) refractory patients, and 20 (60.6%) patients with primary wAIHA and 13 (39.4%) patients with secondary wAIHA. At 6 months, the ORR was 75.8%, with 11.7% of CR. The median days to HGB increase &gt;20 g/L and transfusion independence was 19 days [interquartile range (IQR) 13 - 61.5]. After a median follow-up of 24 months [interquartile range (IQR) 6 - 24], the ORR was 84.8% with 21.2% of CR. 28.6% patients relapsed at a median interval of 12 months [interquartile range (IQR) 5.75 - 19]. 2 patients (6.1%) experienced adverse events grade ≥ 3, both of whom experienced severe pulmonary infection. There was a significant reduction in B cell counts (P = 0.011), but no significant change in quantitative measurement of serum immunoglubulin G (IgG) (P = 0.056), IgA (P = 0.052) and IgM (P = 0.057) after 6 months treatment. Mann-Whitney analysis showed that patients with a higher amount of B cells before RB regimen treatment were more likely to achieve CR (P = 0.02).
Conclusion The combination of rituximab with bortezomib for RR wAIHA patients showed excellent efficacy with rapid responses and safety. The trial was registered at ClinicalTrials.gov as NCT04083014.
Successful Incorporation of Electronic Patient Reported Outcomes Using Promis-29 into Standard of Care after Hematopoietic Stem Cell Transplant and Chimeric Antigen Receptor T Cell Therapy
Authors: Shah Gunjan L. , Lobaugh Stephanie , Sukhu Ranjit , Devlin Sean M. , Atkinson Thomas , Kemeny Elizabeth , Stetson Peter , Perales Miguel-Angel , Giralt Sergio A. , Scordo Michael 
Published: December 2023

Background:
Cellular therapies including hematopoietic stem cell transplant (HCT) and CAR T are mainstays of treatment for hematologic malignancies, but can have significant and prolonged side effects. Patient reported outcome (PRO) measures are instruments which allow a patient to self-report symptoms to their care team and have been shown to be more comprehensive and reliable than provider assessment. Using our center's electronic platform, we aimed to integrate PRO collection into standard of care to improve the clinical experience after HCT and CAR T.
Methods:
Patients received the PROMIS-29 survey through the patient portal. Baseline surveys were automatically generated by a chemotherapy order, and follow-up surveys on Day 0 (infusion), weekly for the first month, monthly for the first year, and every 3 months for the second year were generated off the cell infusion order. Patients were manually censored from further surveys at time of relapse or progression of disease. Survey responses in pre-identified severe ranges prompted instructions to call the clinician's office and for the clinical team to call the patient.
Results:
From May 2019 to December 2022, 1025 patients underwent a cell therapy at MSK (323 allo HCT, 450 allo HCT, 228 commercial CAR T, 24 with both HCT and CAR T) with overall median age of 63 (range 20 -85), 44% female. HCT patients had leukemia (22%), myelodysplastic syndrome (10%), myeloproliferative neoplasm (3%), non-Hodgkin lymphoma (NHL, 18%), Hodgkin lymphoma (5%), plasma cell disorders (40%), or other diseases (1%); while CAR T cell patients had NHL (85%), multiple myeloma (12%), or leukemia (3%). Seventy-eight percent answered at least one survey over the two years, with response rates at baseline, Day 0, week 1, week 2, week 3, and week 4 of 51%, 27%, 26%, 26%, 29% and 29%, respectively (Figure 1). PROMIS-29 physical health summary scores at at baseline, Day 0, week 1, week 2, week 3, and week 4 were 49 [21 - 59], 45 [22 - 59], 43 [21 - 59], 41 [21 - 59], and 42 [21 - 59], respectively (Figure 2). Mental health summary scores were 51 [30 - 64], 49 [29 - 64], 48 [29 - 64], 47 [26 - 64], 48 [24-64] and 49 [30 - 64], respectively.
Conclusions:
We demonstrate the feasibility of incorporating patient reported outcomes into standard of care practice after HCT and CAR T cell therapy. Missing surveys were more common while inpatient, which may be due to toxicity or less use of the patient portal while admitted. Additional work is ongoing to improve the response rates at all time points. Importantly, the electronic system allowed us to capture later timepoints when patients have less frequent visits and may be followed locally. Full survey results will be presented.
Assessment of the Expression of Genes Related to Epigenetic and Chromatin Modifications in Diffuse Large B-Cell Lymphoma Patients Resistant to R-CHOP
Authors: NG Wern Lynn , Calderon-Martinez Evelyn , Ng Lay She , Sangha Lillian , Garg Chandi , Kovalenko Iuliia , Zevallos-Delgado Christian 
Published: December 2023

Introduction
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. The mainstay of frontline therapy remains R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) or R-CHOP-like immunochemotherapy. Patients' responses to R-CHOP therapy vary depending on the stage and/or molecular subtypes of DLBCL. Approximately 40% of advanced-stage DLBCL patients suffer from a refractory or relapsed disease[1]. The outcome for patients with early relapses after rituximab-containing first-line therapy remains poor[2]. DLBCL poses a marked degree of genetic heterogeneity. Here, we compare the expression of genes related to epigenetics and chromatin modifications in DLBCL patients resistant and non-resistant to R-CHOP therapy.
Objective
The aim of this study is to assess the differences in the expression of genes related to epigenetics and chromatin modification in DLBCL patients that could lead to chemoresistance and failure of R-CHOP treatment.
Method
The gene expression profile (GEP) was obtained from Gene Expression Omnibus (GEO) database (Accession number: GSE173263) submitted by Dlouhy et al[3]. The GEP was analyzed in DLBCL cases, including 10 early failure cases (defined as refractory to induction treatment or early relapsing (&lt;12 months from diagnosis)) and 29 responding patients, to identify features associated to primary chemoresistance. The comparison was done using the list of genes proposed by Bakhshi, T. et. al[4] , where he selected the genes that were identified to potentially cause epigenetic and chromatin modifications in DLCBL. All the comparisons were done using a T-test.
Results
There were significant differences in the gene expression related to epigenetics and chromatin modifications between DLBCL patients in the early failure arm versus the remission arm. Patients who had early failure to R-CHOP tended to have higher expression of these genes: SMARCA4 (p=0.010), SETD1B (p=0.018), SETD2 (p=0.024), EP300 (p=0.012), MLL3 (p=0.049), INO80 (p=0.001), CHD8 (p=0.007), NCOR1 (p=0.020), ARID1B (p=0.034), and SETD5 (p=0.007). Compared to the patients who were in remission after R-CHOP therapy, these patients had significantly higher expression of HIST1H1E (p=0.007).
Conclusion
Gene expression related to epigenetics and chromatin modifications significantly impacts the prognosis of DLBCL patients treated with R-CHOP. Differences in gene expression may lead to chemoresistance, and higher expression levels are associated with a worse prognosis. This study sheds light on the importance of chromatin and epigenetic modifications in DLBCL progression, guiding the development of future therapies.
A Novel BCR-ABL1 Degrader, Ubx-362, Can Overcome Resistance By BCR-ABL1 Kinase Domain Mutations in Chronic Myeloid Leukemia
Authors: Lim Ye Seul , Jeong Na-Rae , Yoo Sun-Mi , KIM Han Wool , Lee Song Hee , Kim Dong-Wook 
Published: December 2023

Background
Chronic Myeloid Leukemia (CML) is a clonal hematopoietic stem cell disorder characterized by the presence of the BCR::ABL1 fusion gene. Tyrosine kinase inhibitors (TKIs) have revolutionized CML treatment, providing remarkable responses in patients. However, resistance mutations within the BCR-ABL1 kinase domain can emerge, leading to treatment failure and disease progression.
Method
To overcome TKI resistance, we developed a novel BCR-ABL1 degrader (UBX-362), which is a proteolysis-targeting chimera (PROTAC), and investigated its therapeutic potential using several Ba/F3 cell lines expressing various BCR-ABL1 mutations. UBX-362 is designed to target BCR-ABL1 through the ubiquitin-proteasome system-mediated degradation. Proliferation assays (IC 50) were performed using the Cell Titer-Glo assay, and western blotting was conducted to measure the degradation levels of the BCR-ABL1 protein in the tested cell lines. For the in vivo xenograft mice experiments, 5 × 10 6 K562 cells were subcutaneously injected into Balb/c nude mice. UBX-362 will be orally administered at doses of 5 or 20 mg/kg, and dasatinib or ponatinib will be administered at a dose of 20 mg/kg once daily for 21 days.
Results
We identified potent and orally available PROTACs, among which UBX-362 exhibited superior degradation activity against both wild-type (WT) and mutant BCR-ABL1 proteins in various Ba/F3 BCR-ABL1 kinase domain mutant-expressing cell lines. In vitro experiments showed that UBX-362 effectively degrades WT and various mutant BCR-ABL1 proteins. The levels of WT BCR-ABL1 protein were measured by western blotting, yielding a half-maximal degradation concentration of UBX-362 at ~1.78 nM. Furthermore, the DC 50 of UBX-362 against E255K, V299L, F317L, and F359C mutant BCR-ABL1 proteins were in the single-digit nM range (6.395nM, 7.679nM, 4.635nM, and 5.688nM, respectively). While UBX-362's anti-proliferative activity (~2.562nM) was not found to be superior to dasatinib (~0.378nM), it still demonstrated a strong anti-proliferative effect in the CML cell line K562 and various BCR-ABL1 mutant-expressing Ba/F3 cell lines. Specifically, the IC 50 of UBX-362 was 2.477nM in the Ba/F3 WT cell line. An in vivo anti-cancer efficacy study is currently underway in the K562 xenograft mouse model to compare its effectiveness with dasatinib or ponatinib.
Conclusion
The findings from this pre-clinical study show the possibility of clinical development of a BCR-ABL1 degrader. And, UBX-362 can overcome resistance in CML patients with BCR-ABL1 mutations and can be a good candidate for further clinical development.
Impact of COVID-19 in Thalassemia Patients Undergoing Hematopoietic Stem Cell Transplant Recipients
Authors: Jingxuan Shao , Liu Rongrong , Lai Yongrong , Wei Xinmei , Zhang Ning , Huang Cuifeng , Liu Qifa , Zhang Zhongming , Yang Gaohui , Wei Zhenbin , Liu Lianjin 
Published: December 2023

Objective: This article primarily examines the clinical attributes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in transplant recipients with thalassemia, offering significant insights into the treatment and care of this patient population.
Method: The present study retrospectively analyzed the data of all thalassemia patients who underwent Hematopoietic stem cell transplantation (HSCT) at the First Affiliated Hospital of Guangxi Medical University between December 2019 and December 2022. A total of 280 patients were included, of which 81 had confirmed coronavirus disease 2019 (COVID-19). The study collected information on patient demographics, transplantation type and timing, graft-versus-host disease (GVHD), use of immunosuppressive agents, onset time and severity of COVID-19, and prognosis. Follow-up was conducted until March 31, 2023.Univariate analysis was performed using SPSS v25.0, and GraphPad Prism was used for the cumulative incidence comparisons.
Results: The median age was 3.6(2-19) years.The main type of thalassemia was β type (93.9%). Identical sibling donors accounted for 40%, haploidentical donors accounted for 25.4%, and identical unrelated donors accounted for 34.6% (10/10). The main source of hematopoietic stem cells was bone marrow combined with peripheral blood (85%).There were no significant differences in age, gender, diagnosis, donor type, graft type, use of immunosuppressive agents, GVHD, and pneumonia of pro-COVID-19 between infected patients and non-infected patients with SARS-CoV-2. Most of the patients were mild (74 cases, 91.3%) in terms of the severity of COVID-19 infection, only 8.6% of the moderate cases, and none severe and died. 74 cases were cured without drug treatment. Of the seven patients treated with medications, four were azvudine and three were nematasvir. The median number of days (IQR) of treatment for COVID-19 was 5(5) days. The cumulative incidence in the immunosuppressive group was higher than that in the non-immunosuppressive group over the same time frame. There was no significant difference in the final infection rate of COVID-19 among patients receiving transplantation in different years(2020,2021,2022), which was 24.7 26.8 36.5 ( p=0.368), respectively.
Conclusion:
The low infection rate and no severe cases may be due to scientific protection and timely medication. There are no special risk factors for COVID-19 infection in thalassemia patients after transplantation.
A Novel Indirubin-3-Monoxime Derivative Functions As Regulator of Proteostasis Via Targeting TRIM28 in Multiple Myeloma
Authors: Fang Teng , Sun Hao , Sun Xiyue , Yu Zhen , Zhang Xiaoyu , Liu Lanting , Gong Lixin , Xie Shiyi , Hao Mu , Qiu Lugui 
Published: December 2023

Introduction: Multiple myeloma (MM) remains an incurable plasma cell malignancy. Agents disturbing the proteostasis play indispensable roles in MM treatment. Our previous studies have shown that the indirubin-3-monoxime (I3MO) works as a novel proteasome inhibitor that effectively inhibits MM cell growth. In this study, we aim to investigate the improvement of I3MO combined with histone deacetylase 6 (HDAC6) inhibitors, and clarified the molecular mechanisms.
Methods: We constructed a compound 8b combined with I3MO and HADC6 inhibitor. The anti-MM effects of compound 8b were investigated in vivo and in vitro studies. Western blots, immunofluorescence, and proteasome activity assay were utilized to investigate the effects of 8b on MM cell proteasome activity, aggresome and autophagosome formation. RNA-seq and Dual-luciferase reporter gene assay were performed to identify the downstream targets of 8b treatment. We constructed MM cell lines with TRIM28 overexpression or shRNA knockdown. We further explored the function of TRIM28, one of the targets of 8b treatment, by ChIP-seq and IP-MS.
Results: The novel I3MO derivative 8b more efficiently suppressed myeloma cell growth in vitro and in vivo. Compound 8b not decreased proteasome activity but inhibited the formation of aggresomes and autophagosomes. Interesting, we found that compound 8b efficiently inhibited TRIM28 promoter activity and repressed TRIM28 transcription level further. GEO data analysis demonstrated a positive correlation between TRIM28 and the expression of proteasome subunits as well as autophagy-related genes in MM. Further, we utilized ChIP-seq to confirm that TRIM28 could bind to the promoter region of multiple proteasome subunits-encoding genes, including PSMB1. Our data indicated that TRIM28 knockdown not only decreased the proteasome activity, but inhibited the formation of autophagosomes. Knockdown TRIM28 induced a higher sensitivity to BTZ treatment in MM cells. Furthermore, IP-MS with Co-IP analysis showed that TRIM28 interacts with 14-3-3ζ. TRIM28 acts as an E3 ligase in mediating the ubiquitination and degradation of 14-3-3ζ, a well-known negative regulator of autophagy. 14-3-3ζ degradation induced by TRIM28 activates autophagy in MM cells. These data suggested that TRIM28 suppressed by compound 8b would involve in proteostasis by regulation of proteasome activity and autophagy.
Conclusions: Our study identified a novel compound 8b, I3MO combined with HDAC6i, efficiently suppressed MM cells survival. Additionally, we for the first time provided novel important insights for the roles of TRIM28 in MM pathobiology by regulation of proteasome activity and autophagy.