bluuebunny/crossref_metadata_2025 huggingface dataset:
CAR-Tscm Cells As an Effective Immune Treatment to Multiple Myeloma Patients
Authors: Zhaoyun Liu , Fu Rong
Published: December 2024

Objective：

Since T memory stem cell (TSCM) is a kind of cell with strong self-renewal ability, long-term persistence, proliferation ability and anti-tumor activity, and is an ideal candidate cell for cancer immunotherapy. We aimed to explore the amount of TSCM cells in multiplt myeloma（MM） and the established a method to expansion TSCM in vitro, and to further explore the effect of CAR-T cells prepared by TSCM on MM cells.

Methods：

TSCM cells (CD45RA+CCR7+CD62L+CD95+) were detected with Flow cytometry, further induced TSCM cells expansion in vitro by using IL-2+MEKi+Il-15 combination, TSCM cell-based CAR-T cells were constructed in vitro, further the therapeutic effect of CAR-Tscm cells in MM-loaded NSG mouse model were explored.

Results：

The proportion of TSCM cells is reduced in patients with MM, but their function is stronger than that of CTL cells, and the use of IL-2+ Meki+Il-15 in vitro can induce the expansion of TSCM cells and promote their antitumor capacity; Further, Targeting BCMA CAR-Tscm cells as an effective immune treatment to multiple myeloma patients. CAR-T cells were constructed using TSCM cells in vitro, and in vitro experiments confirmed that they had similar killing effects to conventional CAR-T cells on MM cells in an NSG mouse model of MM tumor burden; CAR-Tscm cells were demonstrated to have similar effects to conventional CAR-T therapy, and demonstrated stronger antitumor effects than conventional CAR-T in contralateral tumorigenic models.

Conclusion：

CAR-Tscm cells are a potentially effective treatment for multiple myeloma.
Efficacy of Outpatient Haploidentical Transplantation in Patients with Refractory Hodgkin Lymphoma
Authors: Tejada Vasquez Ana Cristina , Gutierrez-Aguirre César Homero , Ugarte Pelaez Luis Paulo , Vega Mateos Antonio , Lopez-Garcia Yadith Karina , Garcia-Salas Gerardo , Colunga-Pedraza Perla R. Rocio , Gomez-De Leon Andres , Cantu Olga , Jaime-Pérez José Carlos , Gomez-Almaguer David
Published: December 2024

Background: Hodgkin lymphoma (HL) is a neoplasm potentially curable with first-line chemotherapy. For relapsed or refractory (R/R) patients, rescue chemotherapy and autologous transplant remain the standard. R/R patients face a poor prognosis, and haploidentical hematopoietic stem cell transplantation (haplo-HSCT) offers a potentially curative option.

Methods: A retrospective single-center analysis was performed in adults with R/R HL who underwent haplo-HSCT from 2015 to 2022. Conditioning was based on cyclophosphamide 350 mg/m² plus fludarabine 25 mg/m² for 3 days, followed by either melphalan 140-200 mg/m2 or busulfan 8 mg/m2, GVHD prophylaxis was given with cyclophosphamide 40mg/m2 at day +3 and +4 after infusion of CD34+. The primary outcome was overall survival (OS). Secondary endpoints included engraftment rates, infections, and transplant-related mortality (TRM). Progression-free survival (PFS) and graft-versus-host disease (GVHD) incidence.

Results: 17 patients were included, 52.9% (n=9) female and 47% (n=8) male, with a median age of 27 years (range: 11 to 62). Eight (47%) presented relapse after a previous autologous hematopoietic stem cell transplant (auto-HSCT). The average number of prior lines of treatment was 5 (range, 3-7). Conditioning included melphalan 140 mg/m² in 70% of patients, 200 mg/ m² in 18%, and busulfan 8 mg/m² (11%). The median CD34+x10^6kg infused was 10 million (3 - 16 x10^6). Engraftment of neutrophils and platelets occurred in a median of 14.6 (12-19) and 15 (12-23) days, respectively. The median follow-up was 18 months.

The 4-year OS was 62%, and the median OS was not reached. The 4-year PFS was 42%, with a median PFS of 17 months (95% CI 0-40). The incidence of aGVHD at 100 days was 58%, with the skin being the most frequent organ affected; 42% (n=8), and 18% presented chronic GVHD (cGVHD) during the year of follow-up. Five patients (29%) presented clinically significant infectious complications, including BK virus, cytomegalovirus infection, sepsis due to E. Coli ESBL, and invasive aspergillosis. Four patients relapsed (25%). TRM at 100 days was 23.52% (n=4).

Conclusions: The results highlight the effectiveness of haplo-HSCTin patients with refractory Hodgkin Lymphoma. A high incidence of aGVHD and cGVHD and infectious complications were documented. Haplo-HSCT transplant is a viable option for patients; however, it is essential to prioritize quality of life and minimize the toxicities associated with it. Additional studies are needed to optimize treatment protocols and management of long-term complications.
Public Health Insurance and Cancer-Specific Mortality Risk Among Patients with Lymphoma:a Prospective Cohort Study in Chongqing, Southwest China
Authors: Xiao Chunyan , Zhao Yulan , Ding Yao , Zeng Chensi , Zhang Lingqian , Nan Yingyu , Lei Haike , Liu Yao
Published: December 2024

Objective: Lymphoma, comprising Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL), is one of the common cancers worldwide.Little is known about how health insurance policies and self-paying rate influence lymphoma prognosis. Here, we examined the association between individual health insurance status and lymphoma-specific mortality in China.

Materials and Methods: A prospective longitudinal cohort study was conducted in Chongqing University Cancer Hospital, China from 2015 to 2021.The health insurance plan of patient was classified as either urban resident-based basic medical insurance (URBMI) or urban employee-based basic medical insurance (UEBMI) and was also categorized as self-paying rate (ie, the non-covered/ total charge) below or above the median.lymphoma-specific mortality was the primary outcome.After following the inclusion and exclusion criteria, the chi-square test was used to describe the demographic and clinical characteristics of patients with different insurance types and different self-paying rates. Multivariate logistic regression was used to analyze the relationship between patients with different insurance types, self-paying rates, and lymphoma treatment methods. Finally, the Cox proportional hazard model and the competitive risk model are used to calculate the cumulative hazard ratio of all-cause death and lymphoma-specific death for different insurance types and different self-paying rate groups.

Results:After following the inclusion and exclusion criteria, we included 2947 patients first diagnosed with lymphoma.We found that no matter patients received URBMI or UEBMI, they all more received treatment at the lymphoma later stage. After adjusting for clinical features and lymphoma treatment, compared with patients with insufficient self-paying rate, patients with a higher self-paying rate had a 54% lower risk of lymphoma-specific death (HRs = 0.460, 95%CI: 0.358-0.593, P < 0.001). Every 10% increase in self-paying rate of URBMI reduces the risk of lymphoma-specific death by 19.7%, while every 10% increase in self-paying rate of UEBMI reduces the risk of lymphoma-specific death by 30.2%.

Conclusions: Underinsured and poor patients face a higher risk of lymphoma-specific mortality in china.The National Medical Security Administration should, under the condition of limited medical insurance funds, try to include the original self-paid innovative anti-tumor drugs and Outpatient examinations into the national medical insurance coverage, at the same time, address the high cost of new anticancer medicines is urgent.This can not only reduce the mortality rate of lymphoma patients, but also reduce the family burden of lymphoma patients.
SHMT2-Folate-Folate Receptor Axis Impaired Erythropoiesis in Myelodysplastic Syndrome
Authors: Yang Chaoying , Li Haobo , Wang Yanpeng , Nie Ling , Wang Zeyuan , Guo Zhiming , Han Xu , An Xiuli , Liu Jing , Zhang Ji
Published: December 2024

Myelodysplastic syndromes (MDS) are a group of heterogeneous clonal bone marrow diseases with a high risk of progressing to acute myeloid leukemia. Current therapies for MDS patients include bone marrow transplantation and hypomethylation chemotherapy, however, since MDS is very common in elderly people, many patients cannot tolerate transplantation related complications or acquire drug resistance, making it urgent to develop novel therapy. Abnormal metabolic regulation had been reported to be involved the pathogenesis of many diseases including MDS, but the underlying mechanisms are not fully characterized.

To explore underlying mechanisms and develop novel therapy to treat MDS, we utilized NUP98-HOXD13 knock-in mice which was a well-known MDS mouse model. We purified bone marrow lineage negative cells from MDS and control mice and performed RNA sequencing. After data processing, we found SHMT2 was dramatically up regulated in MDS mice. SHMT2 involved the one-carbon unit cycling and regulated the contents of glycine, serine and folate. Followed metabolomic profiling showed that, only folate, but not glycine and serine, was significantly increased in MDS mice. Furthermore, SHMT2 expression and folate were also significantly increased in MDS patients compared to the healthy cases. These findings indicated that increased SHMT2 expression and overloaded folate may involve MDS pathogenesis. Indeed, high folate diet or folate intraperitoneal injection decreased red blood cell (RBC) number and hemoglobin content, inhibited bone marrow erythropoiesis and shortened the survival of wild mice. And folate intraperitoneal injection into the MDS mice exacerbated anemia symptom. More importantly, using the CRISPR/Cas9 technique and bone marrow transplantation assay, we found that knock-out SHMT2 in MDS mice decreased folate content and alleviated MDS phenotypes. Through a series of assays, we further found that high dose of folate binds to folate receptor 2 (FOLR2) and leads its translocation from membrane to nucleus where FOLR2 regulated gene expression as a transcription factor. FOLR2 up-regulated IRF2 and IRF2BP2 expression levels and inhibited normal erythropoiesis.

Taken together, our findings demonstrated that SHMT2-folate-folate receptor axis inhibited erythropoiesis in MDS, and targeting SHMT2 had therapeutic effectiveness for MDS treatment. Our findings also provided more comprehensive understanding on the relationship between folate and erythropoiesis.
Post-COVID-19 Infant with a Hemizygous PRF1 Mutation and Overlapping Features between MIS-C and Hemophagocytic Lymphohistiocytosis
Authors: Janssen Jesslyn , Nwachukwu Chiamaka , Falcon Corey Paul
Published: December 2024

Hemophagocytic lymphohistiocytosis (HLH) is a rare but life-threatening disorder that requires a high index of suspicion and comprehensive evaluation for timely recognition. Its rarity, diverse clinical manifestations, and overlapping symptoms with other hyperinflammatory syndromes, such as the recently emerged Multisystem Inflammatory Syndrome in Children (MIS-C) during the COVID-19 pandemic, present unique diagnostic challenges.

Herein, we report the case of an 8-month-old infant initially suspected of MIS-C following acute liver failure after COVID-19 exposure. The diagnosis was later revised to secondary HLH with an atypical presentation. Despite initial management for MIS-C, the patient's condition deteriorated, prompting further investigation. Laboratory findings, including elevated ferritin levels, low fibrinogen, and worsening thrombocytopenia, suggested HLH, leading to targeted diagnostic evaluations. Genetic testing revealed a heterozygous PRF1 mutation, and additional laboratory investigations showed markedly elevated IL-2 receptor and CXCL9, with decreased CD107a and perforin expression in NK cells. The patient met four out of five diagnostic criteria for HLH. Treatment with intravenous immunoglobulin (IVIG) and high-dose steroids resulted in significant clinical improvement, and the patient has remained symptom-free since the episode.

This case highlights the diagnostic challenges in differentiating hyperinflammatory syndromes in pediatric patients with COVID-19 exposure. It underscores the importance of considering HLH in the differential diagnosis, even when standard HLH diagnostic criteria are not fully met at presentation and when standard treatments fail in patients suspected of having MIS-C. Given the frequent occurrence of atypical HLH presentations, early evaluation for HLH is crucial in children with hyperinflammation, such as MIS-C, especially when patients exhibit hyperferritinemia, hypofibrinogenemia, cytopenia, acute liver failure or are unresponsive to MIS-C treatment. Thorough assessment and careful consideration are essential to prevent misdiagnosis or delayed recognition of HLH, a condition that can result in severe outcomes, including death. Multidisciplinary collaboration is vital to optimize HLH diagnostic strategies and improve patient outcomes. Further research is needed to elucidate the clinical relevance of heterozygous mutations of HLH-associated genes in HLH and MIS-C.
Impact of Sglt-2 Inhibitors on Sickle Cell Disease Patients with Type 2 Diabetes: A Retrospective Matched Cohort Study
Authors: Nawab Athar , Ivers Lauren , Rizwan Umer , Shafique Nouman
Published: December 2024

Introduction: Sickle cell disease (SCD) is associated with an increased risk of chronic kidney disease (CKD), with 12% of patients developing CKD by a median age of 37 years in one large 40 year longitudinal study. Glucagon-like peptide-1 (GLP-1) agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors have demonstrated reno-protective benefits in type 2 diabetes mellitus (T2DM) and CKD, but their efficacy in SCD nephropathy is not well studied. A retrospective analysis of 7 SCD patients with T2DM found observed treatment with GLP-1 agonists or SGLT-2 inhibitors improved estimated glomerular filtration rate (eGFR) slope, but increased the rate of vaso-occlusive pain episodes (VOEs). Additionally, a large placebo-controlled study showed that empagliflozin increased hemoglobin (Hgb) levels in patients with T2DM, but no SCD. In the previous study, serum erythropoietin (EPO) levels were found to be inappropriately normal or increased in all 27 patients with EPO tested, with a median of 10.3 mIU/mL (6.1-37.3 mIU/mL)

Methods: Using a large federated network database, we identified 75 patients with SCD and T2DM. Less than 20 patients had CKD. For our control group, we had 2,366 patients with SCD and T2DM, who were not on SGLT2 inhibitor therapy. There were 1,754 patients with CKD in this group. In this retrospective study, we matched 65 patient in SGLT2 cohort to 65 control group patients based on sex assigned at birth, age and co-morbidities including stage of CKD (if present), hypertension, obstructive lung disease and heart failure.

Results: We did not observe statistically significant differences in the risk of progression or development of CKD. Similarly, we observed no significant difference in proteinuria, A1c and microalbuminuria between the two groups when comparing mean lab-values on student t-test. However, patients on SGLT-2 inhibitors had significantly higher mean Hgb levels (12.459 g/dL) compared to controls (10.358 g/dL; p<0.0001).

Discussion: Putative mechanisms for this erythrocytosis include increased erythropoietin production, modulation of iron metabolism, and hemoconcentration. The inappropriately normal or increased EPO levels observed in previous study support the role of EPO in the erythrocytosis associated with SGLT-2 inhibitor therapy. The observed increase in Hgb levels in SCD patients with T2DM treated with SGLT-2 inhibitors could potentially increase the risk of VOEs, as seen in a previous small study. Further research is needed to elucidate the risks and benefits of SGLT-2 inhibitor therapy on SCD-related nephropathy.
Evaluating Daratumumab Effectiveness in Relapsed/Refractory Multiple Myeloma: A Meta-Analysis of Clinical Outcomes and Prognostic Indicators
Authors: Shah Vedant , Fernandes Bolivia Crocete Aloysia , Ali Muhammad Ashar , Shah Abhi , Patel Kaushal , Mansabdar Aditya , Alla Arya , Panchal Viraj , Cheriyath Pramil
Published: December 2024

Introduction: Daratumumab, a human IgG monoclonal antibody against CD38 has direct and indirect antimyeloma activity. Daratumumab monotherapy in heavily pretreated patients with multiple myeloma has shown substantial efficacy. We conducted a meta-analysis to demonstrate its efficacy in combination therapy in patients with relapsed or refractory multiple myeloma focusing on clinical outcomes and prognostic factors.

Methods: A comprehensive search was carried out in PubMed, Cochrane and Clinicaltrials.gov using the following MeSH terms: “daratumumab” or “Darzalex” and “multiple myeloma” from 2000 to 2024. Studies comparing daratumumab with combination therapy versus combination therapy alone were taken into consideration. Mantel-Haenzel formula was used to calculate the pooled risk ratio (RR), and Generic Inverse Variance method was used to assess pooled hazard ratio for disease progression in RevMan version 5.4 at 95% confidence interval (CI). P value <0.05 was considered to be significant.

Result: We analyzed 7 phase-III RCTs including 2048 patients. The hazard ratio for progression or death with daratumumab group versus control was significantly lower (HR= 0.44; 95% CI= 0.33 to 0.60; p<0.00001). The RR of overall response rate (ORR) was higher in daratumumab group versus control (RR= 1.25; 95% CI= 1.16 to 1.34; p<0.00001), as were the rates of complete response (CR) (RR= 2.49; 95% CI= 1.91 to 3.24; p<0.00001), very good partial response (VGPR) (RR= 1.64; 95% CI= 1.44 to 1.87; p<0.00001). In terms of prognostic factors, the rate for minimal residual disease (MRD)-negativity rate was also higher for the daratumumab group compared to the control group (RR= 5.32; 95% CI= 3.73 to 7.58; p<0.0001).

Conclusion: Daratumumab affects diverse facets of multiple myeloma and has shown a favorable efficacy in patients with relapsed or relapsed and refractory multiple myeloma. In combination therapy, daratumumab resulted in significantly prolonged disease progression, improved clinical outcomes and prognostic factors through increasing MRD-negativity rates.
ALL-R: An Anchoring Score to Predict Relapse in Acute Lymphoblastic Leukemia (ALL) Using a Zebrafish Patient-Derived Xenograft Model
Authors: Arner Anja , Blaser Bradley Wayne , Ettinger Andreas , Schmid Bettina , Jeremias Irmela , Binder-Blaser Vera
Published: December 2024

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Prognosis after initial diagnosis is good; however, patients suffering from relapse have a poor outcome. The tumor microenvironment is recognized as an important factor for disease relapse but little is known about the molecular mechanisms that are involved in this process.

To study microenvironment-mediated mechanisms of relapse development in ALL, we established a larval zebrafish xenotransplantation model that allows the analysis of Leukemic cells (LCs) within an orthotopic niche using time-lapse confocal microscopy.

LCs from ALL patients experiencing early relapse (ER) or no relapse (NR) collected at the time of initial diagnosis were transplanted into zebrafish embryos. LCs homed, engrafted and proliferated within the caudal hematopoietic tissue (CHT), the hematopoietic niche at the larval stage. Migration patterns within the CHT area were quantified over 12-24 hours in a semi-automated workflow. ER-LCs migrated significantly slower compared to NR LCs (12% reduction in frame-to-frame velocity). Maximum distance traveled by ER-LCs within the niche was significantly less (by 13%), compared to NR LCs. In addition, total displacement was significantly decreased by 17 % for ER-LCs, altogether indicating more restricted movement of ER LCs within the niche, and suggesting the presence of important cell-cell interactions. An anchoring score (ALL-R score) was developed to quantify the migration behavior based on velocity, maximum distance traveled, displacement, confinement ratio and straight-line speed. The ALL-R score for ER patients was significantly higher compared to that for NR patients (Mann-Whitney test, p≤0.01).

These findings suggest the application of the ALL-R score as a relapse-prognostic factor in ALL at the time of initial diagnosis.

To understand the molecular basis for these potential interactions, we performed single cell RNA-sequencing on the ER and NR samples used in the study. Gene expression profiling of LCs and monocytes in ER and NR patients revealed: 1) ER LCs were enriched for expression of adhesion molecules such as CXCR4 (log2fc 2.012288; P-value 0.030) compared to NR LCs, 2) predicted cell-cell interactions (using CellChat) were strongest between ER LCs and ER monocytes and 3) MIF-CD74/CXCR4 and CD99-PILRA were the top-scoring ligand-receptor pairs between these groups of cells.

These data suggest that early relapse in ALL may be related to enhanced LC-niche interactions via specific monocyte signaling pathways. Ongoing work is evaluating whether disruption of these pathways might be beneficial to prevent relapse in ALL.
Outcomes of Immune Thrombocytopenia in Patients with Conditions Linked to Higher Autoimmunity Risk: A National Inpatient Sample Analysis (2016-2020)
Authors: Idoate Domench Daniel , Vijay Rao Aniket , Sanjeevi Aditya
Published: December 2024

Objective: Immune thrombocytopenia (ITP) is an acquired hematological disorder that occurs when the body produces antiplatelet antibodies that bind to circulating platelets, leading to their destruction. This study aims to analyze outcomes of ITP hospitalizations in conditions with increased risk of autoimmunity, using data from the National inpatient sample (NIS) database from 2016 to 2020.

Methods: Data regarding patients demographics, comorbidities and hospital outcomes was obtained from the NIS database 2016-2020, using international classification of diseases (ICD) code, for hospitalizations related to ITP in patients with conditions associated with a higher risk of autoimmunity, including Rheumatoid Arthritis (RA), Systemic Lupus Erythematosus (SLE), Sjogren's Syndrome, Myasthenia Gravis, and Common Variable Immune Deficiency (CVID), as well as in those with Hodgkin Lymphoma, Non-Hodgkin Lymphoma, and Pregnancy. In order to compare the baseline demographics and hospital outcomes, Pearson Chi-square test was used for categorical variables and student T-Test or one-way ANOVA was used for continuous variables, with non-parametric alternatives applied when appropriate. Significance was set at <0.05.

Results: A total of 6,060 patients with ITP and conditions associated with a higher autoimmunity risk were analyzed: SLE (49.50%), RA (18.73%), Sjogren's (8.09%), Myasthenia Gravis (1.24%), CVID (4.04%), Hodgkin Lymphoma (3.05%), Non-Hodgkin Lymphoma (14.60%), and Pregnancy (0.74%). Non-Hodgkin lymphoma had the highest proportion of older patients while SLE and Sjogren were the groups with the highest number of females. SLE was the only group with a higher percentage of African-Americans (41.65%) compared to Whites (31.50%). Regarding outcomes, the highest in-hospital mortality was among Hodgkin Lymphoma (2.70%, p=0.011), while the highest risk of respiratory failure was among non-Hodgkin lymphoma patients (5.08%, p<0.001). The highest number of major bleeding events (30%, p<0.001) and use of IVIG (24.50%, p=0.0009) was among SLE patients. There were no significant differences in the use of PLEX (p = 0,091) between groups. Hospitalization costs and length of stay were significantly higher for Hodgkin Lymphoma ($23,855.80, 4 days, p<0.001), followed by Non-Hodgkin Lymphoma ($19,379.93, 4 days).

Conclusion: This study highlights significant differences in outcomes for ITP patients with conditions that increase the risk for autoimmunity. Lymphoma patients had the highest in-hospital mortality, risk for mechanical ventilation, as well as the highest hospitalization costs and length of stay, while major bleeding was significantly more common among SLE patients. Further research is needed to assess the potential implications of these different conditions and the role they play in ITP outcomes.
Antitumour Effects of Human Antithymocyte Alobulin on Peripheral-T Cell Lymphoma Via Complement-Dependent and -Independent Cytotoxicity in Xenograft Mouse Models
Authors: Gao Beibei , Hu Jiong , Yan Jinsong
Published: December 2024

Background

Peripheral T-cell lymphomas (PTCL) is a group of non-Hodgkin lymphomas characterised by substantial molecular heterogeneity, rapid progression, poor therapeutic response, and unfavourable outcomes. In recent clinical studies, antithymocyte globulin (ATG)-based allogeneic-haematopoietic stem cell transplantation (allo-HSCT) has markedly improved the prognosis and survival of patients with PTCL. This study aimed to explore whether ATG has toxic effects on PTCL cells and evaluate whether ATG combined with chemotherapy has a synergistic antitumour effect.

Methods

The cytotoxicity and proliferative effects of ATG were tested with the CCK-8 assay and verified using the cell colony formation assay in Hut78, Karpas299, and SU-DHL-1 cell lines. After propidium iodide (PI) staining, the proportion of cells at different cell cycle stages was measured using flow cytometry to determine the impact of ATG on the cell cycle. Transwell assays were performed to examine the effect of ATG on PTCL cell invasion. The apoptotic effects induced by ATG in PTCL cells were evaluated from three aspects, including fluorescein isothiocyante annexin-V/PI detection, mitochondrial membrane potential (∆Ψm) analysis with JC-1, and apoptosis-specific morphological changes. BALB/C-nu/nu mice were used to establish a PTCL cell-induced subcutaneous tumour model to investigate the chemotherapeutic effect of ATG and its synergistic effect with anthracycline.

Results

ATG significantly inhibited PTCL cell growth by suppressing cell proliferation and colony formation. Moreover, ATG treatment decreased cell invasion; however it had no effect on cell cycle arrest in PTCL cells. ATG induced PTCL cell apoptosis, which was partially reversed by pan-caspase inhibitor and caspase 8 inhibitor. Additionally, ATG was able to induce complement-dependent cytotoxicity in PTCL cells. Most importantly, the combination of ATG and doxorubicin exhibited enhanced effectiveness against PTCL cells both in vitro and in vivo, suggesting that ATG can exert a synergistic antitumour effect when administered with doxorubicin.

Conclusion

ATG can exert cytotoxic effects in PTCL cells by activating the caspase-dependent apoptotic pathway and complement-dependent cytotoxicity and can exert a synergistic antitumour effect when combined with traditional anthracyclines in vitro and in vivo. This study provides a scientific basis for the clinical application of ATG for PTCL treatment.
In Vivo CAR Delivery As Supercoiled DNA with Polyasparagine Nanoparticles
Authors: Lee Claudia Y , Zhang Grig , Coker Chris Y , Zheng Sisi
Published: December 2024

Background

Strategies for in vivo reprogramming of immune effector cells have been proposed in the hope to recapitulate the success of ex vivo engineered chimeric antigen receptor t cells (CAR-T) while reducing the manufacturing burden, improving the safety profile and recruiting collaborating immune cell types to expand the appliable indications. Viral and non-viral vectors with tissue tropism selected for in vivo reprogramming applications have been attempted, and the efforts to fully address the off-tissue delivery safety concerns for viral vector and a clinically viable dosing scheme to demonstrate efficacy with the brief durability of mRNA in non-viral vectors continue.

Methods

We deploy CAR encoded in supercoiled DNA formulated with multi-arm polyasparagine nanoparticles (STAR). The physical characteristics, the stability, the molecular dynamics and the biodistribution of the DNA/polyasparagine polyplex were characterized. Anti-murine CD19 CAR expression, its durability and the efficacy as the result of the polyplex transfection were evaluated in vitro and in vivo in blood, livers, lymph nodes, spleen and lungs.

Results

The cationic STAR was found to have half-life of less than 24 hours in PBS, while the expression of the DNA payload sustained over one week. 40ug of DNA delivered by 125ug of STAR was tolerable in mice. The polyplex was found to transfect lymphatic tissue, primarily t-cells, following tail vein injection. The DNA encoding anti-murine CD19 CAR was able to achieve b cell ablation in mouse PBMC and in vivo.

Conclusions

We demonstrated a novel technology platform for in vivo CAR delivery.
Treatment Outcome & Complications of Patients with Chronic Lymphocytic Leukemia Treated at King Faisal Specialist Hospital & Research Center - Jeddah over a Decade. a Single Center Experience in the Kingdom of Saudi Arabia
Authors: Albeirouti Bassim T
Published: December 2024

Introduction: Over a decade, there was a significant change in the management of patients with Chronic Lymphocytic Leukemia (CLL) form the diagnostic & therapeutic prospective. The diagnostic approaches moved from flow cytometry based diagnosis toward molecular cytogenetic with molecular profiling and immunoglobulin heavy chain mutation analysis that defined the disease and treatment options that can be offered to CLL patients. At the same time, treatment choices moved from chemotherapy and chemo-immunotherapy (CIT) based therapies to B Cell Receptor (BCR) molecular targeted therapy with the main use of Bruton Tyrosine Kinase Inhibitors (BTKi); namely Ibrutinib & Acalabrutinib. Method: Retrospective analysis of treatment outcome and complications of patients with CLL diagnosed over a decade. IRB approval was obtained and there is no conflict of interest. Results: over a decade (2014 to 2024) 41 patients were identified with CLL, 16 women and 25 men, with a median age of 60-70. Of these 41 patients, 13 died (31%) 4 due Richter's Transformation (RT) (31% of died patient). 3 out of these 4 cases (75%) had RT post CIT and only 1 patient was on BTKi (Ibrutinib). 2 additional cases had RT while on observational stage, one had chemo (ABVD for Hodgkin's Lymphoma), while the other had Venetoclax plus R-CHOP followed by Allogeneic BMT and now he is on Ibrutinib for GvHD & CLL relapse prevention. Of these 41 patients 20 were treated with BTKi of Ibrutinib, but 8 patients (40%) were switched to Acalabrutinib due to different adverse events. Conclusions: CLL management changed dramatically
Inflammation-Driven NFκB Signaling Represses Ferroportin Transcription in Macrophages Via HDAC 1 and 3
Authors: Marques Oriana , Horvat Natalie , Zechner Laura , Colucci Silvia , Sparla Richard , Zimmermann Stefan , Neufeldt Christopher , Altamura Sandro , Ruiyue Qiu , Müdder Katja , Weiss Guenter , Hentze Matthias , Muckenthaler Martina U.
Published: December 2024

Anemia of Inflammation is a prevalent co-morbidity in patients with chronic inflammatory disorders.

Inflammation causes hypoferremia and iron-restricted erythropoiesis by limiting Ferroportin (Fpn)-

mediated iron export from macrophages that recycle senescent erythrocytes. Macrophage cell surface

expression of Fpn is reduced by hepcidin-induced degradation and/or by repression of Fpn (Slc40a1)

transcription via cytokine and Toll-like receptor (TLR) stimulation. While the mechanisms

underlying hepcidin-mediated control of Fpn have been extensively studied, those inhibiting Slc40a1

mRNA expression remain unknown. We applied targeted RNA interference and pharmacological screens in

macrophages stimulated with the TLR2/6 ligand FSL1 and identified critical signalling regulators of

Slc40a1 mRNA repression downstream of TLRs and NFкB signaling. Interestingly, the NFкB regulatory

hub is equally relevant for Slc40a1 mRNA repression driven by the TLR4 ligand LPS, the cytokine

TNFβ/LTA and heat-killed bacteria. Mechanistically, macrophage stimulation with heat-killed

Staphylococcus aureus recruits the Histone deacetylases (HDAC) 1 and 3 to the antioxidant response

element (ARE) located in the Slc40a1 promoter. Accordingly, pre-treatment with a pan-HDAC inhibitor

abrogates Slc40a1 mRNA repression in response to inflammatory cues, suggesting that HDACs act

downstream of NFкB to repress Slc40a1 transcription. Consistently, recruitment of HDAC 1 and 3 to

the Slc40a1 ARE following stimulation with heat-killed Staphylococcus aureus is dependent on NFκB

signaling. These results support a model in which the ARE integrates the transcriptional responses

of Slc40a1 triggered by signals from redox, metabolic and inflammatory pathways. This work

identifies the long-sought mechanism of Slc40a1 transcriptional downregulation upon inflammation,

paving the way for therapeutic interventions at this critical juncture.
Molecular Outcome of Chronic Myeloid Leukemia Affected Patients Not in Deep Molecular Response: The “Others” from the Gimema Labnet Network
Authors: Stagno Fabio , Cucci Rosalba , Marsili Giovanni , Castagnetti Fausto , Galimberti Sara , Izzo Barbara , Sorà Federica , Soverini Simona , Messina Monica , Piciocchi Alfonso , Bonifacio Massimiliano , Cilloni Daniela , Iurlo Alessandra , Martinelli Giovanni , Rosti Gianantonio , Fazi Paola , Vignetti Marco , Breccia Massimo , Allegra Alessandro , Pane Fabrizio
Published: December 2024

Introduction: CML is now managed as a chronic disease requiring both long-term treatment and close molecular monitoring in most patients. Evidence suggests that in a substantial number of patients (pts) who achieved a stable deep molecular response (DMR) TKI treatment can be safely discontinued. Therefore, treatment-free remission (TFR) is increasingly regarded as a feasible treatment goal in about 20% to 40% CML pts. Nevertheless, a proportion of pts with chronic-phase CML treated with TKIs still remain in stable major molecular remission (MR3) or less (MR2 only), do not achieve a DMR and therefore require long-term TKI therapy.

Patients and Methods: Hence, we focused our clinical attention on those CML pts not candidates for a TFR path, having achieved within 6 months, and further maintained, a stable MR3 or less (MR2) by investigating the large LabNet CML database, a network founded by GIMEMA in 2014. This network standardized and harmonized the molecular methodology among 51 laboratories distributed all over Italy for the diagnosis and the molecular residual disease monitoring.

Results: Out of 9,699 pts, 585 met study endpoints and achieved a MR2/MR3 within 6 months with a minimum follow up of 24 months. CML pts received frontline therapy as follows: 219 with IM, 133 with DAS and 233 with NIL. Within 24 months, 375 pts achieved a DMR (MR4, MR4,5), whereas 187 showed a stable MR2/MR3 response and 23 had some molecular fluctuations less than MR2. With the successive follow up > 24 months, 123 out of 187 (66%) achieved a DMR, 59/187 (32%) remained in stable molecular response and 5/187 (2.7%) lost the response. No difference was observed in achieving molecular responses by the three different TKIs. Among the MR2/MR3 cohort the median time to therapy switch was 37 months. Moreover, median observation time (OT) was 5.5 yrs for the total study group (585), 5.5 yrs for the DMR group (375), 5.4 yrs for the stable MR2/MR3 (187) and 4.8 yrs for the MR2 ones (23).

Conclusion: A MR2/MR3 stable response achieved within 24 months seems predictive of a good molecular outcome since 66% of these pts obtained a DMR in the successive follow up of 24 months of. Molecular fluctuations less than MR2, although in pts with a previous obtained MR3, might represent a reliable warning sign.
Elevated CD10ˉ G-MDSC-like Neutrophils Correlate with Non-Response and Poor Prognosis of CD19 CAR T-Cell Therapy for B-Cell Acute Lymphoblastic Leukemia
Authors: Zhu Jinli , Zhou Ji , Liang Xue , An Furun , Jiao Xunyi , Wang Huiping , Zhai Zhimin
Published: December 2024

Objectives: To explore the levels of CD10-CD14-HLA-DR-CD33+CD45+SSC+ (CD10- G-MDSC-like neutrophils, referred to as CD10- neuts) in patients with B-cell acute lymphoblastic leukemia(B-ALL) undergoing CD19 CAR T cell therapy ,and to assess their impact on the efficacy of CAR-T cell treatment. Methods: 44 B-ALL patients undergoing CD19 CAR T therapy and 47 healthy controls (HCs) were included. Peripheral blood sample before CAR T cells infusion was drawn to examine CD10- neuts level by flow cytometry. Three indicators used to reflect CD10- neuts levels including the percent of CD10- neuts in neutrophils (CD10- neuts/neutrophils), and in all nucleated cells (CD10- neuts/nucleated cells), and the absolute count of CD10- neuts. Then we analyzed the correlation of CD10- neuts levels with therapeutic response, relapse-free survival (RFS), overall survival (OS), and CAR T cells persistence time. Results: CD10- neuts/neutrophils, CD10- neuts/nucleated cells, and the absolute count of CD10- neuts were all higher than HCs (34.94% vs 3.07%, 12.18% vs 1.32%, 227.4/uL vs 82.79/uL, all p<0·01). Comparing CD10- neuts levels in non-response patients to remission patients, non-response patients had higher CD10- neuts/neutrophils (64.44% vs 25.43%, p=0·004), CD10- neuts/nucleated cells (28.61% vs 9.81%, p=0·018), and the absolute count of CD10- neuts (766.1/uL vs 152.9/uL, p=0.04). All three CD10- neutrophil indices predicted treatment response (AUC=0.816, 0.774, and 0.733, respectively), with high CD10- neuts/neutrophils (≥53.86%) identified as an independent risk factor. Otherwise, only CD10- neuts/neutrophils predicted both relapse and survival. The ROC curve determined the cutoff point, with patients having high CD10- neuts/neutrophils (≥21.57%) showing significantly shorter RFS compared to those with low CD10- neuts/neutrophils (3.2 months vs 14.5 months, p=0.001). Similarly, high CD10- neuts/neutrophils (≥21.57%) were significantly correlated with shorter OS, with the median OS for low CD10- neuts/neutrophils not reached (p=0.0002). Furthermore, CD10- neuts/neutrophils was an independent risk factor for both RFS and OS (HR=4.704, p=0.004; HR=6.417, p=0.001), and negatively correlated with CD19 CAR T-cell persistence time (r=-0·479, p=0·024). Conclusions: High frequency of CD10- neuts is correlated with poor response, shorter RFS and OS in CAR T therapy. CD10- neuts could influence the efficacy of CAR-T therapy and specific targeted CD10- neuts may be a desirable intervention to improve the outcome.
Global Trends of Burden of Chronic Myeloid Leukemia Based on Socio-Demographic Index (SDI): A Comparative Epidemiological Study
Authors: Chaulagain Prashant , Poudel Ashmita , Aryal Saurav , Sainatham Chiranjeevi , Lutfi Forat
Published: December 2024

Background:

The clinical outcome for patients with chronic myeloid leukemia (CML) has changed dramatically in the past two decades, especially after the rise of Tyrosine Kinase Inhibitors. Conversely, the outcome has been worse for countries with lower socioeconomic statuses. Comprehensive epidemiological research is warranted to evaluate the global burden of CML based on SDI.

Method:

Our team used data from the Global Burden of disease (GBD) 2021 database. The analysis was done using the Institute of Health metrics and evaluation (IHME) GBDx data tool. GBD estimated the burden of diseases, injuries, and risk factors for 204 countries and territories and selected subnational locations. Incidence, death, disability-adjusted life-years (DALYs), and its corresponding age-standardized rate between 1990 to 2021 were used to describe the distribution of CML burden according to age, sex, social-demographic index (SDI).

Results:

The incidence of CML globally in 2021 was 35830 .87(95%, 27938.95-42,581.45) as compared to 39481.75(95%, 33292.61- 45117.18) in 1990. The Estimated total percentage change in incidence has decreased in High SDI and High Middle SDI countries; however, it has increased in Middle, Low Middle, and Low SDI countries.

There were 29220.42 (95%, 23525.47-34250.55) deaths in 1990, distributed as 4% in Low SDI, 14% in Low Middle SDI, 21% in Middle SDI, 23% in high middle SDI and 38% in High SDI countries. Similarly, there were 23159.13(95%, 17502.80-28477.39) deaths due to CML in 2021. Deaths were distributed as 7% in Low SDI, 23% in Low Middle SDI, 28% in Middle SBI, 18% in High Middle SDI and 24% in High SDI Countries. The absolute change in the percentage of deaths decreased globally by -0.21 (-0.01 to -0.34). The absolute change in the percentage of death decreased in High SDI and high middle SDI countries and increased in Middle SDI, Low middle SDI, and Low SDI countries.

The Absolute Percentage Change in DALY in 2020 compared to 1990 decreased -0.36(95%, -0.14 to -0.50) globally. All categories of countries based on SDI had decreased DALY except Low SDI countries, which had an increased absolute change in DALY of 0.17.

Similar results were obtained when data was stratified by age and sex.

Conclusion

The disease burden of CML has decreased globally, especially in countries with higher SBI, in the past three decades. The increase in incidence and death rates was mainly observed in lower SDI countries. Increasing resources and aid to lower SDI countries can help to decrease the global burden of CML.
DLBCL in Older Adults: Is Age Just a Number in LMIC?
Authors: Ali Natasha , Iftikhar Raheel , Khan Zeeshan Ahmed , Ahmed Usman , Mahmood Humera , Aziz Zeba
Published: December 2024

Background and objective: Diffuse Large B-cell Lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma in adults. Limited data is available from low middle income countries (LMIC) in patients aged more than 60 years, with DLBCL. Our objective was to determine the presentation, comorbidities, socioeconomic status (SES), treatment received and outcomes of elderly patients with DLBCL.

Subjects and methods: We conducted a multi-centre, retrospective study from 2015 till 2023 and included all adult patients diagnosed with DLBCL. Patients aged more than 60 years were included in the analysis. The variables assessed were age, gender, ECOG status, SES, presenting signs and symptoms, and treatment received. Kaplan Meier curve was plotted for all patients. T-test was used to calculate comparative means and difference in overall survival (p value <0.05). SPSS version 29 was used to perform the analysis.

Results: A total of 652 cases of DLBCL were identified during the study period of which 154 (24%) patients were more than 60 years of age. The median age was 67 years. Male: female ratio was 1.3:1. Approximately 71% of our patients had ECOG performance scores between 2 and 3 and median IPI score of 3. The most common presenting symptoms were fever, weight loss and night sweats and 83% presented with advanced disease. Rituximab+CHOP (RCHOP) regimen was administered to 51% of patients. Relapse of disease was present in 24% who eventually received salvage treatment with either rituximab, ifosfamide, carboplatin, and etoposide (R-ICE), gemcitabine, cisplatin, methylprednisolone (GemP) or dexamethasone, high-dose cytarabine and cisplatin (DHAP). Approximately 65% of patients who received either first line or salvage chemotherapy were not fit enough to undergo consolidation with autologous transplant after achieving remission. In the limited resource group, 55% of patients had a median disease-free survival (DFS) of 0.4 years. In patients with enhanced resources (40%) the DFS was 1.3 years (p value 0.001). The overall survival (OS) was 0.5 years and 1.5 years in limited and enhanced resources group respectively (p value 0.002). Poor survival outcomes were related to multiple comorbidities, inability to give full dose chemotherapy and recurrent infections.

Conclusion: In 80% of the patients the most common presenting symptoms were fever, weight loss and night sweats. RCHOP was administered in approximately 50%. The DFS and OS were decreased in our cohort as compared to international literature. The OS and DFS was better in patients with enhanced as compared to limited resources group. However comorbidities, recurrent infections and poor performance status also contributed to decreased survival. The results suggest that age along with availability of resources play a vital role in management of DLBCL in LMICs.
Systematic Annotation of Secretory Pathway Genes As a Discovery Tool for New Therapeutic Targets in AL Amyloidosis
Authors: Saunders Brendan , Quetglas Carlos , Fasshauer Dirk , Elsasser Suzanne , Bianchi Giada
Published: December 2024

Background: FLC secretion drives pathogenesis in AL amyloidosis yet molecular mechanisms underlying the protein network supporting FLC secretion are uncharacterised and therapeutic strategies targeting them do not exist. Recently, The Protesotasis Consortium (Elsasser et al.) published a comprehensive annotation of the Human Proteostasis Network; however, genes involved in the vesicular transport system from transgolgi to cell membrane (terminal secretory pathway) were not included. We were interested in systematically annotating these genes to support therapeutic discoveries in AL amyloidosis and other secretory disorders.

Methods: Genes involved in the plasma cell secretory pathway were identified by two criteria: ‘entity-based’ and ‘domain-based’. ‘Entity-based’ inclusion involved genes previously annotated in literature to be involved in the secretory pathway. ‘Domain-based’ inclusion encompassed genes containing structural domains and motifs enriched in the secretory pathway. Twelve motifs were identified: AAA, Arf, C2/Mun, SNARE, NSR, Proppin, Ras, Rhomboid, Rint, SM, SNAP, ZW10; from which novel genes were incorporated.

Results: Using the approach above, we compiled a list of 1262 putative genes involved in the secretory pathway. Entity-based inclusions encompassed 1,087 genes while domain inclusion supplemented 175 genes. We organized these genes based on subcellular localization and function. We detailed 8 localization categories and 13 function categories. We constructed a map combining these 2 variables to obtain a tentative model of the terminal secretory pathway.

Conclusion: This is the first systematic effort to compile a comprehensive, task-oriented annotation of the terminal secretory pathway with the overarching goal to support basic and translational research efforts. Seen through the lens of AL amyloidosis research, this tool will be useful to develop novel treatments targeting light chain secretion to improve outcome for patients.