bluuebunny/crossref_metadata_2025_split huggingface dataset:
Successful Use of Haploid Hematopoietic Stem Cell Transplantation for Severe Glanzmann's Thrombasthenia
Authors: Wang Shuran , Xiao Peifang , Li Jie , Lu Jun , Hu Yixin , Hu Shaoyan , Ling Jing 
Published: December 2023

Objective: Glanzmann's thrombasthenia (GT) is a rare autosomal recessive disorder, which characterized by the clinical manifestations from purpura to severe bleeding. It was caused by mutations of the ITGA2B or ITGB3 gene on chromosome 17, which lead to deficits or reduced expression of the platelet membrane glycoprotein GPIIb/IIIa. We report 5 pediatric patients with severe Glanzmann's thrombasthenia who underwent allogeneic hematopoietic stem cell transplant, to observe the outcomes of allo-HSCT in children with severe Glanzmann's thrombasthenia.
Methods: We retrospectively summarized the clinical and genetic profiles of five patients with Glanzmann's thrombasthenia who underwent allo-HSCT from June 2021 to July 2023. All patients were reduced intensity conditioning (Bufulsan 3.2-6.4mg/kg, CTX 120mg/kg, FLU 180mg/m 2, ATG 10mg/kg). After conditioning chemotherapy, all the patients received stem cells collected via bone marrow harvest and/or peripheral blood apheresis (PBSC) with CD34 dose of 2.89-7.2×10 6/kg and received graft vs. host disease (GvHD) prophylaxis with cyclosporine (CSA) and methotrexate (MTX).
Results: There were five children were involved in this observation, one patient suffered from recurrent epistaxis bleeding which was life-threatening; the second suffered from gastrointestinal bleeding and could only accept liquid diet to 10-years-old; other patients also suffered from epistaxis bleeding, gum bleeding or gastrointestinal bleeding. For all the patients, regular red cell transfusions were required, platelet transfusions and recombinant factor VIIa were also used in severe and life-threatening bleeding events. Two of the five developed antiplatelet antibodies before HSCT. All the patients were successfully treated with allo-HSCT. One case received non-relative matched donor of 10/10 HLA, one case with sibling matched donor, and 3 cases with haploid transplantation of HLA 5-6/10 matched. The mean time to neutrophil engraftment was 11 days (11-12 days), and the mean time to platelet engraftment was 16 days (15-18 days). One case had CMV reactivation, one case had HHV-6b infection, one case had grade II acute GVHD of the skin which was controlled rapidly. There was no evidence of chronic GVHD for all the patients. The platelet disorder was corrected to a normal level after allo-HSCT, with no significant complication related to the transplantation. Comparing with HLA matched donor, either from sibling or non-related, the patients receiving haploid transplantation with 5-6/10 HLA matched got similar outcome.
Conclusions: We proposed haploid transplantation treated with the reduced intensity conditioning regimens produced similar outcomes as HLA matched did which could be recommended as an alternative donor for severe Glanzmann's thrombasthenia.
Trend in Von Willebrand Factor Profile in Women With Von Willebrand Disease During Pregnancy and Postpartum
Authors: Albusoul Linda , Shahid Muhammad , Vuyyala Sowjanya , Otrock Zaher K , Kuriakose Philip 
Published: December 2023

Introduction:
Pregnancy is considered a hypercoagulable state, with levels of multiple coagulation factors including Factor VIII (FVIII) and von Willebrand Factor (VWF), progressively increasing throughout, reaching their peak levels during the third trimester. However, in women with von Willebrand disease (VWD), these changes are variable and could be blunted or absent due to the wide heterogeneity of phenotypes and pathophysiological mechanisms linked to this disorder, posing a significant clinical challenge. This study aims to describe the trend in the VWF profile in women with VWD during each trimester of pregnancy and in the postpartum period.
Methods:
This is a retrospective single-center study that included adult pregnant women diagnosed with VWD, who were followed at Henry Ford Health between 03/2012 and 11/2022. Patients with other bleeding disorders were excluded from the study. Data on baseline characteristics, including age, race, age at childbirth, and parity were collected. Additional data collected included VWF antigen (VWF:Ag) level, FVIII activity level, and VWF ristocetin cofactor (VWF:Rco) activity during the first, second, and third trimesters, as well as in the postpartum period.
Results:
A total of 33 cases were included in our study. At baseline, the mean VWF:Ag level in our patients was 50.5% (reference range 50%-150%). Compared to baseline, the VWF:Ag level increased by 48.71% in the first trimester, 80.59% in the second trimester, and 168.71% in the third trimester. Postpartum, the VWF:Ag level decreased by 51.29% compared to the third trimester; however, it remained 30.89% higher than baseline levels. While the FVIII level (reference range 50%-150%) was an average of 64.8% at baseline, it increased by 21.91% in the first trimester, 74.23% in the second trimester, and 143.67% in the third trimester, compared to baseline. Postpartum, the FVIII level decreased by 48.45% from the third trimester but remained 25.62% higher than baseline. Additionally, the VWF:Rco level was an average of 44.3% (reference range 51%-215%) at baseline. Compared to baseline, the VWF:Rco level increased by 61.85% in the first trimester, 90.52% in the second trimester, and 142.66% in the third trimester. It decreased by 49.12% postpartum compared to the third trimester but remained 23.48% higher than baseline.
Conclusion:
In women with VWD, VWF:Ag level, FVIII level, and VWF:Rco levels steadily increase during pregnancy, reaching their maximum levels during the third trimester. All three levels decreased in the postpartum period; however, they remain higher compared to baseline at a median follow up of 105 days after delivery.
Novel Fusion Gene Aven-NUTM1 Induces Mice Myeloid Leukemia Vulnerable to HDAC Inhibitors
Authors: Dan Yuqing , Ren Ruibao , Li Donghe , Liu Ping 
Published: December 2023

Chromosomal rearrangements involving the NUTM1 gene produce fusion genes commonly found in NUT carcinoma. While recurring NUTM1 fusions have been reported in other neoplasms, including AML, their roles in leukemogenesis remain unclear.
We identified the AVEN-NUTM1 (AN) fusion gene in an AML patient resistant to standard chemotherapy, and went to assess AN's leukemogenicity via bone marrow transduction and transplantation. Mice transplanted with AN-transduced hematopoietic stem/progenitor cells (HSPCs) developed transplantable myeloid leukemia with a median survival of 342 days. RNA sequencing revealed downregulation of genes related to hematopoietic cell lineage commitment and upregulation of genes related to early hematopoietic progenitors and MYC-targeted genes in AN-transformed leukemic cells.
Co-immunoprecipitation confirmed that AVEN-NUTM1 can interact with and activate EP300 as previously reported. To determine whether AN's interaction with EP300 is related to its ability to induce malignant transformation, we mutated the interaction site and constructed mutants of other structural domains. Colony-forming and replating assays showed that HSPCs expressing AN with mutations in the EP300 binding site lost their ability to self-renew and form colonies.
A CUT&RUN assay followed by sequencing showed that the most enriched motif in overlapping peaks between AN and EP300 were ETS motifs, suggesting the involvement of an ETS transcription factor family member in AN-activated EP300-induced leukemia.
We further found that both the patient's primary cells and bone marrow cells from leukemic mice were especially vulnerable to HDAC inhibitors.
These results demonstrate that the AVEN-NUTM1 fusion gene can drive the development of myeloid leukemia in mice, AN's ability to bind and activate P300 is closely linked to its leukemogenicity, and that HDAC inhibitors are effective in targeting AN leukemia cells. The study provids valuable insights for the targeted treatment of NUTM1-related leukemia patients.
Study on the Synthetic Lethal Mechanism of Selective Killing of ALDH2 Deficient Acute Myeloid Leukemia Cells By Inhibiting BRIP1
Authors: Wang Jishi , Hu Xiuying 
Published: December 2023

Background and objective: Although targets related to DNA double strand damage repair have clear tumor therapeutic potential, few have identified DNA double strand damage repair dependence in AML cells through genetic screening to date. In our previous experiments, we found that ALDH2 showed low expression in most newly diagnosed AML, and their unique ALDH2 vulnerability may make them preferentially dependent on BRIP1 by the DNA double-strand damage repair pathway, and have more synthetic lethal effects than other normal cells. Therefore, this study explored whether blocking BRIP1-mediated DNA double-strand damage repair could selectively eliminate AlDH2-deficient AML cells while preserving AlDH2-expressing normal cells present in most human tissues.
Methods: We examined the dependence of ALDH2-expressing cells on BRIP1 and methylation levels of ALDH2 promoters in different AML cell lines. The expressions of BRIP1 and ALDH2 in 6 AML cell lines and clinical samples were detected by Real-time PCR and Western blot, and the reverse expression pattern between the two was studied, and the correlation between the expression of ALDH2 and DNA base excision repair was analyzed. By targeting the inhibition of ALDH2 and BRIP1, in vitro and in vivo models were constructed to observe the proliferation and apoptosis of different AML cell lines and primary cells.
Results: In the group of AML cells with low expression of ALDH2, we found that BRIP1 showed a certain high expression compared with other groups. Among the 46 newly diagnosed AML samples, we divided the clinical samples into high and low groups based on the difference in the expression level and methylation degree of ALDH2. Compared with the group with high expression of ALDH2, BRIP1 in the group with low expression of ALDH2 was significantly increased (P &lt; 0.01). The proliferation level of AML cells was significantly decreased (P &lt; 0.01). BRIP1 inhibition induced apoptosis of U937 and TPH1 cells (AML cell lines with low expression of ALDH2) in a dose - and time-dependent manner (P &lt; 0.05). In addition, in AML cell lines with high expression of ALDH2, we inhibited the expression of both ALDH2 and BRIP1, and the growth of AML cells was significantly down-regulated (P &lt; 0.01). Similarly, we observed the same results when constructing an in vivo AML infiltration model in mice using AML primary cells.
Conclusion: The dependence of ALDH2-deficient cells on BRIP1 and the effect of targeting BRIP1 on the proliferation of AML cells could provide new ideas for finding new molecular targets for the treatment of AML.
Zanubrutinib Combined with R-CHOP As the First-Line Treatment for Newly Diagnosed Diffuse Large B-Cell Lymphoma with Extranodal Involvement: A Prospective Phase II Trial in China
Authors: Hu Chongling , Yang Tao , Jun Li , Zhang Wenjun , Guo Bingling , Wang Chaoyu , Liu Jun , Xiao Chunyan , Huang Dehong , Yang Zailin , Liu Tingting , Li Jieping , Nan Yingyu , Liu Yao 
Published: December 2023

BACKGROUND
About one-third of Diffuse large B-cell lymphoma (DLBCL) arises primarily from extranodal sites, patients with extranodal involvement indicates poor clinical outcomes.There is an urgent need to find new treatments for DLBCL patients with extranodal involvement.
METHODS
We conducted a single-arm, prospective phase II trial for newly diagnosed DLBCL with extranodal involvement to evaluate the efficacy and safety of the zanubrutinib combined with R-CHOP. Patients received therapies: R-CHOP intravenously Rituximab (375mg/m2 on Day0), Cyclophosphamide (750mg/m2on Day1), Doxorubicin (50mg/m2 on Day1), Vincristine(1.4mg/m2 on Day1), and oral Prednisone(50mg/day Day1-5) with Zanubrutinib (160mg bid Day1-21) regimen.This trail was registered at Chinese Clinical Trial Registry(ChiCTR2100053056).
RESULTS
31 patients received ZR-CHOP regimen treatments at least 2 cycles, 26 patients completed 6 cycles. Patients had a median age of 68 years(38-79). 18 patients (58%) had intermediate and high risk of IPI score, 20 patients (65%) had stage III~IV disease, 22 patients (71%) were Non-GCB types, 19 patients (61%) Ki-67 More than 80%. 7 patients (23%) were double-expression lymphoma，5 patients (16%) with positive CD5 and 4 patients (13%) TP53 more than 80%. The objective response rate(ORR) was 96%(26/27), 12 patients(44%) reached complete remission(CR). 1 patient(3%) died for progression disease(PD) and 4 patients(13%) withdrew the trial. The most common adverse events of hematological toxicity were neutropenia, thrombocytopenia and anemia with 19%，13% and 10% grade 3/4 AEs respectively. The most common non-hematological toxicity were pneumonia, nausea and fatigue with 16%，6% and 3% grade 3/4 AEs .
CONCLUSIONS
Our results showed that Zanubrutinib plus R-CHOP(ZR-CHOP) is a safe and effective scheme for DLBCL patients with extranodal involvement. It indicate that the addition of zanubrutinib to the standard first-line treatment can enable these patients to achieve remission in the early stage of treatment and without significantly increasing toxicity.
Prognostication of Large Granular Lymphocytic Leukemia in Clinical Practice: Three New Cases and Literature Review
Authors: Lambert-Swainston Chalette , Varada Neilmegh , Gollard Russell 
Published: December 2023

Large Granular Lymphocytic Leukemia (LGLL) is a rare lymphoproliferative disorder of either CD3+ cytotoxic T-lymphocytes or CD3− natural killer cells with chronic and ill-defined clinical progression. Presentation at diagnosis can include asymptomatic or symptomatic cytopenias, recurrent infections, splenomegaly and rheumatoid arthritis. Multiple cell survival pathways are involved in the pathogenesis of LGLL, and it has been found to be specifically associated with aberrant STAT3 signaling. An increased number of clonal LGL cells in the blood establishes the diagnosis. Treatment regimens historically have included cyclophosphamide, methotrexate, steroids, cyclosporine, and splenectomy, but there are no available targeted therapies or definitive cure available for LGLL. Here we present three cases with varying treatment responses and outcomes that highlight the need for targeted therapy development. All three patients were confirmed to have T-LGLL by flow cytometry analysis.
Patient one is a 64 year old female, presented for moderate recurrent symptoms of LGLL, initially diagnosed 17 years prior and treated with 6 months of cyclophosphamide. On the second presentation she was found to have STAT3 missense mutation and was treated for a second time with cyclophosphamide which improved symptoms. She additionally required subcutaneous immunoglobulin for treatment of recurrent infection.
Patient two is a 72 year old male, presented for recurrent aphthous ulcers with severe leukopenia and neutropenia, found to have STAT3 negative LGLL. He received multiple courses of cyclophosphamide and was refractory to treatment with persistent symptoms despite improvement in leukopenia.
Patient three is a 70 year old male, presented for symptomatic lymphocytosis. He was found on flow cytometry to have LGLL. He improved without further testing or treatment and has remained in remission for several years.
These cases show the variation in presentation and response to therapy for patients with T-LGLL. Previous research has demonstrated the heterogeneity of LGLL and has additionally shown that STAT3 mutation was associated with decreased overall survival. This may be as yet simplifying the pathogenesis for targeting as we can still see heterogeneous clinical response even within STAT3 positive patients. One study showed that the size of the mutated clone correlated with degree of clonal expansion and that immunosuppressive therapy may not be able to reduce the clonal burden at high degrees of mutation. Our cases show that STAT3 positive status is not enough to determine prognosis and treatment course. The degree and types of mutation may need to be quantified as well as additional targets identified. While pursuing targeted treatment therapies for LGLL we must also pursue testing to assess disease burden.
Primary Immune Regulatory Disorders (PIRDs) That Amplify mTOR Signaling Share a T Cell Exhaustion-like Process
Authors: Conrey Peyton E , Campos Jose , Mauracher Andrea , Sayed Samir , Walter Jolan E. , Su Helen , Barmettler Sara , Leiding Jennifer W , Cooper Megan , MacFarland Suzanne P , Ruffner Melanie A , Farmer Jocelyn R , Rao V. Koneti , Henrickson Sarah E 
Published: December 2023

Background: Primary Immune Regulatory Disorders (PIRDs) are a complex and challenging-to-treat subset of Inborn Errors of Immunity (IEI), which are characterized by immune dysregulation leading to recurrent infections, lymphoproliferation, and autoimmunity including refractory cytopenias. Since many ultra-rare monogenic PIRDs exist, it is not feasible to design targeted therapies for each. An alternate strategy is to identify shared aspects of T cell dysfunction and strategies targeting them. We have focused our studies on PIRDs that chronically amplify T cell receptor (TCR) signaling, mimicking chronic infection. Under conditions of chronic inflammation and antigen presentation, seen during chronic infections, CD8 T cell exhaustion (Tex) can result and is characterized by increased inhibitory receptor expression, altered transcriptional networks, epigenetic poise, and impaired T cell functions including cytokine production. Here, we have evaluated CD8 T cell dysfunction in PIRDs, including the potential for Tex.
Methods: Deep immune phenotyping and T cell functional analyses were performed using CyTOF and spectral flow cytometry, in addition to single cell RNA-sequencing and CITE-seq from untreated PIRD and healthy control PBMCs. Finally, CRISPR/Cas9 editing in healthy control CD8 T cells was used to create a cellular disease model.
Results: We identified a Tex-like process in activated PI3 kinase delta syndrome (APDS), CTLA-4 haploinsufficiency, and Ras-associated Autoimmune Leukoproliferative Disease (RALD), which share increased mTOR activation. We identified increased PD-1, CD39, TIGIT and TOX expression on CD8 T cells consistent with a Tex-like phenotype. We also found impaired CD8 T cell cytokine and proliferation consistent with Tex. Lastly, a cellular model of CTLA-4 haploinsufficiency was created for perturbation studies to evaluate best available therapies and target novel therapeutics in these rare disorders.
Conclusion: By identifying shared patterns of CD8 T cell dysfunction in these ultra-rare disorders, we may both identify novel therapeutic strategies and increase our understanding of CD8 T cell function, including cytokine production.
Iron Overload in Dialysis Patients: Serum Ferritin Underestimates Liver Iron Measured By MRI
Authors: Grant Christopher , Juarez Dennis , Pakbaz Zahra 
Published: December 2023

Background: Parenteral iron supplementation and erythropoietin-stimulating agents are the mainstay management for anemia in patients requiring dialysis. Traditionally, iron status in this patient population is determined by monitoring of widely available and inexpensive serum ferritin level. However, serum ferritin is an acute phase reactant and its usefulness is disease specific. Therefore, several non-invasive methods to evaluate body iron storage have been studied, with measurement of liver iron concentration (LIC) by MRI FDA approved. In this retrospective chart review, we explored the utility of serum ferritin for predicting LIC in a convenience sample of adults on dialysis who had LIC measured by MRI.
Methods: Seven adults on dialysis who had been referred to an academic hematology clinic between July 2020 to June 2023 for elevated ferritin and subsequently had completed LIC by MRI were included in this chart review. Liver iron was quantified by T2* Relaxometry in a 1.5 Tesla MRI . Patients age, gender, etiology of end stage renal disease, duration on dialysis, initial LIC, and the ferritin and hemoglobin levels within three month of LIC were collected from patient medical records. Clinical recommendation for holding parenteral iron or starting chelation and patient-follow through were also recorded. In 2 patients, repeat LIC was available. The clinical recommendation for all patients with elevated LICs was to hold parenteral iron and not to start chelation but repeat LIC in 6 month intervals.
Result: The median age was 56 years (min 26 years - max 73 years) and 4 of 7 patients were female. The median time of first LIC from initiation of dialysis was 88.5 months (min 19 months - max 130 months). The median of initial LIC was 6.6 mg/g (min 4.6 mg/g - max 12.5 mg/g). The median ferritin was 1120 ng/mL (min 736 ng/mL - max 2650 ng/mL). The median hemoglobin was 10.8 g/dL (min 8.4 g/dL - max 13.7 g/dL). Figure 1A demonstrates that despite similar ferritin levels (bolded group or underlined group), LICs were very variable. Additionally, it is visible in figure 1A that serum ferritin underestimates the LIC (italicized) in this patient population. Holding iron infusion for 2 years in patient 4, resulted in LIC trending down from 6.3 mg/g to 3.2 mg/g (Figure 1B) with minimal impact on hemoglobin. Despite clinical recommendation to hold iron infusion in patient 5 with an initial LIC of 6.8 mg/g, iron infusion was continued. Repeat LIC for this patient 6 months later remained unchanged at 7.0 mg/g, while serum ferritin trended down from 1084 to 843.
Conclusion: Ferritin underestimates liver iron concentration in dialysis patients. More investigation is required to determine if liver iron assessment by MRI improves iron management in dialysis patients and optimize serum ferritin utility. This data also suggests that, chelation is not required in iron overloaded dialysis patients, and holding IV iron can result in decline in liver iron concentration.