bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Nationwide Analysis of the Outcomes Among Hospitalized Patients with Heparin Induced Thrombocytopenia and Concomitant COVID-19 Infection
Authors: Syal Arshi , Arya Yajur , Casipit Bruce Adrian , Dourado Claudia , Mayo Ryan J , Heller Gordon 
Published: December 2023

Background
Heparin induced thrombocytopenia (HIT) and COVID-19 infection are independently associated with thromboembolic complications. Our study aims to assess outcomes among hospitalised patients with concomitant HIT and COVID-19 infection, since data among this subgroup is lacking.
Methods
We utilized the 2018-2020 National Inpatient Sample (NIS) Database in conducting a retrospective cohort study. We identified patients who have heparin induced thrombocytopenia (HIT) and COVID-19 infection using appropriate ICD-10 CM codes. We stratified patients based on the presence or absence of COVID-19 infection. A survey multivariable logistic and linear regression analysis was used to calculate adjusted odds ratios (ORs) for the primary and secondary outcomes. A p value of &lt;0.05 was considered statistically significant. The aim of this study was to investigate the impact of COVID-19 infection on in-hospital mortality, hospital LOS, total hospitalization charge and risk for arterial or venous thrombosis among hospitalized patients with HIT.
Results
We identified a total of 9896 hospitalized patients with heparin-induced thrombocytopenia (HIT), of which 7.68% (760/9896) had concomitant COVID-19 infection. The overall in-hospital mortality among those hospitalized patients with HIT was 17.14% (1695/9896). Among those with concomitant COVID-19 infection, the mortality rate was significantly higher at 50% (380/760, p=0.001). Further, compared to those without COVID-19 infection, those with concomitant COVID-19 infection had a significantly longer median LOS (21 days vs 11 days, p=0.001) and higher total hospitalization charge ($292,325 vs $143,972, p=0.001). Utilizing a stepwise survey multivariable logistic regression model that adjusted for patient and hospital level confounders, COVID-19 infection was found to be an independent predictor of increased in-hospital mortality (adjusted OR 5.13; 95% confidence interval [CI], 3.36-7.84; p=0.001), longer LOS (adjusted OR 6.21; 95% confidence interval [CI], 3.56-8.86; p=0.001) and higher total hospitalization charge (p=0.001). However, it was not significantly associated with increased risk for arterial (adjusted OR 0.72; 95% confidence interval [CI], 0.18-2.83; p=0.63) or venous (adjusted OR 0.91; 95% confidence interval [CI], 0.48-1.74; p=0.79) thrombosis.
Conclusion
Our analysis showed that among hospitalized patients with HIT, concomitant COVID-19 infection increased the risk for in-hospital mortality, longer LOS and higher total hospitalization charge, however, it did not significantly increase the risk for the development of arterial and venous thrombosis. Prospective studies with control of possible confounders are warranted in order to better describe these associations.
GLUT1 Overexpression Enhances 19-28z CAR-T Cell Expansion and Metabolic Fitness
Authors: SHI Yuzhe , Kotchetkov Ivan S , Hanina Sophie Alexandra , Sadelain Michel 
Published: December 2023

The tumor microenvironment presents many obstacles to effective CAR T cell therapy. One of these obstacles is glucose competition from tumor and myeloid cells to the detriment of CAR T cells. We hypothesize here that CAR T cells with elevated levels of glucose transporter are better fit under such conditions, which will result in improved therapeutic efficacy.
We overexpressed either GLUT1 or GLUT3 in CD19-targeted CAR T cells engineered with a clinically validated CAR (19-28z). GLUT1 is ubiquitously expressed in tissues and GLUT3 has a higher affinity for glucose. Upon in vitro antigen stimulation, 1928z-GLUT1 and 1928z-GLUT3 showed greater enrichment of CAR+ T cells and underwent more cell divisions than control 1928z-LNGFR under glucose-limiting conditions. In repetitive antigen stimulation assays, 1928z-GLUT1 expanded significantly more than 1928z-LNGFR cells in 10 mM or 5 mM glucose medium. Surprisingly, 1928z-GLUT3 CAR T cells faired markedly less well than 1928z-LNGFR controls, associated with reduced viability of 1928z-GLUT3 CAR T cells after 2 or 3 exposures to antigen. In the NALM6 acute lymphoblastic leukemia model, low-dose CAR T cell treatment with 1928z-LNGFR and 1928z-GLUT3 did not curtail rapid tumor progression, while 1928z-GLUT1 CAR T cells significantly increased survival. More abundant CAR+ T cells were found in the bone marrow and spleen of 1928z-GLUT1-treated mice. Interestingly, we observed consistent increases in CD62L+CD45RA+ Tscm population in 1928z-GLUT1 cells, including both CD8 and CD4 T cells. We flow-sorted CAR T cells from treated mice and performed SMARTer RNA-seq. GLUT1, but not GLUT3, significantly upregulated TCF7 and genes encoding glycolytic enzymes and electron transport chain, indicating that GLUT1 overexpression enhances both glycolysis and oxidative phosphorylation.
To further test GLUT1-CAR-T function in tumor lines with high levels of glucose transporter, we generated a renal cell carcinoma (RCC) patient-derived xenograft (PDX) with ectopic expression of human CD19. CAR-T cells were repetitively stimulated with the RCC PDX under titrated glucose concentrations. 1928z-GLUT1 significantly improved CAR T cell viability compared to 1928z-LNGFR in low glucose conditions. The expansion of GLUT1 CAR-T cells in 10 mM and 5 mM glucose also surpassed that of LNGFR CAR-T cells. In vivo, 1928z-GLUT1-treated mice showed significantly less tumor burden than 1928z-LNGFR-treated mice.
Overall, we developed a novel strategy for enhancing the metabolic fitness of 1928z CAR-T cells by constitutively overexpressing GLUT1. GLUT1 but not GLUT3 enhances glycolysis and oxidative phosphorylation in CAR-T cells, which sustains T-cell expansion and increases therapeutic efficacy. This strategy is under investigation with other CAR formats.
Autophagy Inhibition Prevents CAR-T Exhaustion and Terminal Differentiation Via TCF7 Accumulation
Authors: Teng Xinyi , Shao Mi , Guo Xin , Cheng Tao , Qian Pengxu , Huang He 
Published: December 2023

Introduction: Chimeric antigen receptor T (CAR-T) cell therapy has achieved remarkable success in hematological malignancies. However, CAR-T cell dysfunction due to exhaustion has been identified as a major roadblock to effective CAR-T cell therapy. Autophagy mediates T cell differentiation, survival, and memory by regulating the degradation of organelles and specific proteins. A recent study reported that inhibition of autophagy significantly enhanced the killing effect of CD19 CAR-T cells. Yet, the impact of autophagy inhibitors on CAR-T cell exhaustion and maintenance is still unclear. The study aims to systematically evaluate the role and mechanism of autophagy inhibitors on CAR-T cells.
Methods and Results: To explore whether autophagy inhibitors could prevent CAR-T cell exhaustion triggered by antigen-independent CAR tonic signaling, we applied 3 autophagy inhibitors: SBI0206965, MRT67307, Compound C, respectively, to the culture medium of CD19.4-1BBz CAR-T cells. We found that all the 3 autophagy inhibitors could reduce CAR-T cell exhaustion and terminal differentiation. The results were replicable with GD2.28z CAR-T cells. Among the three inhibitors, SBI0206965 showed the most significant effect. Thus, we chose SBI0206965 for further research. CD19.4-1BBz CAR-T cells pretreated with SBI0206965 demonstrated enhanced killing capacity against Nalm-6 cells in vitro. Using the Nalm-6-bearing leukemia xenograft model, we found that compared to DMSO pretreated CD19.4-1BBz CAR-T cells, SBI0206965 pretreated CD19.4-1BBz CAR-T cells showed superior persistence and antitumor efficacy, exhibited a less exhausted and differentiated state, and further prolonged mice survival (Fig.1). To evaluate whether SBI0206965 could protect CAR-T cell exhaustion triggered by antigen stimulation, we cocultured CD19.4-1BBz CAR-T cells with Nalm-6 cells in the medium with or without SBI0206965. We demonstrated that the addition of SBI0206965 could effectively inhibit CAR-T cell exhaustion and terminal differentiation driven by antigen exposure. By performing proteomics, we identified TCF7 enriched in SBI0206965-treated cells. We validated the differences using Western blot analysis, which showed increased TCF7 levels in CAR-T cells treated with SBI0206965 for 24 hours. Thus we speculated that inhibition of autophagy might contribute to the accumulation of TCF7 and further improve CAR-T maintenance. To further verify whether TCF7 was degraded in an autophagy-dependent manner, we next determined TCF7 turnover rates in the presence of cycloheximide (CHX) in CAR-T cells with or without SBI0206965 treatment. CHX chase assay showed that SBI0206965 treatment could slower the TCF7 degradation rate(Fig.2).
Significance: Our research provides a strategy to optimize CAR-T antitumor efficacy and persistence via TCF7 accumulation by autophagy inhibition.
αGal9Ab Treatment As a Novel Therapy for Blood Cancer
Authors: Lee Miyoung , Henry Curtis James 
Published: December 2023

Blood cancers are the most common cancer in children accounting for roughly 28% of all childhood cancers. Of these, acute lymphoblastic leukemia ( ALL) and acute myeloid leukemia ( AML) are the most prevalent. Advancements in treatment regiments for these diseases have led to a 5-year overall survival rate of 90% for pediatric ALL and 65~70% for pediatric AML; however, in patients with relapsed or refractory disease, the overall survival rates decline to 30~50% post-treatment.
We have recently demonstrated that antibody-mediated targeting of Galectin-9 ( GAL-9), is highly cytotoxic to human B-ALL cells in vitro and confers a significant degree of protection for disease progression in pre-clinical models of B-ALL (M. Lee et al., Nature Communications, 2022). In unpublished studies, we have subsequently found that anti-GAL-9 antibody ( αGAL-9Ab) treatment is highly cytotoxic to human T-ALL and AML cells. Notably, we have found that human pediatric cell lines are more sensitive to this treatment than those derived from adult patients. Mechanistically, we have uncovered a previously unreported link between GAL-9-mediated regulation of checkpoint kinase 1 ( CHEK1) and anti-apoptotic protein myeloid leukemia 1 ( MCL-1), with αGAL-9Ab treatment leading to a deregulation of both proteins in T-ALL cells. Notably, αGAL-9Ab treatment synergized with multiple CHEK1 inhibitorscurrently being tested in phase I or II clinical trials (GDC-0575, Prexasertib and PF477736) to enhance the in vitro killing of human T-ALL, B-ALL, and AML cells. Furthermore, using xenograft models, we found that single-agent αGAL-9Ab treatment was superior to single-agent chemotherapy and vehicle treatment at conferring protection against T-ALL progression.
In conclusion, single-agent αGAL-9Ab treatment appears to be cytotoxic against multiple acute leukemia subtypes ( ALs) and its efficacy is enhanced with CHEK1 inhibition. To validate this novel combinatorial approach for treating ALs, additional studies need to be performed to define the mechanisms of action and further pre-clinical experiments will be invaluable in determining the efficacy and safety of these therapies.
Effects of Air Pollution on Respiratory Events and Pain Crises Among Children with Sickle Cell Disease in New York City
Authors: De Aliva , Jung Kyung hwa , Davis Haley , Siddiqui Abeer , Kattan Meyer , Quinn James , Rundle Andrew G. , Lovinsky-Desir Stephanie , Green Nancy S. 
Published: December 2023

Introduction: Sickle cell disease (SCD) has the highest U.S. disease burden among Black and Hispanic populations, who more commonly live in urban areas with poor ambient air quality. The effect of air pollution exposure and social environmental factors on health outcomes in SCD have not been extensively studied, especially among children, and may further contribute to health disparities.
Objectives: This study aims to examine the associations between air pollution exposure and acute respiratory and pain events and to determine whether neighborhood-level social disadvantage would modify their associations.
Methods: We collected retrospective data on unscheduled outpatient visits, emergency department (ED) visits, and hospital admissions for respiratory events (i.e., respiratory tract infections, asthma exacerbation, acute chest syndrome) and vaso-occlusive pain crises requiring hospitalization (VOCs) for children with SCD in a tertiary care center in New York City (NYC) from 2015-2018. A total of 114 children with SCD (Table 1) were included in this study and had between 1-4 annual repeated measures of annual average air pollutants (i.e., black carbon (BC), fine particulate matter (PM 2.5), and nitrogen dioxide (NO 2)) with a total of 425 visits. Using home addresses, modeled data from the NYC Community Air Survey data were used to estimate street-level, annual average exposure to air pollution. The area deprivation index (ADI), a composite index of neighborhood-level social disadvantage, was dichotomized at the upper tertile (higher vs lower). Multivariable Poisson regression in generalized estimating equation (GEE) models were used to estimate relative risks (RR), after adjusting for potential covariates.
Results: Overall, there were no significant associations between air pollution levels and acute respiratory and pain events among children with SCD. When stratified by ADI, increased exposure to PM 2.5 and NO 2, but not BC, was significantly associated with more frequent respiratory outpatient and ED visits among children residing in higher ADI neighborhoods (RR (95%CI)= 1.13 (1.00, 1.28) and 1.43 (1.01, 2.02) for PM 2.5 and NO 2, respectively, p&lt;0.05 for all), but not among those in lower ADI neighborhoods (P-value for interaction=0.2 and 0.02 for PM 2.5 and NO 2, respectively) (Figure 1). Associations of air pollution with hospital admissions and VOCs were not observed for neither high ADI nor low ADI neighborhoods (p-value&gt;0.05).
Conclusions: Exposure to air pollutants increased respiratory complications among children living in deprived neighborhoods.
MRI Reliably Captures Bone Marrow Metrics in Myelofibrosis
Authors: Robison Tanner , Levinson Annabel , Lee Winston , Pettit Kristen Marie , Malyarenko Dariya , Johnson Timothy D , Chenevert Thomas , Ross Brian , Talpaz Moshe , Luker Gary 
Published: December 2023

Purpose
Biopsy remains the clinical standard for evaluating bone marrow of patients with myelofibrosis (MF). However, randomly sampling a small volume of bone marrow, typically from the ilium, fails to capture heterogeneity of disease across anatomic sites. The invasive, painful nature of the procedure limits patient acceptance of repeated biopsies to monitor disease status and response to therapy. Here, we present a non-invasive, MRI technique for evaluating bone marrow in MF.
Participants and Methods
We analyzed bone marrow of 66 study participants (45 with MF; 15 with essential thrombocytosis or polycythemia vera; and 6 healthy controls). We assessed participant bone marrow across three anatomic sites (vertebral bodies, ilium, and femoral heads), using three quantitative MRI sequences: proton density fat fraction (PDFF) for fat content; apparent diffusion coefficient (ADC) for cellular effect on water mobility; and magnetization transfer (MT) for macromolecular structure and fiber deposition. We correlated these MRI metrics with patient prognosis (dynamic international prognostic scoring system; DIPSS) and iliac biopsy data for cellularity and fibrosis (MF grade).
Results
Participants with MF had elevated MT ratio (MTR) and ADC and lower PDFF compared to healthy participants. Non-MF MPN participants demonstrated the same trend, though to a lesser extent. Individual MRI metrics correlated strongly across anatomic sites (r pearson from 0.57 to 0.89, p-value &lt; 0.01), with notable heterogeneity both within and among different regions. DIPSS risk groups had limited correlation with MRI metrics. To understand to what extent quantitative MRI biomarkers identify fibrotic marrow, we developed a multivariate logistic regression model to stratify the 45 participants with MF by early fibrosis (MF grades 0-1) and overt fibrosis (MF grades 2-3). Of the seven total anatomy-MRI metric combinations, three had the greatest contributions toward grading marrow fibrosis: PDFF in the vertebral bodies and ilium along with ADC in the ilium. We developed the logistic regression model to predict early and overt fibrosis with these three parameters using a 70%/30% train/test split with 5-fold cross validation. Based on this model, quantitative MRI metrics are associated with the severity of fibrosis in the bone marrow (test set performance: accuracy = 84.6%, sensitivity to predict overt fibrosis = 88.9%, specificity = 75%, area under the receiver operator curve = 0.94).
Conclusion
Quantitative bone marrow MRI reliably captures relevant metrics of MF bone marrow, including cellularity and fat replacement by fibrosis, and may be useful in clinical drug trials and patient management for MF.
A Mutation in Complement Factor H (W1183R) Enhances VWF Proteolysis By ADAMTS13 Under Shear
Authors: Cao Wenjing , Liu Yi , Zhang X. Frank , Zheng X. Long 
Published: December 2023

Introduction: Complement factor H (CFH) is the primary negative regulator of complement activation in the alternative pathway in both fluidic phase and on cell surface. Loss of function of CFH such as W1183R is associated with atypical hemolytic uremic syndrome (aHUS). Homozygous mutation W1206R in the murine CFH, corresponding to W1183R in human CFH, results in acute aHUS. Interestingly, in these mice, while plasma VWF antigen levels are significantly increased, plasma VWF multimer size is markedly reduced in ADAMTS13-depedent manner. However, the molecular mechanism underlying such a dramatic effect of the mutant CFH (W1206R) on VWF multimer distribution is not known. The goal of this study is to determine how wild type CFH and mutant CFH W1183R affects VWF proteolysis under shear, and the mechanism of action.
Methods: Recombinant WT CFH, CFH W1183R, ADAMTS13, and VWF fragments were expressed in mammalian cells and purified to homogeneity. The effects of WT CFH or CFH W1183R on proteolytic cleavage of VWF73 peptide and full-length multimeric VWF were determined. Additionally, the binding and unfolding events were determined by micro scale thermophoresis (MST) and optical tweezer, respectively.
Results : WT CFH showed no effect on the cleavage of peptide VWF73 substrate, but CFH W1183R enhanced the proteolytic cleavage of VWF73 by ADAMTS13 in a dose-dependent manner ( Fig. 1). Counterintuitively, WT CFH appeared to inhibit the proteolytic cleavage of multimeric VWF by ADAMTS13 under arterial shear, but CFH W1183R exhibited an opposite effect, modestly enhancing the proteolytic cleavage of multimeric VWF by ADAMTS13 under the same conditions. The MST binding assay demonstrated that both WT CFH and CFH W1183R bind to a short A1, a long AIM-A1, and A1-A2-A3 fragments with a dissociation constant ( K D) of 6.4 x 10 -7, 3.0 x 10 -9 M, and 3.3 x10 -9 mol/L, respectively. These results suggest that CFH may bind to the AIM, A1-A2 junction, and A2 domain. To further assess the impact of CFH binding to A2, we performed optical tweezer experiments. The results showed that both WT CFH (Lc: from 27.4 nm at 12 nM to 40 nm at 1.0 mM) and CFH W1183R (Lc: from 26 nm at 12 nM to 31.8 nm at 1.0 mM) resulted in significantly extended contour length (Lc) of VWF-A2 domain in a concentration-dependent manner ( Fig. 2), suggesting a dramatic conformational change in the A2 domain upon binding by WT CFH or CFH W1183R.
Conclusions : Our results demonstrate that WT CFH at physiological concentrations may exhibit a modest inhibitory activity towards cleavage of VWF by ADAMTS13 under shear, but such an inhibitory activity disappears as the result of a point mutation in the C-terminal end of CFH (e.g., W1183R). Instead, the mutant CFH W1183R appears to enhance the VWF cleavage by ADAMTS13, likely through direct binding to the AIM, A1-A2 junction, and A2 domain of VWF, resulting in conformational changes in the central A2 domain.
Continuous Dosing of Apohemoglobin-Haptoglobin in Beta Thalassemic Mice to Establish Safety and Efficacy
Authors: Munoz Carlos J , Lucas Daniela , Muller Cynthia R , Martinez Jacinda , Govender Krianthan , Gopal Srila , Cabrales Pedro 
Published: December 2023

Thalassemia is a blood disorder that affects the production of hemoglobin (Hb), the crucial protein responsible for carrying and delivering oxygen to tissues. It is caused by mutations in the genes that control the production of hemoglobin, leading to decreased or absent production of one of the globin chains (alpha or beta) that make up hemoglobin. Individuals with thalassemia often need regular blood transfusions to maintain adequate Hb levels. However, frequent transfusions can cause iron overload in the body, necessitating chelation therapy to remove excess iron and prevent organ damage. The iron overload also results in higher levels of hemolysis, leading to the release of free acellular Hb and heme, which the body's natural scavenging proteins (hemopexin and haptoglobin) cannot effectively handle.
To address this problem, our research group has recently explored a promising solution using a bioengineered Hb and heme scavenger called apohemoglobin-haptoglobin (apoHb-Hp) complex. This complex works as a scavenger for heme and hemoglobin from the circulation, helping to eliminate vasoconstriction, enhance perfusion, and reduce inflammation. We conducted a study to test the safety and effectiveness of apoHb-Hp in beta-thalassemic mice, and the results were quite encouraging.
Initially, we treated twenty beta-thalassemic mice with different dosing regimens of apoHb-Hp, ranging from 25 to 100 mg/kg. The mice received the complex every other day for a total of three doses. After the final dose, we measured various parameters, including total bilirubin concentration, plasma LDH, and plasma iron. As the dosing amount increased, there was a progressive decrease in all three measurements, reaching a therapeutic plateau at 75 mg/kg.
In he second part of the study, we treated eight beta-thalassemic mice with a dose of 80 mg/kg of apoHb-Hp for six weeks, every other day. Again, we measured total bilirubin concentration, plasma LDH, and plasma iron, and observed a significant drop compared to baseline levels at the start of the study.
These promising results suggest that apoHb-Hp could be a safe and effective treatment option for beta-thalassemia. Its ability to scavenge heme and Hb, along with its positive effects on various markers, makes it a potential game-changer in the management of this genetic blood disorder. Further research and testing will be necessary to fully explore the potential of apoHb-Hp as a therapeutic option for individuals with beta-thalassemia.