Bone Marrow Research Articles

RNF128 deficiency in macrophages promotes colonic inflammation by suppressing the autophagic degradation of S100A8

Macrophages play important roles in maintaining intestinal homeostasis and in the pathogenesis of inflammatory bowel diseases (IBDs). However, the underlying mechanisms that govern macrophage-mediated inflammation are still largely unknown. In this study, we report that RNF128 is downregulated in proinflammatory macrophages. RNF128 deficiency leads to elevated levels of effector cytokines in vitro and accelerates the progression of IBD in mouse models. Bone marrow transplantation experiments revealed that RNF128 deficiency in bone marrow cells contributes to the worsening of DSS-induced colitis. Mechanistically, RNF128 interacts with and destabilizes S100A8 by promoting its autophagic degradation, which is mediated by the cargo receptor Tollip. Moreover, the administration of an S100A8 neutralizing antibody mitigated the development of colitis and improved survival in DSS-treated Rnf128−/− mice. Overall, our study underscores the anti-inflammatory role of RNF128 in macrophages during the progression of colitis and highlights the potential of targeting the RNF128-Tollip-S100A8 axis to attenuate intestinal inflammation for the treatment of colitis.

Studying the Global Progress and Regulatory Landscape of Stem Cell Therapy Research

Objective: Stem cell therapy has emerged as a pioneering front in the biomedical domain, characterized by its rapid strides in innovation and progress. Such advancements hold profound implications for public health. Notably, Europe, the United States, Japan, and China have all crafted comprehensive regulatory frameworks to expedite the fruition of stem cell therapy. This article meticulously scrutinizes and evaluates the progression of clinical trials in cell therapy across major global jurisdictions. It delineates the trajectory of regulatory evolution in Europe, the United States, Japan, and China, and systematically collates the pivotal normative guidelines. This article is crafted with the intent to serve as a reference for regulatory agents, enterprises, and professionals in the field. Methods: Stem cell therapy, a paragon of innovative medical technology, heralds a new era of treatment possibilities for hitherto intractable diseases. It is more than just a benchmark of technological advancement; it represents a revolutionary shift in the pharmaceutical landscape. Since Dr.Thomas was awarded the Nobel Prize for his research on bone marrow transplantation in 1990, he has gradually moved from the laboratory to the clinical application stage, bringing new hope for treatment to patients. Stem cell therapy is a type of cell therapy. There are various types of cell therapy, which can be classified into stem cell therapy and immune cell therapy based on their cell sources. They can also be classified into autologous, allogeneic, and heterologous cells based on their donor sources. As a cutting-edge application technology in life science research, cell therapy has shown great therapeutic potential in various disease fields such as malignant tumors, genetic diseases, and chronic degenerative diseases. Multiple cell therapy products have been successfully launched and demonstrated excellent efficacy, among which stem cell therapy stands out due to its long application history and active research trend. Bone marrow/hematopoietic stem cell therapy is the earliest stem cell therapy, mainly used for bone marrow/hematopoietic stem cell transplantation to treat hematological malignancies such as leukemia. Human derived stem cells and their derived therapeutic products, as important regenerative medicine products, have great potential in cell replacement, tissue repair, disease treatment, and other fields. Nearly 70% of the stem cells used in clinical studies are hematopoietic stem cells and mesenchymal stem cells derived from bone marrow, peripheral blood, and umbilical cord. Technical methods include purification, in vitro culture and amplification, drug treatment, or gene modification. Immune cell therapy is a method of treating diseases using immune cells, which was originally mainly used to treat malignant tumors. According to the specificity of immune cell therapy, it can usually be divided into specific immune cell therapy and non-specific immune cell therapy. Specific immune cell therapy includes chimeric antigen receptor T-cell (CAR-T) therapy, T-cell receptor engineered T cell therapy, chimeric antigen receptor natural killer cell therapy (CAR-NK), and DC-CIK immunotherapy. Nonspecific immune cell therapy mainly includes lymphokine activated killer cell therapy and cytokine induced killer cell therapy. In addition, extracellular vesicles, as cell derivatives, have the advantage of non-living properties that are easier to characterize, store, package, and transport than living cells, and their research has shown explosive growth. Extracellular vesicle is a general term for lipid bilayer membrane-bound vesicles released by cells into the extracellular space, with a diameter range of 50-2,000 nanometers. Exosomes are extracellular vesicles with a diameter of 30-150 nanometers. At present, the Food and Drug Administration (FDA) has approved at least 8 extracellular vesicle products to enter phase II/III clinical trials. In recent years, the development of organoid technology, cell lineage tracing technology, single-cell spatial omics-sequencing technology, single-molecule technology, micro proteomics and proximity labeling technology has greatly promoted the progress of stem cell research and laid a good technical reserve for achieving functional organ reconstruction. Results: In the realm of emerging technologies, industry development often precedes regulatory frameworks. The swift progression of innovative stem cell therapy products not only propels medical innovation but also challenges existing regulatory technologies and institutions. Regulatory agencies must, therefore, continually innovate their strategies and technologies. Conclusion: Countries worldwide have crafted regulatory policies and technical evaluation systems tailored to their specific contexts. The variety of stem cell therapy types and applications defined by national regulations reflects this diversity. This article delves into the clinical research status of stem cell therapy through statistical analysis and dissects the regulatory frameworks governing it across nations, offering a valuable resource for stakeholders in this dynamic field.

α-Actinin-1 deficiency in megakaryocytes causes low platelet count, platelet dysfunction, and mitochondrial impairment

Cytoskeletal remodeling and mitochondrial bioenergetics play important roles in thrombocytopoiesis and platelet function. Recently, α-actinin-1 mutations have been reported in patients with congenital macrothrombocytopenia. However, the role and underlying mechanism of α-actinin-1 in thrombocytopoiesis and platelet function remain elusive. Using MK-specific α-actinin-1 knockout (PF4-Actn1-/-) mice, we demonstrated that PF4-Actn1-/- mice exhibited reduced platelet counts. The decreased platelet number in PF4-Actn1-/- mice was due to defects in thrombocytopoiesis. H&E staining and flow cytometry revealed a decrease in the number of MKs in the bone marrow of PF4-Actn1-/- mice. The absence of α-actinin-1 increased the proportion of 2 N-4 N MKs and decreased the proportion of 8 N-32 N MKs. CFU-MK colony formation, the ratio of proplatelet formation-bearing MKs, and MK migration in response to SDF-1 signaling were inhibited in PF4-Actn1-/- mice. Platelet spreading, clot retraction, aggregation, integrin αIIbβ3 activation, and P-selectin exposure in response to various agonists were decreased in PF4-Actn1-/- platelets. Notably, PF4-Actn1-/- platelets inhibited calcium mobilization, ROS generation, and actin polymerization in response to collagen and thrombin. Furthermore, the PF4-Actn1-/- mice exhibited impaired hemostasis and thrombosis. Mechanistically, proteomic analysis of low-ploidy (2-4 N) and high-ploidy (≥8 N) PF4-Actn1-/- MKs revealed that α-actinin-1 deletion reduced platelet activation and mitochondrial function. PF4-Actn1-/- platelets and Actn1 KO 293T cells exhibited reduced mitochondrial membrane potential, mitoROS generation, mitochondrial calcium mobilization, and mitochondrial bioenergetics. Overall, in this study, we report that mice with α-actinin-1 deficiency in MKs exhibit low platelet count and impaired platelet function, thrombosis, and mitochondrial bioenergetics.

Exosomes as promising frontier approaches in future cancer therapy

In this editorial, we will discuss the article by Tang et al published in the recent issue of the World Journal of Gastrointestinal Oncology . They explored an innovative approach to enhancing gemcitabine (GEM) delivery and efficacy using human bone marrow mesenchymal stem cells (HU-BMSCs)-derived exosomes. The manufacture of GEM-loaded HU-BMSCs-derived exosomes (Exo-GEM) has been optimized. The Tang et al ’s study demonstrated that Exo-GEM exhibits enhanced cytotoxicity and apoptosis-inducing effects compared to free GEM, highlighting the potential of exosome-based drug delivery systems as a more effective and targeted approach to chemotherapy in pancreatic cancer. Additional in vivo studies are required to confirm the safety and effectiveness of Exo-GEM before it can be considered for clinical use.

Molecular measurable residual disease before transplantation independently predicts survival and relapse risk in adult lysine methyltransferase 2a-rearranged acute myeloid leukemia.

Patients with lysine methyltransferase 2a (KMT2A)-rearranged (KMT2A-r) acute myeloid leukemia (AML) are assigned to intermediate-risk and adverse-risk categories at diagnosis. However, the value of molecular measurable residual disease (MRD) status in patients who have KMT2A-r AML before allogeneic hematopoietic stem cell transplantation (allo-HSCT) in adult cohorts has rarely been evaluated. Patients with KMT2A-r AML who achieved complete remission and subsequently underwent allo-HSCT between January 2015 and January 2023 were included in this analysis. Real-time quantitative polymerase chain reaction was used to detect molecular MRD in bone marrow samples. The end points were overall survival (OS), leukemia-free survival (LFS), the cumulative incidence of relapse (CIR), and nonrelapse mortality (NRM). Pretransplantation molecular MRD was identified in 52 of 125 patients (42%) with KMT2A-r AML. The presence of KMT2A-r MRD was associated with inferior 3-year OS (51% vs. 82%; p<.001), LFS (42% vs. 81%; p<.001), CIR (33% vs. 12%; p<.001), and NRM (11% vs. 5%; p=.12). In multivariate models, molecular MRD status before transplantation independently predicted OS, LFS, and CIR. Thesurvival of adult patients with KMT2A-r AML was heterogeneous, depending onthe KMT2A translocation partners, and was more favorable in patients who hadt(9;11) and t(10;11) than in those who had t(11;19) and t(6;11). In addition, flow cytometry-based MRD analysis conferred no additional prognostic value to the results of molecular MRD status. Residual KMT2A-r before allo-HSCT independently predicts the risk of survival and relapse, and donor lymphocyte infusion or posttransplantation maintenance therapies should be considered for patients who have AML with detectable molecular MRD.

Bone Marrow Adipocytes as Novel Regulators of Metabolic Homeostasis: Clinical Consequences of Bone Marrow Adiposity.

Bone marrow adipose tissue is a distinctive fat depot located within the skeleton, with the potential to influence both local and systemic metabolic processes. Although significant strides have been made in understanding bone marrow adipose tissue over the past decade, many questions remain regarding their precise lineage and functional roles. Recent studies have highlighted bone marrow adipose tissue's involvement in continuous cross-talk with other organs and systems, exerting both endocrine and paracrine functions that play a crucial role in metabolic homeostasis, skeletal remodeling, hematopoiesis, and the progression of bone metastases. The advancement of imaging techniques, particularly cross-sectional imaging, has profoundly expanded our understanding of the complexities beyond the traditional view of bone marrow adipose tissue as an inert depot. Notably, marrow adipocytes are anatomically and functionally distinct from brown, beige, and classic white adipocytes. Emerging evidence suggests that bone marrow adipocytes, bone marrow adipose tissue originate from the differentiation of bone marrow mesenchymal stromal cells; however, they appear to be a heterogeneous population with varying metabolic profiles, lipid compositions, secretory properties, and functional responses depending on their specific location within the bone marrow. This review provides an up-to-date synthesis of current knowledge on bone marrow adipocytes, emphasizing the relationships between bone marrow adipogenesis and factors such as aging, osteoporosis, obesity, and bone marrow tumors or metastases, thereby elucidating the mechanisms underlying musculoskeletal pathophysiology.

The effects of bone marrow humoral components of B-cell acute lymphoblastic leukemia patients on natural killer cell suppression.

B-cell acute lymphoblastic leukemia (B-ALL) is the most common form of cancer diagnosed in children. While the majority of patients survive with conventional treatment, chemotherapeutic agents have adverse effects and the potential for relapse persists even after full recovery. Given their pivotal function in anti-cancer immunity, there has been a surge in research exploring the potential of natural killer (NK) cells in immunotherapy, which has emerged as a promising avenue for treating leukemia. Nevertheless, the efficacy of NK cell immunotherapy is less pronounced than expected, which suggests the external conditions that affect NK cell functions after the administration to patients with leukemia. In this study, the effects of humoral components in the bone marrow humoral components of B-ALL patients on healthy NK cells were investigated. Healthy peripheral blood mononuclear cells were cultured with and without bone marrow-derived plasma samples of B-ALL patients. The expression of PD-1 and IL-10 were found to be increased whereas the proliferative capacities of NK cells were found to be decreased at the presence of B-ALL plasma samples. Moreover, high IL-10 versus low IL-18 levels were detected in bone marrow plasma samples of B-ALL patients. These findings indicate that humoral components in the bone marrow of B-ALL patients exert a suppressive effect on NK cell functions.

Panzerina lanata accelerates methicillin-resistant Staphylococcus aureus eradication by promoting migration and activation of neutrophils

BackgroundPanzerina lanata (Lanata) is generally used to treat pustule infection in Inner Mongolia folk medicine and is called “the holy medicine for pustule.” However, the pharmacological mechanism of Lanata in treating pustule infection is still unclear.AimsThis study aimed to investigate the therapeutic effects of Lanata on skin infection and explore the underlying mechanisms.MethodsA skin wound methicillin-resistant Staphylococcus aureus (MRSA) infection mouse model was established to evaluate the healing effect of Lanata on infected wounds. In vitro assays were also conducted to determine the antibacterial activity of Lanata. Flow cytometry and immunohistochemistry were used to dynamically detect the number of neutrophils in the bone marrow, peripheral blood, and MRSA-infected wound. Protein expression in the infected wound skin was detected by a protein chip. Using an air pouch MRSA infection mouse model, the number of neutrophils, reactive oxygen species (ROS) level in neutrophils, and neutrophil extracellular trap (NET) formation were dynamically detected by flow cytometry and immunofluorescence. RNA-seq, RT-qPCR, flow cytometry, ELISA, and CXC chemokine receptor 2 (CXCR2) and P-selectin glycoprotein ligand-1 (PSGL-1) inhibitors were used to explore the mechanism of Lanata in regulating neutrophils.ResultsIn vitro assays showed that Lanata had no direct antibacterial activity. In skin wound MRSA-infected mouse, Lanata promoted the rapid migration of neutrophils from the bone marrow via peripheral blood to the wound site to eradicate MRSA in the acute stage of infection and accelerate wound healing. Skin protein chip analysis showed that Lanata upregulated CXCR2 and PSGL-1 protein levels in skin wounds. Furthermore, analysis using the air pouch MRSA infection mouse model found that Lanata not only promoted the rapid migration of neutrophils from peripheral blood to the air pouch but also enhanced the activation of neutrophils, including the increase of ROS and the release of NETs, and upregulated the expression of CXCR2, PSGL-1, and myeloperoxidase (MPO) in neutrophils. Inhibition of CXCR2 and MPO significantly attenuated the effect of Lanata on promoting migration and activation of neutrophils.ConclusionPanzerina lanata resists MRSA infection by promoting migration and activation of neutrophils to rapidly eradicate MRSA.

Lactate accumulation promotes immunosuppression and fibrotic transformation of bone marrow microenvironment in myelofibrosis

BackgroundClonal myeloproliferation and fibrotic transformation of the bone marrow (BM) are the pathogenetic events most commonly occurring in myelofibrosis (MF). There is great evidence indicating that tumor microenvironment is characterized by high lactate levels, acting not only as an energetic source, but also as a signaling molecule.MethodsTo test the involvement of lactate in MF milieu transformation, we measured its levels in MF patients’ sera, eventually finding a massive accumulation of this metabolite, which we showed to promote the expansion of immunosuppressive subsets. Therefore, to assess the significance of its trafficking, we inhibited monocarboxylate transporter 1 (MCT1) by its selective antagonist, AZD3965, eventually finding a mitigation of lactate-mediated immunosuppressive subsets expansion. To further dig into the impact of lactate in tumor microenvironment, we evaluated the effect of this metabolite on mesenchymal stromal cells (MSCs) reprogramming.ResultsOur results show an activation of a cancer-associated phenotype (CAF) related to mineralized matrix formation and early fibrosis development. Strikingly, MF serum, enriched in lactate, causes a strong deposition of collagen in healthy stromal cells, which was restrained by AZD3965. To corroborate these outcomes, we therefore generated for the first time a TPOhigh zebrafish model for the establishment of experimental fibrosis. By adopting this model, we were able to unveil a remarkable increase in lactate concentration and monocarboxylate transporter 1 (MCT1) expression in the site of hematopoiesis, associated with a strong downregulation of lactate export channel MCT4. Notably, exploiting MCTs expression in biopsy specimens from patients with myeloproliferative neoplasms, we found a loss of MCT4 expression in PMF, corroborating changes in MCT expression during BM fibrosis establishment.ConclusionsIn conclusion, our results unveil lactate as a key regulator of immune escape and BM fibrotic transformation in MF patients, suggesting MCT1 blocking as a novel antifibrotic strategy.

Biomimetic Extracellular Vesicles Containing Biominerals for Targeted Osteoporosis Therapy.

Osteoporosis (OP) is a systemic skeletal disorder characterized by decreased bone mineral density and a heightened risk of fractures. Therapies for OP have primarily focused on balancing bone formation and bone resorption, but enhancing the remineralization of osteoporotic bone is also a key strategy for effective repair. Recent insights into biomineralization mechanisms have highlighted the essential role of mineral-containing extracellular vesicles (EVs) secreted by osteoblasts in promoting bone marrow mesenchymal stromal/stem cell (BMSC) differentiation and initiating matrix mineralization. Drawing from these principles, we developed a biomimetic approach to replicate the structure and function of the osteoblast-derived EVs by engineering biomimetic mitochondrial minerals with bone marrow homing cell membranes (CMs). This bone-targeted biomimetic system exhibits excellent biocompatibility, enhancing osteogenic differentiation and stimulating angiogenesis by regulating cellular energy metabolism. Additionally, the CM-coated structure shows affinity for collagen fibrils, effectively enhancing intrafibrillar collagen mineralization, thereby facilitating osteoporotic bone repair. Overall, the biomimetic system offers a safe and efficient therapeutic alternative, positioning it as a platform for bone tissue engineering and regenerative medicine.

How I Treat Anemia in Myelofibrosis.

Anemia is a common consequence of myelofibrosis. The treatment of myelofibrosis-associated anemia is complicated by a multifactorial pathobiology, as well as a lack of therapies that result in normalization of the bone marrow and complete restoration of its function. Established agents that are used to treat anemia in other bone marrow failure states such as myelodysplastic syndromes and aplastic anemia, are used for the treatment of myelofibrosis-associated anemia. However, there has been rapid development of new anemia-directed therapies; some of which have garnered regulatory approval. In addition to adopting therapies from other disease states, better understating of the root causes of myelofibrosis-associated anemia has positioned the field to be on the cutting edge of new anemia treatments, spearheading the advancement of agents that work on the hepcidin pathway to improve red cell production.

Leukemic Phase of ALK-Negative Anaplastic Large Cell Lymphoma Presenting as Leukostasis: The First Case Report in Thailand

Anaplastic large cell lymphoma (ALCL) is an aggressive T-cell lymphoma characterized by hallmark cells that are CD30-positive. ALCL is subcategorized as anaplastic lymphoma kinase (ALK)-positive and ALK-negative types. The leukemic phase of ALK-negative ALCL is extremely rare and usually has a poor prognosis. We report the first case of the leukemic phase of ALK-negative ALCL in Thailand. A 60-year-old man presented bilateral cervical lymphadenopathy and night sweats for 6 months. He was admitted to the hospital with acute fever, progressive dyspnea on exertion, severe headache and blurred vision. His complete blood count revealed marked leukocytosis (352.5 x 109/L) with numerous atypical medium- to large-sized mononuclear cells. The results of his laboratory investigations were compatible with spontaneous tumor lysis syndrome and disseminated intravascular coagulation. The flow cytometry analysis from bone marrow aspiration along with histopathologic findings and immunohistochemistry from bone marrow study were consistent with ALK-negative ALCL. The patient was treated with leukapheresis, renal replacement therapy and high-dose dexamethasone. After achieving hemodynamic stability, a computed tomography scan of the brain was performed due to persistent alteration of consciousness. The results showed extensive intracerebral hemorrhage with severe brain edema and tonsillar herniation. Due to this complication, the treatment plan was adjusted to palliative care with supportive treatment after discussion with his family. The patient subsequently passed away from septic shock.

Searching for the minimum required dose of daratumumab to induce effective plasma cell depletion in antibody-mediated rejection of the kidney graft: a case report.

There is no established treatment for late or chronic antibody-mediated rejection of a kidney graft. Rituximab-based treatment is not effective, since long-lived high-affinity plasma cells do not express CD20 and do not depend on previous maturation steps to generate donor-specific antibodies. Conversely, daratumumab, an anti-CD38 monoclonal antibody, directly targets plasma cells, with proven efficacy in multiple myeloma. Early reports in heart and kidney transplantation showed its efficacy in the setting of antibody-mediated rejection or desensitization. However, the dosage to beused was assumed to be the same as inmultiple myeloma treatment. We present the case of a patient with late antibody-mediated rejection, resistant to two cycles of rituximab-based therapy, who underwent a cycle of plasma exchange and intravenous gammaglobulins preceded and followed by only 2 doses of daratumumab. Bone marrow aspirate after the cycle demonstrated negativization of CD38 + cells, which was followed by negativization of the donor-specific antibodies and improvement of microinflammation at kidney biopsy. This suggests that the myeloma-like dosage used in previous reports may not be necessary for non-neoplastic diseases like antibody-mediated rejection. We propose a pragmatic approach, based on the assessment of bone marrow plasma cells after treatment, to avoid unnecessary side effects and optimize resources.

Venetoclax in combination with chidamide and azacitidine for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia with the MLL-AF4 gene: a case report and literature review

B-cell acute lymphoblastic leukemia (B-ALL) with the MLL-AF4 fusion gene has a poor prognosis, and the mortality rate exceeds 90%, particularly in cases of extramedullary relapse (EMR). Herein, we present a case of a 46-year-old male patient who developed relapsed B-ALL with MLL-AF4. The patient initially achieved a complete remission (CR) after induction therapy and underwent haploidentical hematopoietic stem cell transplantation. Five months post-transplantation, he developed enlarged lymph nodes and subcutaneous masses. A lymph node biopsy confirmed EMR, without leukemia in the bone marrow or peripheral blood. The patient received the VCA regimen (venetoclax, chidamide, and azacitidine) and was regularly monitored through blood counts, marrow cell morphology analysis, flow cytometry, and computed tomography or positron emission tomography-computed tomography imaging. After the first VCA course, the patient achieved a second CR with only transient myelosuppression. Following two VCA courses, he received chimeric antigen receptor T-cell therapy, which led to complete metabolic remission and improved prognosis. This case underscores the potential of the VCA regimen as a bridging therapy for EMR in B-ALL with MLL-AF4, although further studies are warranted.

Inferior Outcomes of Fludarabine–Cyclophosphamide–Rituximab Chemotherapy in Korean Chronic Lymphocytic Leukemia Patients with Concurrent Thrombocytopenia and Anemia

Background/Objectives: Anti-CD20 monoclonal antibodies combined with alkylator-based chemotherapy enhance survival in chronic lymphocytic leukemia (CLL). However, the risks of infection and bone marrow suppression may mean that new, targeted therapies are more appropriate for some patients than fludarabine–cyclophosphamide–rituximab (FCR). In the Republic of Korea, where insurance limits coverage to novel agents, FCR therapy should be carefully considered for patients with CLL. Methods: Using clinical data from 144 FCR-treated patients with CLL, we retrospectively analyzed clinical characteristics impacting survival outcomes, the impact of cytopenia after FCR, and the durable remission status in terms of measurable residual disease (MRD). We compared the impact of bicytopenia with those of other hematologic conditions. Results: The 5-year overall survival (OS) and 5-year progression-free survival (PFS) for all patients were 84.4% and 68.3%, respectively. FCR-treated patients in the bicytopenia and TP53-positive groups exhibited poor OS and PFS; in particular, the bicytopenia group often experienced prolonged anemia and thrombocytopenia (6–12 months). The responder group achieved sustained remission for a median of 5 years for MRD negativity. Conclusions: In bicytopenia, FCR can induce prolonged cytopenia, making it difficult to switch to second-line therapy or complete cycles of chemoimmunotherapy, directly affecting poor survival outcomes. The cautious application of FCR therapy in CLL without bicytopenia or TP53 positivity can achieve long-term remission.

The dynamic effects of nutritional status on chemotherapy-related toxicity in patients with non-Hodgkin's lymphoma.

Understanding the dynamic changes in nutritional status of patients with non-Hodgkin's lymphoma (NHL) during chemotherapy is crucial, as it significantly impacts chemotherapy-related toxicity and survival outcomes. This multi-center study included newly diagnosed NHL patients. Nutritional status and chemotherapy-related toxic effects were assessed over the first five chemotherapy sessions, with follow-ups conducted every 3 months. Patients were categorized into three groups based on pre-chemotherapy Patient-Generated Subjective Global Assessment (PG-SGA) scores: Group A (0-1), Group B (2-8), and Group C (>9). Repeated-measures ANOVA and Generalized Estimating Equations (GEE) models were used for analysis, with survival outcomes evaluated via Kaplan-Meier and Cox regression. A total of 143 patients (mean age 50.26 ± 15.02 years) completed the study, over a median follow-up of 18.8 months. PG-SGA scores were highest in Group C during chemotherapy (P < 0.001), with significant time-group interaction effects (P < 0.001). Liver and kidney impairments worsened across all groups (P < 0.05), while gastrointestinal toxicity and bone marrow suppression initially decreased before increasing. GEE analysis showed that nutritional status positively influenced gastrointestinal toxicity (β = 0.05, P = 0.001) and bone marrow suppression (β = 0.04, P = 0.014). Malnourished patients exhibited worse pulmonary infection-free survival and overall survival (P < 0.05). NHL patients are highly susceptible to malnutrition during chemotherapy, which exacerbates chemotherapy-related toxicities, particularly gastrointestinal effects and myelosuppression. Maintaining good initial nutrition is vital for reducing toxicities and improving survival outcomes.

Decreased STING predicts adverse efficacy in bortezomib regimens and poor survival in multiple myeloma

PurposeSTING (stimulator of interferon genes) is involved in viral and bacterial defense through interferon pathway and innate immunity. Increased susceptibility to infection is a common manifestation of multiple myeloma (MM). Thus, we aimed to explore the clinical significance and possible mechanism of STING in MM.Materials and methodsImmunohistochemistry and qPCR were used to detect STING expression in the bone marrow of MM patients, and flow cytometry was used to detect the amount of intracellular STING. All data were analyzed with clinical characteristics.ResultsSTING expression was remarkably reduced in MM tissues compared to normal tissues and was not associated with stage. Multivariate analysis identified STING as an independent prognostic factor in MM patients (P = 0.001). In the bortezomib-containing regimens, patients with low STING expression were more difficult to achieve remission. A model incorporating STING and m-SMART significantly improved the predictive accuracy of overall survival in bortezomib regimens (AUC, 0.511 to 0.630, P = 0.044). Bortezomib efficacy has been reported to correlate with activated immunity, but the low expression group manifested as immune apathy. Although baseline characteristics showed intergroup differences in infection, the low expression group had an increased proportion of bacterial infections (1.7-fold) and a prolonged duration of antibiotic/antifungal medication (3.55 additional days); these patients were accompanied by a decreased neutrophil-to-lymphocyte ratio (NLR) and rarely activated neutrophils and leukocytes. The intracellular STING ratio was also defective in neutrophil-dominated leukocytes.ConclusionOur study revealed that STING had a strong association with bortezomib and could serve as a potential target for immunotherapy in multiple myeloma.

Modified Endothelial Activation and Stress Index: A New Predictor for Survival Outcomes in Classical Hodgkin Lymphoma Treated with Doxorubicin-Bleomycin-Vinblastine-Dacarbazine-Based Therapy

Background: Although the cure rates of classical Hodgkin Lymphoma (cHL) are as high as 90% using the current treatment protocols, the prognosis is poor for primary refractory patients. Thus, a biomarker that can predict patients with early progression at the time of diagnosis is an unmet clinical need. Endothelial activation and stress index (EASIX) and its variant modified EASIX (mEASIX) is a scoring system currently used for the prediction of prognosis in hematologic malignancies. This study aimed to investigate the prognostic value of the mEASIX score in newly diagnosed cHL patients. Methods: Data from 206 patients who underwent positron emission tomography (PET)-guided doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) therapy for cHL between January 2007 and November 2023 were retrospectively analyzed. The prognostic value of the mEASIX score was evaluated using the receiver operating characteristic (ROC) analysis, Cox regression analysis, and the Kaplan–Meier method, and then compared with standard risk assessment methods. Results: The median age at diagnosis was 33 years, and the rate of patients in the advanced stage was 67%. ROC analysis determined an optimal mEASIX score cut-off of 17.28, categorizing patients into mEASIXhigh (47%) and mEASIXlow (53%) groups. The 5-year progression-free survival (PFS) (60% vs. 84.3%) and overall survival (OS) (79.6% vs. 95.8%) were significantly lower in the mEASIXhigh group (p &lt; 0.001). Additionally, multivariate analysis showed that the independent variables affecting PFS included the nodular sclerosing subtype (HR: 0.4), bone marrow involvement (HR: 2.6), and elevated mEASIX (HR: 3.1). Independent variables, which had an effect on OS included elevated mEASIX (HR:3.8) and higher IPS-3 scores (HR:1.9). Furthermore, a higher mEASIX score (≥17.28) was identified as an independent variable indicating primary refractory disease (OR: 6.5). Conclusions: mEASIX is a powerful and easy-to-access marker for the detection of primary refractory disease and prognosis in newly diagnosed cHL cases.

Efficacy of bortezomib combined with Hyper-CVAD in adults with relapsed acute lymphoblastic leukemia or positive measurable residual disease; effect of bortezomib in leukemia

PurposeDespite advances in the treatment of adult acute lymphoblastic leukemia (ALL), relapse remains the most significant challenge in improving prognosis. Measurable residual disease (MRD) assessment can predict bone marrow relapse based on MRD positivity. As access to innovative therapies remains limited because of the high cost, chemotherapy is the widely utilized treatment option. The efficacy of a combination of bortezomib and Hyper-CVAD has been reported in patients with multiple myeloma; however, its efficacy has not yet been confirmed in patients with ALL.MethodsThis prospective cohort study involved patients with ALL who presented with MRD-positive results or relapse and received treatment with a combination of bortezomib and Hyper-CVAD at two reference centers in Mexico City.ResultsOf the 20 patients with positive MRD included in this study, 60% (n = 12) exhibited MRD negative results after combination treatment, 30% (n = 6) persisted positive MRD results, and 10% (n = 2) passed away. Of the 23 patients with bone marrow relapse, 43.5% (n = 10) achieved a second complete remission (2CR), 34.8% (n = 6) exhibited refractory status, and 21.7% (n = 5) passed away. To achieve a 2CR, 20% (n = 2) patients required less than four cycles of treatment, 50% (n = 5) required four cycles (two A and B cycles each), and 30% (n = 3) required six cycles.ConclusionThe combination of bortezomib and Hyper-CVAD treatment exhibited better results in achieving MRD negative results, indicating its potential as a promising first-line treatment strategy for ALL.

CD9/SOX2-positive cells in the intermediate lobe of the rat pituitary gland exhibit mesenchymal stem cell characteristics.

Adult tissue stem cells of the anterior pituitary gland, CD9/SOX2-positive cells, are believed to exist in the marginal cell layer (MCL) bordering the residual lumen of the Rathke's pouch. These cells migrate from the intermediate lobe side of the MCL (IL-MCL) to the anterior lobe side of the MCL and may be involved in supplying hormone-producing cells. Previous studies reported that some SOX2-positive cells of the anterior lobe differentiate into skeletal muscle cells. These findings suggest that CD9/SOX2-positive cells in the anterior pituitary have mesenchymal stem cell (MSC) properties. To substantiate this hypothesis, we examined whether CD9-positive cells isolated from IL-MCL of adult male rats differentiate into mesenchymal cells, such as endothelial cells, adipocytes, chondrocytes, and osteocytes. Immunohistochemical analysis revealed that the CD9-positive cells were positive for the MSC markers, CD349, CD105, CD271, and CD273 and were detected in the early postnatal period at the boundary between the posterior and intermediate lobes but not in the embryonic period. In addition, some adult tissue stem cells derived from neural crest cells and bone marrow haematopoietic stem cells were positive for both CD9 and MSC markers, indicating that several CD9/SOX2-positive cells in the IL-MCL of the pituitary gland are MSCs that invaded from external tissues during pituitary development in the early postnatal period and exist in the adult tissue stem cells as suppliers of hormone-producing and endothelial cells in the anterior lobe. These findings should have implications for the application of CD9/SOX2-positive cells in regenerative therapy of the pituitary.