G-CSF Research Articles

The efficacy and safety of the prophylactic application of PEG-rhG-CSF in radiotherapy with weekly concurrent chemotherapy for cervical cancer.

To evaluate the efficacy and safety of pegylated recombinant human granulocyte colony stimulating factor (PEG-rhG-CSF) in preventing neutropenia during concurrent radiotherapy combined with weekly chemotherapy in patients with cervical cancer. From September 2019 to November 2020, 180 patients with cervical cancer who required concurrent chemoradiotherapy (CCRT) were enrolled in this study. The patients were randomly divided into the following three groups at a ratio of 1:1:1: Group A (PEG-rhG-CSF), Group B (PEG-rhG-CSF + rhG-CSF) and the control group (rhG-CSF). Cisplatin or carboplatin was administered weekly. The primary endpoint was the incidence of grade 3/4 neutropenia. The secondary endpoints were the incidence of febrile neutropenia (FN), delay of radiotherapy, chemotherapy dose reduction, rate of PFS at 2 years and 3 years, and incidence of adverse reactions. Sixty patients were randomly assigned to each group. Two patients in Group B withdrew from the trial for personal reasons. The incidence of grade 1/2 neutropenia in the Control group was significantly lower than that in Group A and Group B (P < 0.001). However, the incidence of grade 3/4 neutropenia in the Control group was significantly greater than that in Group A and Group B (P < 0.001). There was no significant difference in the incidence of FN among the three groups (P = 0.771). The rate of platinum dose reduction in Group A (6.7%) and Group B (5.2%) was significantly lower than that in the Control group (30.0%) (P < 0.001). The delay rate of radiotherapy in Group A (10%) and Group B (13.8%) was obviously inferior to that in the Control group (31.7%) (P = 0.006). The 2-year PFS rates of Group A, Group B, and the Control group were 93.3%, 98.3%, and 91.7%, respectively, with no statistically significant difference (P = 0.270). The 3-year PFS rates were 89.8%, 94.1%, and 84.9%, respectively, with no statistically significant difference (P = 0.178). No treatment-related serious adverse events occurred in any of the patients. In Group A and Group B, The prophylactic application of PEG-rhG-CSF during conventional chemoradiotherapy combined with weekly chemotherapy for patients with cervical cancer can reduce the incidence of grade 3/4 neutropenia and does not increase the incidence of adverse reactions when compared to Control group. chictr.org.cn, ChiCTR1900026309, registered 29 September 2019-prospectively registered.

Pimicotinib Significantly Improves Outcomes for Patients with Tenosynovial Giant Cell Tumor

Results from the Phase 3 MANEUVER trial (NCT05804045) of pimicotinib (ABSK021), an investigational orally administered, highly selective, and potent small-molecule inhibitor of colony-stimulating factor-1 receptor (CSF-1R) being developed by Abbisko Therapeutics, met its primary endpoint, demonstrating significant improvement in objective response rate (ORR) in patients with tenosynovial giant cell tumor (TGCT). The ORR for pimicotinib at week 25 was 54.0% compared with 3.2% for placebo (p&lt;0.0001).

Abstract 4116714: Macrophage Colony Stimulating Factor as a Causal Metabolic Mediator of Cardiovascular Disease: An Observational and Mendelian Randomization Analysis

Background: Macrophage biology plays a key role in the pathogenesis of atherosclerosis and circulating macrophage colony-stimulating factor (M-CSF) is a marker of macrophage activity. However, there is conflicting evidence regarding its role as a mediator of cardiovascular disease. Methods: We evaluated the association between plasma M-CSF concentration with myocardial infarction, stroke, heart failure and mortality in a large substudy involving 9992 participants drawn from 14 countries and followed for a median period of 9.8 years (Interquartile Range 8.9 years - 11.4 years) utilizing a nested case-cohort design in the Prospective Urban Rural Epidemiology (PURE) study. We then conducted a two-sample Mendelian randomization (MR) analysis to evaluate the upstream determinants (using genome wide association data from the PURE biobank and publicly available consortia) and downstream effects on clinical events.. Results: The strongest causal upstream determinant of M-CSF concentration was body mass index (BMI), which showed a positive association with plasma M-CSF concentration (Beta: 0.17 SD increase; 95% CI: 0.08 - 0.27). In a survival analysis, M-CSF was independently associated with increased incident myocardial infarction (HR: 1.25 per 1 SD M-CSF increase; 95% CI: 1.13-1.38), stroke (HR: 1.17; 95% CI:1.04-1.32), and heart failure (HR: 1.34; 95% CI: 1.15-1.56) and other cardiovascular disease risk factors. Circulating M-CSF concentration also showed a strong association with long-term risk of overall mortality (HR: 1.44; 95% CI: 1.39-1.60). Mendelian randomization analyses confirmed that increased M-CSF was associated with increased risk of MI, heart failure, and ischemic stroke (specifically large artery atherosclerotic and cardioembolic stroke). Conclusions: M-CSF is a strong causal driver of cardiovascular disease morbidity whose concentration is causally influenced by body mass index. Our analysis suggests a role for macrophage activity in mediating the relationship between body mass index and cardiovascular disease outcomes.

Clinicopathological Characteristics of Neutrophil-Rich Hepatocellular Carcinoma: An Uncommon Subtype of Primary Liver Cancer.

Introduction. Neutrophil-rich hepatocellular carcinoma (HCC) is an extremely uncommon subtype of HCC with an overall incidence of <1%. Neutrophil-rich HCC shows poor cellular differentiation and sarcomatoid transformation in most patients. There is prominent neutrophilic inflammatory cell infiltration in the tumor. These tumors are associated with poor prognosis, high rate of recurrence, and metastasis. Methods. Herein, we investigated 4 patients with neutrophil-rich HCC reported at our center. Clinical, radiological, and pathological findings were reviewed. Immunophenotypic characterization of the tumors were done. Granulocyte colony-stimulating factor (G-CSF), programmed cell death ligand 1 (PD-L1), and mismatch repair immunostains were performed in all 4 tumors. Results. We report 4 neutrophil-rich HCCs in 3 male patients and one female patient with an age range of 43 to 64 years. Three underwent living donor liver transplantation and one underwent right hepatectomy. Tumor measured 0.5 cm to 12 cm in maximum dimension. Histologically, tumors demonstrated moderate to marked cellular pleomorphism. Spindle cell transformation was noted in 3 tumors. Three tumors showed vascular invasion, and one tumor showed bile duct invasion. Immunopositivity for Hep Par-1, arginase-1, and glypican-3 was present in all tumors. Tumors also expressed stemness markers including KRT19 and EpCAM. Cytoplasmic positivity for G-CSF and immunoexpression of PD-L1 was demonstrated. We also report proficient mismatch repair by immunohistochemistry in all tumors. Conclusion. Neutrophil-rich HCC is an aggressive primary liver cancer which demonstrates stemness-related features. Programmed cell death ligand 1 expression in tumor cells suggests distinct immunogenic features and potential role of anti-PD-L1 therapies in inoperable disease.

Exploring optimal administration timing of pegylated recombinant human granulocyte colony-stimulating factor for chemotherapy-induced neutropenia in early breast cancer treated with pharmorubicin and endoxan: a prospective randomized controlled clinical trial.

Pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) is a treatment for preventing febrile neutropenia (FN) in patients with early breast cancer. However, the optimal injection timing of PEG-rhG-CSF after chemotherapy is obscure. The trial was designed to explore the best administration timing of PEG-rhG-CSF when breast cancer patients could benefit most. Patients with early breast cancer were randomly assigned to receive a preventive injection on the 7th or 3rd day following chemotherapy. The experimental group (n = 80) received PEG-rhG-CSF treatment on day 7 after chemotherapy, whereas the control group (n = 80) received it on day 3. The occurrence of grades 3-4 neutropenia and FN in the first cycle was the primary endpoint. The secondary endpoint was the frequency of PEG-rhG-CSF dose reduction. In comparison to the control group, the experimental group exhibited higher white blood cell count (WBC) and absolute neutrophil count (ANC) on the 9th and 13th days following chemotherapy (P < 0.05). Additionally, the incidence of grade 3-4 neutropenia was significantly lower in the experimental group (P = 0.038). Furthermore, a greater proportion of patients in the experimental group met the criteria for reducing the PEG-rhG-CSF dose compared to the control group (69.74% vs. 35.06%, P < 0.001). In comparison with PEG-rhG-CSF injection on day 3 after chemotherapy, the incidence of grade 3-4 myelosuppression is lower, and the safety is more manageable after the injection on day 7. This approach potentially allows for a wider adoption of PEG-rhG-CSF dose reduction, leading to a consequential decrease in overall medical costs for patients. Clinical Trials: NCT04477616. Registered July 16, 2020.

Cost-effectiveness of using granulocyte colony-stimulating factor in the treatment of uterine body leiomyosarcomas. A retrospective analysis

Background. The main approach in the treatment of patients with uterine leiomyosarcoma is surgery followed by chemotherapy, which is the basis of treatment. Febrile neutropenia (FN) is a life-threatening condition, so the use of granulocyte colony-stimulating factor (G-CSF) after each cycle of chemotherapy in this category of patients remains an integral part. Aim. To evaluate the pharmacoeconomic efficacy of the use of short and long-acting G-CSF forms in a round-the-clock inpatient facility (RIF). Materials and methods. A retrospective analysis of economic expenditures was performed at the Chelyabinsk Regional Clinical Center of Oncology and Nuclear Medicine in the RIF setting for the period from January 2018 to December 2023 for the treatment of 62 patients with high-grade uterine leiomyosarcomas of stage IB–IVA according to the classification of the International Federation of Gynecology and Obstetrics (2009). All patients underwent surgical treatment, complete hysterectomy with appendages, followed by antitumor drug therapy with a high risk of FN. In the economic cost analysis, the treatment regimens gemcitabine 900 mg/m2 on day 1 and day 8 + docetaxel 100 mg/m2 + empegfilgrastim (regimen code sh1207.1) and gemcitabine 900 mg/m2 on day 1 and day 8 + docetaxel 100 mg/m2 + filgrastim (regimen code sh1070) were compared. The costs of clinical blood tests and staying in RIF were also considered. Results. The stay in the RIF was 9 bed days with a long-acting G-CSF regimen and 15 days with a short-acting G-CSF regimen. When using a treatment regimen with filgrastim in 6 patients, the number of bed days increased to 18 due to persistent neutropenia. No FN events were reported. The calculations consisted of the cost of a bed day in the RIF (1,660 rubles) and purchasing of short- and long-acting G-CSF, without the cost of the main therapy. The costs of treating patients with short-acting G-CSF were comparable to those with long-acting G-CSF. Conclusion. The regimen with long-acting G-CSF is effective, easy to use, and cost-effective in RIF settings.

The role of macrophage migratory behavior in development, homeostasis and tumor invasion

Tumor-associated macrophages (TAMs) recapitulate the developmental and homeostatic behaviors of tissue resident macrophages (TRMs) to promote tumor growth, invasion and metastasis. TRMs arise in the embryo and colonize developing tissues, initially to guide tissue morphogenesis and then to form complex networks in adult tissues to constantly search for threats to homeostasis. The macrophage growth factor, colony-stimulating factor-1 (CSF-1), which is essential for TRM survival and differentiation, is also responsible for the development of the unique motility machinery of mature macrophages that underpins their ramified morphologies, migratory capacity and ability to degrade matrix. Two CSF-1-activated kinases, hematopoietic cell kinase and the p110δ catalytic isoform of phosphatidylinositol 3-kinase, regulate this machinery and selective inhibitors of these proteins completely block macrophage invasion. Considering tumors co-opt the invasive capacity of TAMs to promote their own invasion, these proteins are attractive targets for drug development to inhibit tumor progression to invasion and metastasis.

Evaluation of the effectiveness of hematopoietic blood stem cell mobilization using empegfilgrastim (Extimia®, BIOCAD) in patients with lymphoproliferative diseases: the experience of several centers in the Russian Federation. A retrospective study

Aim. To evaluate the effectiveness of autologous hematopoietic stem cell (HSC) mobilization with empegfilgrastim in patients with lymphoproliferative diseases (LPDs) and to identify prognostic factors affecting the effectiveness of mobilization. Materials and methods. The paper analyzes the effectiveness of HSC mobilization with Extimia® by JSC "BIOCAD" (INN: empegfilgrastim) in patients with LPDs. The study included 89 patients with LPDs (Hodgkin's lymphoma, B- and T-cell lymphomas, plasma cell tumors) who were treated in 5 research centers of the Russian Federation (in Moscow and St. Petersburg). The median age of patients was 39 (18–67) years. In 26 (29%) patients, HSC mobilization was performed "in a stable state of hematopoiesis" using only pegylated granulocyte colony-stimulating factor (PEG-G-CSF), and in 63 (71%) patients after chemotherapy (CT). Empegfilgrastim was administered as a single dose of 7.5 mg subcutaneously in two regimens: 24 hours after the end of CT or at a random time. Results. Two groups of patients were identified, analyzed, and compared: those with ineffective (n=23, 26%) and effective (n=66, 74%) HSC mobilization. Univariate and multivariate statistical analyses (binary logistic regression and multiple bidirectional binary logistic regression, respectively) were sequentially performed to determine the factors associated with ineffective mobilization. In a one-factor analysis, we studied the sex, age, diagnosis, bone/bone marrow involvement, the number of previous CT lines, the status of the disease (remission/no remission), the history of radiation therapy, the time interval from the administration of empegfilgrastim to the decision to perform leukapheresis, the mode of granulocytopoiesis stimulation ("in a stable state of hematopoiesis" or after CT), the leukocyte and platelet counts. The subsequent multifactorial analysis of the two selected parameters (diagnosis and time interval from drug administration to the decision to perform leukapheresis) showed the following statistically significant risk factors for ineffective mobilization: T-cell lymphoma; T-cell lymphoma versus other (combination) diagnoses (B-cell lymphoma, Hodgkin's lymphoma and plasma cell tumor): p=0.046, Wald test, odds ratio 4.18 (95% confidence interval 0.96–19.4). The time interval from the administration of empegfilgrastim to the first leukapheresis in the effective mobilization group depended on the diagnosis. The longest period was observed in patients with plasma cell tumors and the shortest in those with T-cell lymphomas: 10 (4–10) vs 5.5 (4–6) [p=0.01, Kruskal–Wallis test]. Empegfilgrastim proved equally effective for HSC mobilization both "on stable hematopoiesis" and after CT. Conclusion. The results of the first multicenter experience with Extimia® by JSC "BIOCAD" (INN: empegfilgrastim) to mobilize autologous HSCs in LPD patients demonstrate its high efficacy with a favorable safety and tolerability profile: 74% (66/89) successful mobilizations after a single administration of a fixed dose of the drug.

Discerning potent CSF-1r inhibitors for targeting and therapy of neuroinflammation using computational approaches

Microglia, the primary cellular mediator of neuroinflammation, plays a pivotal role in numerous neurological disorders. Precise and non-invasive quantification of microglia is of paramount importance. Despite various investigations into cell-specific biomarkers for assessing neuroinflammation, many suffer from poor cellular specificity and low signal-to-noise ratios. Colony-stimulating factor-1 receptor (CSF-1R), also known as FMS kinase, has emerged as a promising neuroinflammation biomarker with significant relevance to inflammatory diseases. Additionally, CSF-1R inhibitors (CSF-1Ri) have shown therapeutic potential in central nervous system (CNS) pathological conditions by depleting microglia. Therefore, the development of more specific CSF-1R inhibitors for targeting and treating various CNS insults and neurological disorders is imperative. This study focuses on the search for novel CSF-1R inhibitors. Based on the literature on CSF-1R inhibitors, we proposed and investigated ten ligands as novel CSF-1R inhibitors. Among these, the top three ligands, selected based on their maximum binding scores in docking calculations, are subjected to 100 nanoseconds of molecular dynamics (MD) simulation, alongside three reference ligands. All protein-ligand complexes remain stable throughout the dynamics and exhibit minimal fluctuations during the analysis. The results obtained through this study may prove significant for the future design of CSF-1R inhibitors with potential applications in the field of biomedicine.

Prognostic Impact of Neutropenia Recovery and G-CSF Use in Onco-Hematological Neutropenic Patients Admitted to Intensive Care Unit for Acute Respiratory Failure: A Retrospective, Real World Analysis.

The effect of neutropenia and theuse of granulocyte colony-stimulating factor (G-CSF) in critically ill patients with cancer are controversial, notably in those with lung injury. Neutropenia recovery can be associated with an acute respiratory failure (ARF) requiring intensive care unit (ICU) admission, especially when G-CSF is administered. In a single-center retrospective study, we evaluated (1) the effect of neutropenia recovery on the 90-day mortality and (2) the impact of G-CSF use on the outcome of patients with cancer and neutropenia with ARF admitted to the ICU. Among 1098 screened patients, 152 were neutropenic at ICU admission. The 90-day mortality was 44.7%. Factors independently associated with the 90-day mortality were invasive mechanical ventilation, ground-glass opacities and nodules on computed tomography scans, a disease in progression and the Simplified Acute Physiology Score (SAPS II) at ICU admission. The lack of neutropenia recovery during the ICU stay was associated with the 90-day mortality. Using G-CSF had no effect on the 90-day mortality or the neutropenia duration, but the PaO2:FiO2 ratio was significantly lower after neutropenia recovery in patients who received G-CSF. Thus, respiratory deterioration can occur in the neutropenia recovery period, potentially exacerbated by G-CSF. Our study suggests that neutropenia recovery was associated with survival in critically ill patients with cancer and neutropenia with ARF admitted to ICU, and the G-CSF could worsen the respiratory parameters.

Mobilization and Apheresis Collection Strategies to Reduce Platelet Loss in G-CSF Mobilized Healthy Adult Donors.

Granulocyte-colony stimulating factor (G-CSF) mobilizes hematopoietic progenitor cells (HPC) into the peripheral blood. Donor peripheral blood platelet loss has been observed during both G-CSF mobilization and apheresis collection. This study evaluates two strategies to reduce donor platelet loss, preserve product CD34+ cell yield and collection efficiency and increase volume of whole blood (WB) processed. One hundred and two adults healthy donors were mobilized with either standard dose G-CSF (9.5-12 mcg/kg/day × 4 days) or lower dose G-CSF (7.5-10 mcg/kg/day × 4 days) according to their pre-mobilization platelet count. Apheresis centrifugal force was adjusted by lowering the packing factor (PF) setting on the apheresis instrument. Between-group differences were observed in absolute donor platelet loss (p = 0.04) favoring lower G-CSF dosing, while percent donor platelet loss trended towards significance (p = 0.10). Lowering PF from the manufacturer's default of 4.5 to 4.0 demonstrated between-group differences in absolute donor platelet loss (p < 0.05), percent donor platelet loss (p < 0.001), and apheresis product platelet content (p < 0.001). No differences were observed in the product CD34+ cell content and CD34+ cell collection efficiency when PF was reduced to 4.0. Additionally, a higher volume of WB could be processed due to reduced donor platelet loss. Together, these two strategies may mitigate the risk of cumulative platelet loss in G-CSF mobilized healthy donors undergoing apheresis collection, thereby increasing the likelihood of completing the target total blood volume to be processed while maintaining donor safety.

Inter-alpha Inhibitor Proteins Modulate Microvascular Endothelial Components and Cytokines After Exposure to Hypoxia-Ischemia in Neonatal Rats.

Inter-alpha inhibitor proteins (IAIPs) are neuroprotective and attenuate lipopolysaccharide (LPS)-mediated blood-brain barrier (BBB) disruption in neonatal rodents. We investigated some mechanism(s) fundamental to neuroprotection by IAIPs including changes in cerebral endothelial components and inflammation. Postnatal day-7 rats exposed to sham surgery and placebo or carotid ligation plus 8% FiO2 (90min) were given IAIPs (30 or 60mg/kg) or placebo and were killed 6, 12, 24, or 36h after hypoxia-ischemia (HI). Proteins regulating BBB permeability to leukocytes (vascular cell adhesion molecule 1, VCAM-1), lipid-soluble (P-glycoprotein, PGP), and lipid-insoluble molecules (zonula occludens-1, ZO-1) were measured by immunoblot, and cytokines were measured in serum and cortex. HI resulted in reductions in ZO-1 and increases in VCAM-1, PGP, interferon-γ (IFN-γ), interleukin-12 (IL-12), vascular endothelial growth factor (VEGF), IL-α, and macrophage colony-stimulating factor (M-CSF) in cortex and increases in IL-4, IL-5, IL-10, and granulocyte colony-stimulating factor (G-CSF) in serum. IAIPs attenuated the reductions in ZO-1 and delayed increases in VCAM-1 and PGP in cortex and attenuated increases in cytokines in serum (IL-4, IL-5, IL-10, IFN-γ, G-CSF) and cortex (IL-1α, IL-12, IFN-γ, VEGF, M-CSF) after HI. We conclude that vascular endothelial proteins and cytokines exhibit sequential changes after HI and IAIPs modulate some of these HI-related changes in neonatal rats.

Titanium Surface Synergy: Strontium Incorporation and Controlled Disorder Nanotopography Optimize Osteoinduction.

Osteoporotic fractures and arthritis represent a major socioeconomic health burden. Fragility fracture fixation and joint replacement are often undertaken using titanium (Ti) or Ti alloy implants. Ideally these should induce bone formation and reduce osteoclast formation. Nanoscale topographies are potent inducers of osteogenesis, and strontium (Sr) has both osteogenic and antiosteoclastic effects. We incorporated strontium into a titanium surface with an osteogenic disordered nanoscale topography. The surface comprises 120 nm diameter, 100 nm deep pits in a near-square order with deliberate offset from the center pit position up to ±50 nm, providing a pattern with an average center-center pit spacing of 300 nm (called near-square 50, NSQ50). Several surfaces were assessed, including NSQ50 alone, strontium incorporated alone, and combined, compared with control surfaces. We assessed the surfaces using a human bone marrow stromal cell (BMSC)/ bone marrow hematopoietic cell (BHSC) coculture capable of osteogenesis and osteoclastogenesis. The samples eluted Sr over long-term culture, and uptake of Sr was better with eluted Sr than with Sr added to the culture media. The NSQ50 pattern in Ti was osteogenic, and addition of Sr elution increased osteogenesis further for both flat and NSQ50 samples. Interestingly, BMSCs on all Ti samples did not secrete the receptor activator of nuclear factor kappa-Β ligand (RANKL) or macrophage colony-stimulating factor (M-CSF) while secreting osteoprotegrin (OPG) at high levels. This meant that no osteoclast formation was observed on any Ti surface. Therefore, using Sr-incorporated nanotopographical imprinting, we generated highly osteogenic Ti surfaces that inhibited osteoclast formation.

A case of methotrexate toxicity in induced abortion

Background: Methotrexate is an anticancer drug from the antimetabolite class which is being used in cases of unruptured ectopic pregnancy and as an abortifacient as well. Giving correct dosage according to the body weight and body surface area is of utmost importance to avoid the complications.Case: A 29-year-old, G4P3L3 at 8+3 weeks of gestation with previous three cesarean sections, presented to our hospital with complaints of fever, abdominal pain, multiple episodes of diarrhea and vomiting and oral ulcers for two days. On enquiring, it was found that she received two doses of injection methotrexate (75 and 50 mg) as an abortifacient for an unwanted intrauterine pregnancy from a local doctor nearby. On presentation, her general condition was poor, she was dehydrated, temperature was 101.3°F, pulse rate was 130 beats/minute, blood pressure was 102/64mmHg, respiratory rate was 25/minute and SPO2 was 99% on room air. Her body weight was 55 kgs. Skin pigmentation and multiple oral ulcers were present. Per speculum and per vaginal examination was suggestive of minimal spotting and bulky uterus. Initial blood investigations revealed a hemoglobin level of 8.8 gm/dl, TLC of 1000/mm3, platelet count of 1.45L, INR of 1.37, and normal liver and renal function tests. A provisional diagnosis of methotrexate toxicity was made. Management of the patient was started in consultation with medical oncologist along with supportive treatment. She received IV fluids, antibiotics, and blood products (2-unit PCV and 12-RDP). She received oral leucoverin 15 mg QID and two doses of 300 mg granulocyte stimulating factor each. Gradually, her condition improved and thereafter tablet misoprostol was given for abortion. She was discharged after 13 days of hospital stay with contraceptive advice.Conclusion: The successful management of this case who presented with a constellation of symptoms and deteriorating hematological parameters exhibits the significance of a multidisciplinary approach and vigilant monitoring. Strategies to reduce the side effects and their early recognition include a safety checking procedure like SMART (safety of methotrexate therapy by assessing risks and toxicity) and determining plasma methotrexate concentrations.

Volume of hepatoid component and intratumor M2 macrophages predict prognosis in patients with hepatoid adenocarcinoma of the stomach.

Hepatoid adenocarcinoma of the stomach (HAS), a subtype of gastric cancer (GC), includes multiple tumor components, such as enteroblastic and tubular adenocarcinoma components. However, which component mostly contributes to the aggressive behavior of HAS remains unclear. Moreover, the role of tumor-associated macrophages (TAMs) has not been explored in HAS. This study evaluated the clinical significance of the proportion of the hepatoid component within the tumor, CD163 + macrophages, and macrophage colony-stimulating factor-1 (CSF-1) in HAS. In total, 56 cases of primary HAS were analyzed. In each case, hepatoid (HC), enteroblastic (EC), and tubular (TC) components were identified, and the ratio of HC to the entire tumor (hepatoid component ratio, HCR) was assessed to examine the correlation between HCR and clinicopathological features. Immunohistochemical staining for CD163 and CSF-1 was performed, and differences in immunohistochemical results among the three tumor components were analyzed. In each tumor component, the prognostic impact of CD163 and CSF-1 was examined. A high HCR was associated with worse overall survival (OS). CD163 + TAMs and CSF-1 immunoreactivity score in HC were significantly higher than those in the other components. High infiltration of CD163 + TAMs and a high CSF-1 immunoreactivity score in HC were associated with an aggressive course and worse OS. Multivariate analysis revealed the proportion of HC in HAS as an independent prognostic factor (HR = 3.176, p = 0.006). The HCR and CD163 + TAMs may be useful prognostic predictors, and TAMs may be novel therapeutic targets of HAS.

Nicotine promotes M2 macrophage polarization through α5-nAChR/SOX2/CSF-1 axis in lung adenocarcinoma

α5-nicotinic acetylcholine receptor (α5-nAChR) plays a vital part in lung adenocarcinoma (LUAD). However, it is not comprehensively understood that how the α5-nAChR affects LUAD. Through diverse bioinformatics analyses and immunohistochemistry, the expressions of α5-nAChR and SOX2 as well as their relations were dissected. α5-nAChR regulated the differentiation of monocytes into M2 macrophages by targeting the STAT3/SOX2/CSF-1 signaling in the coculture system by western blotting and ChIP. α5-nAChR-mediated macrophage-mediated LUAD cell migration via SOX2/CSF-1 signaling in the cocultured medium. Correlations of α5-nAChR, SOX2 and M2 phenotype tumor-associated macrophages (TAMs) were validated in mouse LUAD models and clinical samples. α5-nAChR expression was connected to SOX2 expression, smoking and bad prognosis of LUAD among clinical samples. Nicotine-induced SOX2 expression was mediated by α5-nAChR via STAT3. Additionally, SOX2-mediated macrophage colony-stimulating factor (CSF-1) expression contributed to LUAD progression in vitro. Furthermore, α5-nAChR expression was strongly linked to pSTAT3, SOX2 and M2 macrophage marker CD206 expression and negatively correlated with M1 macrophage marker CD86 expression in vivo. It is indicated that M2 macrophages are mediated by the new α5-nAChR /SOX2/CSF-1 axis in nicotine-related LUAD, which is a potential therapeutic strategy for cancer.

Structural diversity and function of the granulocyte colony-stimulating factor in medaka fish.

Diversity in the granulocyte repertoire, including neutrophils, basophils, and eosinophils, has been reported in vertebrate species. Medaka fish (Oryzias latipes) have only neutrophils; however, the storage pool of granulopoiesis tissues and the molecular mechanism of granulopoiesis in medaka fish have not been explored. Granulocyte colony-stimulating factor (G-CSF) is a cytokine responsible for neutrophil differentiation, survival, and proliferation. We performed in silico analysis to molecularly characterize the medaka G-CSF and G-CSF receptor (G-CSFR) genes. This study showed that medaka G-CSF differs considerably from human and mouse G-CSF in terms of the primary protein structure; however, the predicted tertiary structure was largely conserved. Analyses of lipopolysaccharide stimulation and G-CSF knockout and overexpression in medaka revealed that G-CSF mobilizes neutrophils into the peripheral blood. The analysis of G-CSF-deficient medaka revealed that G-CSF is involved in erythropoiesis. These findings represent an important first step toward understanding granulocyte hematopoiesis in non-mammalian species.

Outcomes of Pediatric Liver Transplantation in Glycogen Storage Disease Type 1b-A Single-Center Experience.

Liver transplantation (LT) normalizes fasting tolerance in glycogen storage disease type (GSD) 1b. However, reported outcomes post-LT with respect to correction of neutropenia, infection risk and growth are varied. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been recently shown to improve neutropenia in GSD1b patients. In this single-center retrospective study, we reviewed all children who underwent LT for GSD1b. Neutropenia, dose of granulocyte colony-stimulating factor (G-CSF), unplanned hospital attendance, anthropometrics, graft rejection, survival, and the effects of dapagliflozin were analyzed. Data from protocol biopsies obtained at 1, 5, and 10 years post-LT and immunosuppression levels were collected. Eight children (6 female), all on G-CSF pre-transplant, underwent cadaveric LT for GSD1b at median age 3.6 years (IQR 3.3-5.1) with mean follow-up time of 10.3 years (95% CI 7.5-13.1). Neutrophil count and G-CSF requirement did not improve post-LT. Although a reduction in unplanned hospital attendance due to infection (0.98 [95% CI 0.76-1.26] vs. 0.49 [95% CI 0.41 to 0.57] per person-year, p < 0.01) was observed, gastrointestinal complaints and graft dysfunction accounted for a similar hospitalization burden pre- versus post-LT. Body mass index (BMI) reduced post-LT (Z-score 1.47 [95%CI 0.39-2.23] vs. 0.56 [95% CI -0.74 to 1.45], p = 0.02), with no significant change in height. Although all children and grafts have survived, 75% of recipients developed rejection, despite adequate immunosuppression levels, with two children having been found to have developed significant fibrosis on their 5-year protocol biopsy. Although dapagliflozin allowed cessation of G-CSF, no improvement in neutrophil count was observed. Despite this, a reduction in gastrointestinal and infection-related morbidity was noted following dapagliflozin. Although LT normalizes fasting tolerance in GSD1b and reduces hospital attendance due to infection, morbidity from infection and gastrointestinal manifestations persist. Children in our cohort experienced high rates of rejection necessitating titration of immunosuppression to balance risk of infection against organ rejection. Future studies should investigate whether early introduction of SGLT2 inhibitors post-LT impact morbidity in this group.

Alternative therapy for lymphoma with febrile neutropenia using traditional Chinese medicine: A case report

IntroductionFebrile neutropenia is a common complication in patients undergoing chemotherapy for hematologic malignancies and is associated with significant morbidity and mortality. Primary granulocyte colony-stimulating factor (G-CSF) prophylaxis is consistently associated with a notable reduction in the risk of febrile neutropenia. However, the use of G-CSF in patients who are already neutropenic from chemotherapy remains controversial. Studies have shown that 12.9% of cancer patients incorporate traditional Chinese medicine (TCM) to alleviate chemotherapy side effects in Taiwan; thereby providing an alternative management strategy for neutropenic fever in cancer patients. Case presentationThis is an 18-year-old female with newly diagnosed precursor T-lymphoblastic lymphoma. After chemotherapy, the patient developed febrile neutropenia. Despite the use of antibiotics and G-CSF, the febrile neutropenia persisted for two months. Approximately ten days after the initiation of traditional Chinese medicine decoction with the strategy of tonifying the spleen and stomach, clearing yin fire, and uplifting yang, her absolute neutrophil count (ANC) had gradually increased. Additionally, after two weeks of treatment, her fever subsided. The patient continued with chemotherapy and was discharged in stable condition. DiscussionAntibiotic use aligns with the TCM perspective of an “attack” approach. Conversely, our TCM decoction was designed to raise the ANC by tonifying the spleen and stomach, clearing Yin Fire, and uplifting Yang. Li Dongyuan, one of the four great masters of the Jin Yuan Dynasty, created the formula: Bupiwei Shengyang Sanhuo Decoction that is notable in this regard. The herbs in our decoction have shown hematopoietic and myelosuppression-alleviating effect. For many patients who do not respond adequately to G-CSF alone, integrative treatments involving both TCM and Western medicine can offer additional therapeutic benefits by increasing blood cell counts.

Post-transplant G-CSF impedes engraftment of gene-edited human hematopoietic stem cells by exacerbating p53-mediated DNA damage response.

Granulocyte-colony-stimulating factor (G-CSF) is commonly used to accelerate recovery from neutropenia following chemotherapy and autologous transplantation of hematopoietic stem and progenitor cells (HSPCs) for malignant disorders. However, its utility after exvivo gene therapy in human HSPCs remains unexplored. We show that administering G-CSF from day 1 to 14 post-transplant impedes engraftment of CRISPR-Cas9 gene-edited human HSPCs in murine xenograft models. G-CSF affects gene-edited HSPCs through a cell-intrinsic mechanism, causing proliferative stress and amplifying the early p53-mediated DNA damage response triggered by Cas9-mediated DNA double-strand breaks. This underscores a threshold mechanism where p53 activation must reach a critical level to impair cellular function. Transiently inhibiting p53 or delaying the initiation of G-CSF treatment to day 5 post-transplant attenuates its negative impact on gene-edited HSPCs. The potential for increased HSPC toxicity associated with post-transplant G-CSF administration in CRISPR-Cas9 autologous HSPC gene therapy warrants consideration in clinical trials.