G-CSF Research Articles

PEGylated Granulocyte Colony-Stimulating Factor and Plerixafor Enhance Autologous Stem and Progenitor Cell Mobilization and Transplantation in Pediatric Patients.

Autologous hematopoietic stem cell transplantation is used to restore bone marrow function after high-dose chemotherapy. For apheresis, granulocyte colony-stimulating factor (G-CSF) is standard of care, but obtaining sufficient stem cells can be challenging. Other mobilization agents include plerixafor and PEGylated G-CSF (PEG-G-CSF). While efficacy of these is established in adults, limited data for their use in pediatric patients are available. Here, we compare Good versus Poor Mobilizers and study success of different mobilization regimens in regard to CD34+cell-collection, -quality, -phenotype and hematologic reconstitution in pediatric patients. In this multi-center retrospective study, we analyzed data of 278 patients with solid tumors and lymphoma, mobilized with either G-CSF (n = 224), PEG-G-CSF (n = 34), or G-CSF/PEG-G-CSF with additional plerixafor (n = 20). In Poor Mobilizers (13.7% of all patients), addition of plerixafor to G-CSF augmented CD34+cell collection, without adverse effects on hematologic reconstitution and CD34+cell quality. PEG-G-CSF-aided mobilization was successful as first-line treatment in two-thirds of patients and did not impair hematological reconstitution, compared to G-CSF-only. Within the Poor Mobilizer group, G-CSF+plerixafor increased primitive (CD45RA-CD38-CD90+CD49f+) and CXCR4-expressing CD34+cells in apheresis products compared to G-CSF-only, without exceeding levels of Good Mobilizers. No plerixafor-related increase in tumor cells was observed in apheresis products. In conclusion, our comprehensive study supports the use of plerixafor and furthermore demonstrates the potential of patient-friendly PEG-G-CSF for mobilization of pediatric patients.

Study of PEG-rhG-CSF for the prevention of neutropenia in concurrent chemoradiotherapy for nasopharyngeal carcinoma.

To study the efficacy and safety of Polyethylene glycolated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) in the prevention of neutropenia during concurrent chemoradiotherapy for nasopharyngeal carcinoma (NPC). This is a single-center, prospective, randomized controlled study conducted from June 1, 2021, to October 31, 2022 on patients diagnosed with locally advanced NPC. Participants were divided into an experimental group and a control group. The experimental group received PEG-rhG-CSF injections post-chemotherapy cycles, whereas the control group received standard care without additional intervention. Outcomes assessed included grade 3/4 neutropenia incidence, blood cell count changes, febrile neutropenia rates, delays or interruptions in chemotherapy/radiotherapy due to hematological toxicity, oral mucositis incidents, and bone pain occurrences, comparing these between both groups. 1. 88 patients with locally advanced NPC were included, the incidence of grade 3 neutropenia in the experimental group was lower than that in the control group (P = 0.026); 2. The white blood cell count and neutrophil count in D7, D10, D14, and D21 in the experimental group were higher than those in the control group (P<0.01); 3. The rate of delayed chemotherapy in the experimental group was lower than that in the control group (2.3% vs. 29.5%), P = 0.001; the rate of interruption of radiotherapy in the experimental group was lower than that in the control group (2.3% vs.27.3%), P = 0.003; 4. The incidence of bone pain in the experimental group was 34.1%, of which most were mild bone pain, and no severe bone pain occurred. The leukocyte and neutrophil counts of the patients in the bone pain group were significantly higher than those of the patients in the no bone pain group, P(WBC) = 0.001, P(ANC) = 0.002. The preventive use of PEG-rhG-CSF decreases the incidence of neutropenia in patients undergoing concurrent chemoradiotherapy for NPC, thereby reducing rates of chemotherapy delays and radiotherapy interruptions, with mild adverse reactions that are tolerable by patients.

Combination therapy of low-dose radiotherapy and immunotherapy in advanced metastatic nasopharyngeal carcinoma: a case report and literature review.

Nasopharyngeal cancer (NPC) is a common head and neck malignant tumor, which is difficult to treat at the advanced NPC due to its occult and high metastatic potential to the cervical lymph nodes and distant organs. Low-dose radiotherapy (LDRT) is increasingly being investigated for potential cancer treatment. When combined with immune checkpoint inhibitors, LDRT has been shown to significantly improve the immune microenvironment of tumors, thereby promote the immune attack on tumor cells. However, the therapeutic effect of LDRT combined with immunotherapy in advanced NPC is not well understood. We report a case of a 31-year-old man was diagnosed with advanced metastatic nasopharnygeal non-keratinizing carcinoma (T4N3M1 stage IVb AJCC8th). The patient was treated with a high-dose of radiation therapy combined with LDRT and immunotherapy to inhibit tumor cell proliferation and activate the body's immune system. The initial treatment procedure was as follows: chemotherapy regimen (nedaplatin + docetaxel + fluorouracil) induction, followed by radical radiotherapy for the primary lesion, LDRT for the L5 vertebral body metastasis, and concurrent use of low-dose capecitabine beat chemotherapy and toripalimab immunotherapy. The patient was also administered with human granulocyte-macrophage colony-stimulating factor and aspirin to enhance the immune function. This combination therapy approach alleviated patient symptoms, improved bone changes in the L5 vertebral body and resolved the tumor without any adverse effects signals. The progression-free survival (PFS) has reached 27 months and he is currently stable without tumor recurrence. The combination of chemotherapy and LDRT with aspirin and human granulocyte macrophage colony-stimulating factor improved the disease state of advanced NPC cancer, effectively reducing the level of tumor markers, enhanced the immune function without significant adverse reactions.

Metabolically activated and highly polyfunctional intratumoral VISTA+ regulatory B cells are associated with tumor recurrence in early-stage NSCLC

B cells have emerged as central players in the tumor microenvironment (TME) of non-small cell lung cancer (NSCLC). However, although there is clear evidence for their involvement in cancer immunity, scanty data exist on the characterization of B cell phenotypes, bioenergetic profiles and possible interactions with T cells in the context of NSCLC. In this study, using polychromatic flow cytometry, mass cytometry, and spatial transcriptomics we explored the intricate landscape of B cell phenotypes, bioenergetics, and their interaction with T cells in NSCLC. Our analysis revealed that TME contains diverse B cell clusters, including VISTA+ Bregs, with distinct metabolic and functional profiles. Target liquid chromatography-tandem mass spectrometry confirmed the expression of VISTA on B cells. VISTA+ Bregs displayed high metabolic demand and were able to produce different cytokines, including interleukin (IL)-10, transforming growth factor (TGF)-β, IL-6, tumor necrosis factor (TNF), and granulocyte–macrophage colony-stimulating factor (GM-CSF). Spatial analysis showed colocalization of B cells with CD4+/CD8+ T lymphocytes in TME. The computational analysis of intercellular communications that links ligands to target genes, performed by NicheNet, predicted B-T interactions via VISTA-PSGL-1 axis. Colocalization analyses revealed that PSGL-1 T cells and VISTA+ B cells are adjacent in the TME. Notably, tumor infiltrating CD8+ T cells expressing PSGL-1 exhibited enhanced metabolism and cytotoxicity. In NSCLC patients, prediction analysis performed by PENCIL revealed the presence of an association between PSGL-1+CD8+ T cells and VISTA+ Bregs with lung recurrence. Our findings suggest a potential interaction between Bregs and T cells through the VISTA-PSGL-1 axis, that could influence NSCLC recurrence.

Recent Advances of Precision Immunotherapy in Sepsis

Abstract Precision immunotherapy signifies the administration of the required type of immune intervention tailored to the state of immune activation at the appropriate time window. The classification of patients into the different states of immune activation is usually done by either a protein blood biomarker or a molecular blood endotype which is diagnostic of the precise immune state. Evidence coming from trials of the last decade suggests that immune interventions should be split into strategies aiming to attenuate the exaggerated immune responses, strategies aiming to restore sepsis-induced immunoparalysis (SII) and strategies aiming to restore the vascular tone. Suggested strategies to attenuate the immune responses are anakinra, nangibotide and tocilizumab. Biomarkers which guide their use are ferritin and sTREM-1 (soluble triggering receptor expressed on myeloid cells-1). Suggested strategies to restore SII are nivolumab, recombinant human interferon-gamma, CYT107 and GM-CSF (granulocyte macrophage colony stimulating factor). Biomarkers which guide their use are the expression of the human leukocyte antigen DR on blood monocytes, the absolute lymphocyte count, and blood levels of IgM. One recently suggested strategy to restore vascular tone is adrecizumab, the use is guided by the blood levels of bio-adrenomedulin. The use of these precision treatment strategies is still hampered by the need of large scale randomized controlled trials.

Trifluridine/Tipiracil (FTD/TPI) in Metastatic Colorectal Cancer in Hong Kong: A Territory-Wide Cohort Study.

Randomized phaseIII trials showed that using trifluridine/tipiracil (FTD/TPI) in patients with pre-treated metastatic colorectal cancer (mCRC) conferred survival benefit versus placebo. Here, we investigated the effectiveness and safety of FTD/TPI and sought to identify prognostic factors among the mCRC population in Hong Kong. A non-interventional, retrospective, multicenter cohort study enrolled patients with mCRC who received FTD/TPI in seven public hospitals in Hong Kong between 2016 and 2020. Overall survival (OS) was the primary endpoint; treatment duration and occurrence of neutropenia were secondary endpoints. We also performed a post hoc analysis to identify factors influencing OS and treatment duration. Overall, 456 patients were included (median age, 64.0years; 57.5% men). Approximately half (225/456; 49.3%) had RAS wild-type tumors; the median treatment duration was 12.4weeks (95% confidence interval [CI] 11.1-13.1). Median OS was 7.59months (95%CI 7.00-8.21). Overall, 289 (63.4%) patients developed neutropenia of any grade and 159 (34.9%) developed grade ≥ 3 neutropenia. Neutropenia at 1month occurred in 193 (43.1%) patients. The use of granulocyte colony-stimulating factor for neutropenia was reported for 42 (9.2%) patients. The development of neutropenia, absolute neutrophil count decrease of ≥ 2 grades in 1month, absence of liver metastasis, and RAS wild-type status were associated with significantly longer OS and, except for RAS wild-type status (not analyzed), longer treatment duration (p < 0.05 for all comparisons). Our data show that treatment with FTD/TPI offers survival benefits in patients with refractory mCRC in Hong Kong consistent with randomized controlled trials and other real-world studies. Furthermore, the prognosis in patients receiving FTD/TPI appears to be significantly better in those who develop neutropenia, with RAS wild-type status, or those without liver metastases, despite a higher rate of dose reduction in the real-world setting.

Venetoclax in combination with fludarabine, cytarabine, granulocyte colony stimulating factor, and idarubicin (FLAG-Ida) in patients with acute leukemia of ambiguous lineage and acute lymphoblastic leukemia

Venetoclax in combination with fludarabine, cytarabine, granulocyte colony stimulating factor, and idarubicin (FLAG-Ida) in patients with acute leukemia of ambiguous lineage and acute lymphoblastic leukemia

The Ability of SOCS1 to Cross-Regulate GM-CSF Signaling is Dose Dependent.

Suppressor of cytokine signaling (SOCS) 1 is a key negative regulator of interferon (IFN), interleukin (IL)12, and IL-2 family cytokine signaling through inhibition of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. To investigate the temporal induction of SOCS1 in response to cytokine in live cells and its selective regulation of signaling pathways, we generated a mouse expressing a Halo-tag-SOCS1 fusion protein (Halo-SOCS1) under control of the endogenous Socs1 promoter. Homozygous Halo-SOCS1 mice (Halo-Socs1KI/KI) were viable with minor T cell abnormalities, most likely due to enhanced Halo-SOCS1 expression in thymocytes compared with the untagged protein. IFNγ and IL-4 induced Halo-SOCS1 expression in macrophages derived from Halo-Socs1KI/KI mice, and a critical level of SOCS1 expression was required for inhibition of both IFNγ and granulocyte macrophage-colony stimulating factor (GM-CSF)-driven JAK-STAT signaling. In contrast, IFNγ priming to induce SOCS1 did not cross-regulate IL-4 signaling. This study indicates that while SOCS1 expression needs to exceed a critical threshold to inhibit IFNγ signaling, its selective regulation of cytokine signaling results from an as yet undetermined, level of regulatory control.

PEG-rhG-CSF versus rhG-CSF in supporting neutrophil recovery after induction chemotherapy for patients with newly diagnosed acute lymphoblastic leukemia.

To compare the efficacy and safety of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) and rhG-CSF in the recovery of neutrophils after induction therapy in ALL patients, PEG-rhG-CSF was injected subcutaneously within 24 ~ 48h after the end of intravenous infusion of daunorubicin/idarubicin during induction chemotherapy. In rhG-CSF group, patients were given rhG-CSF. The main outcome indexes were the incidence and duration of grade 4 chemotherapy-induced-neutropenia (CIN, ANC less than 0.5 × 109/L), the incidence of severe agranulocytosis (ANC less than 0.2 × 109/L). The incidence of grade 4 CIN in the PEG-rhG-CSF group was significantly lower than that in the rhG-CSF group (P = 0.007). There was no significant difference in the incidence of severe neutrophil deficiency and the median time of neutrophil deficiency in PEG-rhG-CSF group and rhG-CSF group. There was no significant difference in day 28 complete response (CR) rate of bone marrow cytology between the two groups (P = 0.985). Compared with rhG-CSF, PEG-rhG-CSF can reduce the incidence of agranulocytosis after induction chemotherapy in newly diagnosed ALL patients, without affecting the efficacy of chemotherapy. Meanwhile, it can reduce the pain of patients, with good safety and tolerance.

Extended clinical phenotypes and treatment modalities in 32 JAGN1-deficient patients. A multicenter study by EBMT IEWP.

JAGN1 (Jagunal-homolog1) is a ER-resident transmembrane protein which is part of the early secretory pathway and granulocyte colony-stimulating factor receptor mediated signaling. Autosomal recessively inherited variants in the JAGN1 gene lead to congenital neutropenia, early-onset bacterial infections, aphthosis and skin abscesses due to aberrant differentiation and maturation of neutrophils. In addition, bone metabolism disorders and a syndromic phenotype, including facial features, short stature and neurodevelopmental delay, have been reported in affected patients. Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a treatment option for patients who respond poorly to therapy with colony-stimulating factors (GM-CSF, G-CSF) and those who suffer from complicated infections despite treatment. In a retrospective multicenter study by EBMT IEWP in close collaboration with ESID and the French Neutropenia registry, data from 32 patients with JAGN1 deficiency were collected to describe the natural course of the disease, perform a phenotype-genotype analysis and evaluate the responses to various treatment modalities. Patients presented with nine distinct homozygous mutations in JAGN1. All patients experienced early-onset infectious complications. Twelve patients presented a syndromic phenotype with short stature and facial features. Neurodevelopmental delay was observed only in four patients from three families. The most common variant c.3G>A p.Met1, found in nine patients in our cohort was never connected to extramedullary symptoms except for a short stature in one patient, whereas patients with the variants c.63G>T, p.Glu21Asp and c130c>T p.His44 Tyr presented more often with syndromic facial features and bone metabolism disorders. Six patients received allogeneic stem cell transplantation due to therapy-refractory neutropenia and severe infections, and one received the graft because of myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (AML). Two patients had to undergo a second transplantation because of autologous reconstitution despite receiving myeloablative regimens. One untransplanted patient died at the age of five years due to pancolitis and septicemia. All 31 other patients were reported to be alive and healthy at the last follow-up under supportive care.

Clozapine Induces Agranulocytosis via Inflammatory and Hematopoietic Cytokine Induction of the JAK-STAT Signaling Pathway: Evidence From Network Pharmacology and Molecular Docking.

Clozapine exhibits significant therapeutic efficacy in schizophrenia, especially treatment-resistant schizophrenia. However, clozapine can cause agranulocytosis, a fatal adverse effect, and the aim of this study is to explore this mechanism based on network pharmacology and molecular docking. Six and two databases were used to identify targets associated with clozapine and agranulocytosis, respectively. The bioinformatics online platform was used to identify overlaps between the drug and disease targets. The protein-protein interaction (PPI) network was characterized using Cystoscope 3.10.1 and STRING. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) were analyzed using the DAVID online platform. A drug-target-pathway-disease network was constructed utilizing Cystoscope 3.10.1. The Auto Dock Vina and PyMOL software were used to verify the molecular docking of clozapine and core targets. The analysis revealed 188 overlapping targets. The PPI and KEGG enrichment pathway analyses demonstrated that clozapine induces agranulocytosis by modulating the hematopoietic cell lineage and JAK-STAT signaling pathways via interleukin-3 (IL3), IL6, IL2 receptor subunit alpha (IL2RA), and granulocyte colony-stimulating factor. Binding energies between clozapine and core targets were favorable (< -7.0 kcal/mol). Clozapine-induced agranulocytosis may be linked to the JAK-STAT inflammatory signaling pathway through inflammatory and hematopoietic-related cytokines. Our findings enhance our comprehension of the potential mechanisms underlying clozapine-induced agranulocytosis.

Outcomes of Patients with Hematological Malignancies Admitted to the Intensive Care Unit at a Tertiary Care Center in Saudi Arabia

Abstract Background: Patients with hematological malignancies (HM) are at risk for complications, including neutropenia and admission to the intensive care unit (ICU). Granulocyte colony-stimulating factors (GCSF) can accelerate progenitor cells’ proliferation and differentiation, and thus compensate for neutropenia. In patients with HM admitted to ICUs in Saudi Arabia, the outcome and impact of GCSF use on neutropenia duration and severity is understudied. Objective: To evaluate the outcome and impact of GCSF on neutropenia in patients with HM admitted to the ICU of a tertiary care center in Saudi Arabia. Methods: This retrospective study included all consecutive patients diagnosed with an HM admitted to the ICU at King Saud University Medical City, Riyadh, Saudi Arabia, from 2018 to 2022. Data on demographics, clinical information, ICU admission, and outcomes were collected. Results: A total of 44 patients with HM admitted to the ICU were included, of which 43.2% were females and the mean age was 50.2 ± 21.1 years. The mean length of ICU stay was 12.3 ± 14.7 (range: 0–62) days. ICU mortality was 61.4%, with no further mortality within 90 days after discharge. There was no significant association between survival and age (P = 0.205), gender (P = 0.7), and neutropenia (P = 0.566) or the use of GCSF prior to ICU admission (P = 0.882). There was a significant association between the category of ICU intervention and survival (P = 0.007). Conclusion: Patients with hematological malignancies who were admitted to an ICU in Saudi Arabia had a high mortality, regardless of neutropenia or the use of granulocyte colony-stimulating factor.

Integrated proteomic and metabolomic analysis reveals the potential therapeutic mechanism of Quanduzhong capsule in rats with spontaneous hypertension and knee osteoarthritis

Quanduzhong capsule (QDZ), derived from Eucommia ulmoides Oliv., has been traditionally used in Chinese medicine for its beneficial effects on musculoskeletal health. Its clinical application has extended to conditions such as spontaneous hypertension combined with knee osteoarthritis (SKOA). However, the specific mechanisms by which QDZ alleviates symptoms and improves outcomes in this complex condition remain to be fully elucidated. This study aims to evaluate the therapeutic potential of QDZ in treating SKOA. By performing serum proteomics and metabolomics, we seek to explore the related biological pathways and elucidate the mechanisms underlying QDZ's effects on SKOA. Serum samples from control, spontaneous hypertension (SHR), SKOA, and SKOA treated with QDZ groups were analyzed using data-independent acquisition-based proteomics to identify differentially expressed proteins. Serum levels of angiotensin II, norepinephrine, endothelin-1, classical pro-inflammatory factors such as macrophage colony-stimulating factor, tumor necrosis factor-alpha, and interleukin-1 beta were measured. Additionally, serum metabolomics was performed to examine the changes in metabolite profiles. Correlation analysis was conducted to link changed proteins and metabolites with key pathways affected by QDZ. Proteomics analysis revealed significant alterations in serum protein expression between control, SHR, and SKOA groups, with changes in pathways related to immune regulation and vascular function. KEGG enrichment analysis highlighted pathways such as endocytosis, synaptic vesicle cycling, and immune responses were enriched in SKOA group compared with control group. QDZ treatment significantly modulated above pathways and reduced inflammatory and cardiovascular markers which were upregulated in SKOA group. Metabolomics analysis showed that QDZ reversed SKOA-induced changes in amino acid and organic acid metabolism, affecting pathways including valine, leucine, and isoleucine metabolism, as well as the TCA cycle. Correlation analysis revealed significant relationships between key proteins and metabolites, underscoring the integrated role of immune and metabolic pathways in QDZ's effects. Our results indicate QDZ has a significant therapeutic potential for SKOA by modulating both protein and metabolite profiles associated with inflammation, vascular dysfunction, and metabolic imbalance. Our findings provide insights into the mechanisms through which QDZ exerts its effects and support its use as a promising treatment for SKOA. This study highlights the impact of QDZ on proteomic and metabolomic alterations, offering a basis for its broader application in treating SKOA.

Study on the Efficacy of Autologous Platelet-Rich Plasma Combined with Recombinant Human Granulocyte Macrophage Colony-Stimulating Factor Gel in the Treatment of Venous Lower Extremity Ulcers

Study on the Efficacy of Autologous Platelet-Rich Plasma Combined with Recombinant Human Granulocyte Macrophage Colony-Stimulating Factor Gel in the Treatment of Venous Lower Extremity Ulcers

Distribution and clinicopathological characteristics of G-CSF expression in tumor cells and stromal cells in upper tract urothelial carcinoma

Abstract Background Urothelial carcinoma (UC) is a common type of malignant disease; however, the diagnostic and prognostic markers of upper urinary tract urothelial cancer (UTUC) remain poorly understood because of its rarity. Methods To clarify the clinicopathological significance of granulocyte-colony stimulating factor (G-CSF) in UTUC, we analyzed the expression and distribution of G-CSF in 112 upper tract urothelial carcinoma (UTUC) samples with immunohistochemistry. Results In normal urothelium, G-CSF expression was weak or absent, whereas high expression of G-CSF was observed in UTUC tissues, both in tumor cells (TCs) and stromal cells (SCs). G-CSF expression in the TCs and SCs was associated with nodular/flat morphology, high grade, advanced T stage, and lymphovascular invasion in UTUC. G-CSF expression in SCs was associated with poor prognosis and was an independent prognostic factor. Public data showed that G-CSF expression was also associated with decreased progression-free survival and disease-specific survival. A prognostic model was constructed by incorporating the presence or absence of G-CSF expression along with clinicopathologic factors, which allowed for a more accurate prediction of poor prognosis. We further showed that G-CSF expression was associated with a high Ki-67 labeling index and with PD-L1, HER2, and p53 expression in UTUC. Conclusion G-CSF expression in TCs and SCs may play a crucial role in UTUC tumor progression. Notably, stromal G-CSF expression showed significant prognostic value, even when compared to major clinicopathological factors, suggesting that the evaluation of G-CSF expression may contribute to clinical decision-making in patients with UTUC.

Comparison of HiDAC Versus FLAG-IDA in the Treatment of Relapsed Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome.

Relapsed acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (HR-MDS) are associated with a poor prognosis. It is unknown which re-induction therapy provides the highest chance of durable remission. Commonly used therapies are high dose cytarabine (HiDAC) and triple therapy consisting of fludarabine, cytarabine, and idarubicin combined with granulocyte colony-stimulating factor (FLAG-IDA). Two patient cohorts with relapsed AML or HR-MDS treated with HiDAC or FLAG-IDA between October 2015 and December 2021 in two academic hospitals in the Netherlands were retrospectively analyzed. Patients were treated with either HiDAC (n=22) or FLAG-IDA (n=25). Rates of CR (71% vs. 74%, P=0.85), 1-year OS (47% vs. 51%, P=0.99) and EFS (38% vs. 35%, P=0.71) were comparable between HiDAC and FLAG-IDA. Durations of neutropenia (median 24 days (IQR 20-26) vs. 30 days (IQR 22-39), P=0.014) and thrombocytopenia (22 days (IQR 17-26) vs. 36 days (IQR 26-53)) were significantly shorter in the HiDAC group than in the FLAG-IDA group. While remission rates and survival outcomes were similar, FLAG-IDA was associated with longer periods of myelosuppression and transfusion dependency compared to HiDAC in these two cohorts. HiDAC can be considered as a salvage chemotherapyfor relapsed AML/HR-MDS based on our study.

Correlation of fecal microbiome dysregulation to synovial transcriptome in an equine model of obesity associated osteoarthritis.

Osteoarthritis (OA) is increasingly thought to be a multifactorial disease in which sustained gut inflammation serves as a continued source of inflammatory mediators driving degenerative processes at distant sites such as joints. The objective of this study was to use the equine model of naturally occurring obesity associated OA to compare the fecal microbiome in OA and health and correlate those findings to differential gene expression synovial fluid (SF) cells, circulating leukocytes and cytokine levels (plasma, SF) towards improved understanding of the interplay between microbiome and immune transcriptome in OA pathophysiology. Feces, peripheral blood mononuclear cells (PBMCs), and SF cells were isolated from healthy skeletally mature horses (n=12; 6 males, 6 females) and those with OA (n=6, 2 females, 4 males). Horses were determined to have OA via lameness evaluation, response to intra-articular (IA) diagnostic analgesia, and radiographic and arthroscopic evidence. Horses were excluded who had received medications or joint injections within 2 months. Cytokine analyses of plasma and SF were performed via multiplex immunoassay. Fecal bacterial microbial 16s DNA sequencing was performed and correlated to bulk RNA sequencing of SF cells and PBMC performed using an Illumina based platform. Horses with OA had higher body condition scores (P=0.009). Cytokines were elevated in plasma [interleukin (IL)-2, IL-6, IL-18, interferon gamma (IFN-γ), interferon gamma inducible protein 10 (CXCL10 or IP-10), granulocyte colony-stimulating factor (G-CSF)] and SF (IL-1β, IL-6, IL-17A, IL-18, IP-10, G-CSF) in OA. Microbial principal coordinate analysis (PCoA) using Bray-Curtis dissimilarity for β-diversity demonstrated distinct grouping of samples from OA versus healthy horses (P=0.003). Faith alpha diversity was reduced in OA (P=0.02). Analysis of microbiome composition showed differential relative abundance of taxa on multiple levels in OA. Specific phyla (Firmicutes, Verrucomicrobia, Tenericutes, Fibrobacteres), correlated to transcriptomic differences related to cell structure, extracellular matrix, collagen, laminin, migration, and motility, or immune response to inflammation in OA. These findings provide compelling evidence for a link between obesity, gut microbiome dysbiosis and differential gene expression in distant joint sites associated with development of OA in a relevant large animal model, establishing a connection here that provides a platform from which development of therapeutic interventions targeting the gut microbiome can build.

Let It Grow: The Role of Growth Factors in Managing Chemotherapy-Induced Cytopenia.

Chemotherapy-induced cytopenia (CIC) is characterized by neutropenia, anemia, and thrombocytopenia, which are common and serious complications in cancer treatment. These conditions affect approximately 60% of patients undergoing chemotherapy and can significantly impact quality of life, treatment continuity, and overall survival. The use of growth factors, including granulocyte colony-stimulating factors (GCSFs), erythropoietin-stimulating agents (ESAs), and thrombopoietin receptor agonists (TPO-RAs), has emerged as a promising strategy for managing CIC. However, the use of these growth factors must be approached with caution. This review provides an overview of the mechanisms, efficacy, and safety of growth factors in the management of CIC. Additionally, we discuss predictive markers for treatment response, potential risks, and highlight areas for future research.

Human Monocyte-Derived Macrophages Demonstrate Distinct Responses to Ambient Particulate Matter in a Polarization State- and Particle Seasonality-Specific Manner.

Macrophages are professional phagocytic immune cells that, following activation, polarize on a spectrum between the proinflammatory M1 and the proresolution M2 states. Macrophages have further been demonstrated to retain plasticity, allowing for the reprogramming of their polarization states following exposure to new stimuli. Particulate matter (PM) has been repeatedly shown to modify macrophage function and polarization while also inducing worsening respiratory infection morbidity and mortality. However, limited work has considered the impact of the initial macrophage polarization state on subsequent responses to PM exposure. PM composition can demonstrate seasonality-specific compositional changes based on differences in seasonal weather patterns and energy needs, introducing the need to consider the seasonality-specific effects of airborne PM when investigating its impact on human health. This study sought to determine the impact of airborne PM collected during different seasons of the year in Xinxiang, China, on macrophage function in a polarization state-dependent manner. Macrophages were differentiated using the macrophage colony-stimulating factor (M-CSF) on CD14+CD16- monocytes isolated from the blood of healthy human volunteers. The resulting macrophages were polarized into indicated states using well-characterized polarization methods and assessed for phagocytic function, bioenergetic properties, and secretory profile following exposure to PM collected during a single day during each season of the year. Macrophages demonstrated clear polarization state-dependent phagocytic, bioenergetic, and secretory properties at the baseline and following PM exposure. Specific PM seasonality had a minimal impact on phagocytic function and a minor effect on bioenergetic properties but had clear impacts on the secretory profile as demonstrated by the enriched secretion of well-characterized mediator clusters by particle season. Together, these data suggest that both particle seasonality and macrophage polarization state must be considered when investigating the impact of PM on macrophage function. These factors may contribute to the negative outcomes linked to PM exposure during respiratory infections.

CXCL4 deficiency limits M4 macrophage infiltration and attenuates hyperoxia-induced lung injury

BackgroundBronchopulmonary dysplasia (BPD), a chronic lung disease prevalent among premature infants, significantly impacts lifelong respiratory health. Macrophages, as key components of the innate immune system, play a role in lung tissue inflammation and injury, exhibiting diverse and dynamic functionalities. The M4 macrophage, a distinctive subtype primarily triggered by chemokine (C-X-C motif) ligand 4 (CXCL4), has been implicated in pulmonary inflammatory and fibrotic processes. Nonetheless, its contribution to the pathophysiology of BPD remains uncertain.ObjectiveThis study aimed to elucidate the involvement of CXCL4 in hyperoxia-induced neonatal lung injury and fibrosis, with a particular focus on its influence on M4 macrophages.MethodsA BPD model in neonatal mice was established through continuous exposure to 95% O2 for 7 days. Comparative analyses of lung damage and subsequent regeneration were conducted between wild-type (WT) and CXCL4 knockout (KO) mice. Lung tissue inflammation and fibrosis were assessed using histological and immunofluorescence staining, enzyme-linked immunosorbent assay, Western blot, and real-time quantitative polymerase chain reaction. Differentiation of M0 and M4 macrophages was performed in vitro using macrophage colony-stimulating factor and CXCL4, while expressions of S100A8 and MMP7, along with migration assays, were evaluated.ResultsElevated CXCL4 levels and M4 macrophage activation were identified in the lung tissue of BPD model mice. CXCL4 deficiency conferred protection to alveolar type 2 epithelial cells, reduced sphingosine-1-phosphate metabolic activity, mitigated pulmonary fibrosis, and limited M4 macrophage progression. This deletion further enhanced lung matrix remodeling during recovery. In vitro, CXCL4 promoted M4 macrophage differentiation and increased macrophage migration via chemokine (C-C motif) receptor 1.ConclusionCXCL4 contributes to hyperoxia-induced lung injury and fibrosis through modulation of cytokine release, alveolar cell proliferation, lipid metabolism, and the regulation of macrophage phenotype and function.