Immunophenotype of myeloid granulocytes in Chinese patients with BCR::ABL1-negative myeloproliferative neoplasms.

Typical BCR::ABL1-negative myeloproliferative neoplasms (MPN) are mainly referred to as polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofbrosis (PMF). Granulocytes in MPN patients are involved in their inflammation and form an important part of the pathophysiology of MPN patients. It has been shown that the immunophenotype of granulocytes in MPN patients is altered. We used flow cytometry to explore the immunophenotype of MPN patients and correlate it with clinical parameters. The results showed that PMF patients and PV patients had higher CD15+CD11b+ granulocytes than ET patients and normal controls. When grouped by gene mutation, changes in the granulocyte immunophenotype of MPN patients were independent of the JAK2V617F and CALR mutations. There was no significant heterogeneity in immunophenotype between ET patients and Pre-PMF, and between Overt-PMF and Pre-PMF patients. Granulocytes from some MPN patients showed an abnormal CD13/CD16 phenotype with a significant increase in mature granulocytes on molecular and cytomorphological grounds, and this abnormal pattern occurred significantly more frequently in PMF patients than in ET patients. CD15-CD11b- was negatively correlated with WBC and Hb and positively correlated with DIPSS score, whereas high CD10+ granulocytes were significantly and negatively associated with prognostic system IPSS and DIPSS scores in PMF patients. In conclusion, this study demonstrates the landscape of bone marrow granulocyte immunophenotypes in MPN patients. MPN patients, especially those with PMF, have a significant granulocyte developmental overmaturation phenotype. CD10+ granulocytes may be involved in the prognosis of PMF patients.

Ferroptosis contributes to airway epithelial E-cadherin disruption in a mixed granulocytic asthma mouse model.

Aberrant expression of airway epithelial E-cadherin is a key feature of asthma, yet the underlying mechanisms are largely unknown. Ferroptosis is a novel form of regulated cell death involved in asthma pathogenesis. This study was aimed to evaluate the role of ferroptosis and to investigate whether ferroptosis mediates E-cadherin disruption in mixed granulocyte asthma (MGA). Two murine models of MGA were established using toluene diisocyanate (TDI) or ovalbumin with Complete Freund's Adjuvant (OVA/CFA). Specific antagonists of ferroptosis, including Liproxstatin-1 (Lip-1) and Ferrostatin-1 (Fer-1) were given to the mice. The allergen-exposed mice displayed markedly shrunk mitochondria in the airway epithelia, with decreased volume and denser staining accompanied by down-regulated GPX4 as well as up-regulated FTH1 and malondialdehyde, which are markers of ferroptosis. Decreased pulmonary expression of E-cadherin was also observed, with profound loss of membrane E-cadherin in the airway epithelia, as well as increased secretion of sE-cadherin. Treatment with Lip-1 not only showed potent protective effects against the allergen-induced airway hyperresponsiveness and inflammatory responses, but also rescued airway epithelial E-cadherin expression and inhibited the release of sE-cadherin. Taken together, our data demonstrated that ferroptosis mediates airway epithelial E-cadherin dysfunction in MGA.

New insights into the treatment of polycystic ovary syndrome: HKDC1 promotes the growth of ovarian granulocyte cells by regulating mitochondrial function and glycolysis.

Polycystic ovary syndrome (PCOS) is an endocrine disease, and its pathogenesis and treatment are still unclear. Hexokinase domain component 1 (HKDC1) participates in regulating mitochondrial function and glycolysis. However, its role in PCOS development remains unrevealed. Here, female C57BL/6 mice were intraperitoneally injected with dehydroepiandrosterone (DHEA; 60 mg/kg body weight) to establish an in vivo model of PCOS. In vitro, KGN cells, a human ovarian granular cell line, were used to explore the potential mechanisms. DHEA-treated mice exhibited a disrupted estrus cycle, abnormal hormone levels, and insulin resistance. Dysfunction in mitochondria and glycolysis is the main reason for PCOS-related growth inhibition of ovarian granular cells. Here, we found that the structure of mitochondria was impaired, less ATP was generated and more mitochondrial Reactive Oxygen Species were produced in HKDC1-silenced KGN cells. Moreover, HKDC1 knockdown inhibited glucose consumption and decreased the production of glucose-6-phosphate and lactic acid. Conclusively, HKDC1 protects ovarian granulocyte cells from DHEA-related damage at least partly by preserving mitochondrial function and maintaining glycolysis.

[Possible Risk Factors for Bone Marrow Fibroplasia in Patients with Polycythemia Vera].

OBJECTIVE: To understand the biological characteristics of polycythemia vera (PV) patients with myeloid fibroplasia, and further analyze the risk factors affecting myeloid fibroplasia in PV patients, so as to provide ideas for predicting the occurrence of myeloid fibroplasia in PV patients. METHODS: Forty patients with PV in the Department of Hematology, Xiyuan Hospital of China Academy of Chinese Medical Sciences were collected and divided into two groups, with (hyperplasia group) and without (Non-proliferative group) hyperplasia of bone marrow fibers. The differences of basic clinical characteristics, blood routine, biochemistry, bone marrow cells, coagulation function and other indicators between the two groups were compared, and the independent risk factors affecting the proliferation of bone marrow fibrous tissue in PV patients were further analyzed by multivariate regression. RESULTS: Compared with Non-proliferative group, the JAK2 mutation rate (95% vs 70%，P=0.037), eosinophilic cell count (0.19 vs 0.11, P=0.047) and eosinophilic percentage (1.84 vs 1.27, P=0.001) in PV patients with hyperplasia were significantly increased, triglycerides (1.55 vs 1.91, P=0.038) and low-density lipoprotein (1.50 vs 3.08, P=0.000) were significantly reduced, bone marrow hematopoietic volume (0.85 vs 0.6, P=0.001), granulocyte/erythrocyte ratio (3.40 vs 1.89, P=0.033), lymphocyte/erythrocyte ratio (0.60 vs 0.42, P=0.033), and granulocyte+lymphocyte/erythrocyte ratio (3.72 vs 2.37, P=0.026) were significantly increased, thrombin time (18.84 vs 18.12, P=0.043) was significantly prolonged. Multivariate regression analysis results showed that peripheral blood eosinophil ≥2% and low-density lipoprotein ≤2 mmol/L were independent risk factors for bone marrow fibrous tissue hyperplasia in PV patients (P<0.05). CONCLUSION: Increased proportion of peripheral blood eosinophils and decreased low density lipoprotein are risk factors for bone marrow fibrous tissue hyperplasia in PV patients.

Adenosquamous carcinoma of the gallbladder simultaneously producing granulocyte-colony-stimulating factor and parathyroid hormone-related protein.

We report a rare case of adenosquamous carcinoma of the gallbladder which simultaneously produces granulocyte-colony-stimulating factor (G-CSF) and parathyroid hormone-related protein (PTHrP), confirmed serologically and histologically. A 71-year-old man was examined for a gallbladder tumor with multiple lymph nodes and liver metastases. Histopathological evaluation by endoscopic ultrasound fine-needle aspiration revealed adenosquamous carcinoma of the gallbladder. Laboratory data showed markedly elevated white blood cell (WBC) count of 34,700 µL and corrected serum calcium level of 14.9 mg/dL. Serum G-CSF (191 pg/mL) and PTHrP (23.1 pmol/L) levels were high. Zoledronic acid and calcitonin were administered to treat hypercalcemia, which normalized serum calcium levels. Gemcitabine-cisplatin chemotherapy was started for cStage IVB gallbladder cancer. After chemotherapy initiation, WBCs showed a rapid downward trend; however, the patient suddenly developed acute respiratory distress syndrome; thus, chemotherapy was discontinued. Subsequently, WBC count increased again, and the patient's overall condition deteriorated. The patient died on day 27. Immunohistochemistry using autopsy specimens demonstrated patchy staining for G-CSF in the squamous cell carcinoma portion and diffuse and weak positive staining for PTHrP in the squamous cell carcinoma and poorly differentiated adenocarcinoma portions of the tumor, suggesting simultaneous G-CSF and PTHrP production by the tumor. This is the first report of a patient with gallbladder cancer with serological and histological evidence for G-CSF and PTHrP production.

Altered granulocyte count and erythrocyte measures in middle-aged, healthy carriers of APOE and PICALM risk genes for Alzheimer's disease.

APOE­Îµ4 genotype (apolipoprotein E, epsilon 4) is the strongest genetic risk factor for Alzheimer's disease (AD). Despite years of research, it is still not known how it contributes to dementia development. APOE has been implicated in many AD pathology mechanisms, like Aß clearance, brain metabolism, changes within microglia and other glial functions and inflammatory processes. In fact, immunological/inflammatory processes are recently discussed as an important factor in Alzheimer's development and granulocyte profiles changes are reported in patients. However, the exact link between the immune system and risk­genes is unknown. In particular, it is not known whether and how they interact throughout the lifetime, before the disease onset. The aim of the study was to investigate the relationship between granulocyte count and the APOE/PICALM genes in healthy individuals with an increased genetic risk of AD. An exploratory analysis regarding other blood cells was also conducted. Blood samples were collected from 77 healthy middle­aged (50-63 years old) participants, who were also asked to complete a health and life­style questionnaires. Groups with different AD risk­genes were compared. Differences in granulocyte profiles were found in healthy carriers of AD risk­genes who had slightly elevated eosinophil levels as compared to non-risk carriers. An exploratory analysis showed some alteration in mean corpuscular hemoglobin content and concentration (MCH/MCHC) levels between risk­carriers subgroups and non-risk carriers. No other differences in blood count or lipoprotein profile were found between healthy APOE/PICALM risk­carriers and non-risk carriers. Longitudinal studies will reveal if and how those changes contribute to the development of AD pathology.

Treatment-Induced Bone Marrow Enhancement at MRI in Breast Cancer Patients Receiving Granulocyte-Colony Stimulating Factor Adjunct to Chemotherapy.

RATIONALE AND OBJECTIVES: Granulocyte-colony stimulating factor (G-CSF) induces the reconversion of fatty bone marrow to hematopoietic bone marrow. The bone marrow changes are detectable as signal intensity changes at MRI. The aim of this study was to evaluate sternal bone marrow enhancement following G-CSF and chemotherapy treatment in women with breast cancer. MATERIALS AND METHODS: This retrospective study included breast cancer patients who received neoadjuvant chemotherapy with adjunct G-CSF. The signal intensity of sternal bone marrow at MRI on T1-weighted contrast-enhanced subtracted images was measured before treatment, at the end of treatment, and at 1-year follow-up. The bone marrow signal intensity (BM SI) index was calculated by dividing the signal intensity of sternal marrow by the signal intensity of the chest wall muscle. Data were collected between 2012 and 2017, with follow-up until August 2022. Mean BM SI indices were compared before and after treatment, and at 1-year follow-up. Differences in bone marrow enhancement between time points were analyzed using a one-way repeated measures ANOVA. RESULTS: A total of 109 breast cancer patients (mean age 46.1 ± 10.4 years) were included in our study. None of the women had distal metastases at presentation. A repeated-measures ANOVA determined that mean BM SI index scores differed significantly across the three time points (F[1.62, 100.67] = 44.57, p < .001). At post hoc pairwise comparison using the Bonferroni correction BM SI index significantly increased between initial assessment and following treatment (2.15 vs 3.33, p < .001), and significantly decreased at 1-year follow-up (3.33 vs 1.45, p < .001). In a subgroup analysis, while women younger than 50 years had a significant increase in marrow enhancement after G-CSF treatment, in women aged 50 years and older, the difference was not statistically significant. CONCLUSION: Treatment with G-CSF as an adjunct to chemotherapy can result in increased sternal bone marrow enhancement due to marrow reconversion. Radiologists should be aware of this effect in order to avoid misinterpretation as false marrow metastases.

Mild generalised pustular psoriasis patient with a heterozygous hypomorphic MPO variant successfully treated with granulocyte and monocyte adsorption apheresis.

Pathogenic variants in MPO, which encodes the myeloperoxidase, were reported as causative genetic defects in several cases of generalised pustular psoriasis (GPP) in addition to patients with myeloperoxidase deficiency in 2020. However, which clinical subtypes of GPP patients have pathogenic variants in MPO remains largely undetermined, and elucidating this is clinically important. The present report outlines a mild case of GPP with a rare missense heterozygous variant, c.1810C>T p.(Arg604Cys), in MPO. Our structural analysis and functional assays to measure myeloperoxidase activity suggest that the present MPO substitution is a hypomorphic variant in MPO. Thus, the mild phenotype of the present GPP patient might be associated with an incomplete hypomorphic loss-of-function variant in MPO. Additionally, the severe intractable edematous pustules and erythema improved dramatically after five rounds of granulocyte and monocyte adsorption apheresis (GMA) therapy. This is the first report of GMA treatment for GPP associated with a pathogenic variant in MPO, as far as we know. Our findings suggest that GMA might be a useful and powerful tool for controlling GPP in patients with myeloperoxidase deficiency.

A case of granulocyte-colony-stimulating factor-producing gallbladder cancer with lymph node metastasis together with a literature review.

The granulocyte-colony-stimulating factor (G-CSF) glycoprotein stimulates precursor cell proliferation and differentiation in the bone marrow. Various G-CSF-producing tumors have been reported; they showed early progression and an extremely poor prognosis. Here, we report a case of G-CSF-producing gallbladder cancer with lymph node metastasis. In addition, we reviewed 30 previous case reports of G-CSF-producing gallbladder cancers to elucidate the characteristics and most appropriate treatment. During a routine visit to her local doctor for monitoring of diabetes and hypertension, a 68-year-old female was found to have an elevated white-blood-cell (WBC) count and C-reactive protein (CRP) level, and a gallbladder mass. Laboratory tests revealed a high serum G-CSF level, and imaging revealed a tumor of the gallbladder with regional lymphadenopathy. We diagnosed a G-CSF-producing gallbladder cancer and performed liver resection of segment IVa/V: regional lymph node dissection with extrahepatic bile duct resection. Pathologically, the tumor was a poorly differentiated squamous cell carcinoma. G-CSF immunostaining for tumor cells was positive. She is alive without recurrence at 16 months after surgery. If a patient exhibits a gallbladder tumor, with an elevated WBC count and CRP level but no symptoms of infection, a G-CSF-producing gallbladder cancer should be suspected; radical resection should be performed immediately after diagnosis.

Granulocyte transfusion during cord blood transplant for relapsed, refractory AML is associated with massive CD8+ T-cell expansion, significant cytokine release syndrome and induction of disease remission.

In high-risk myeloid malignancy, relapse is reduced using cord blood transplant (CBT) but remains the principal cause of treatment failure. We previously described T-cell expansion in CBT recipients receiving granulocyte transfusions. We now report the safety and tolerability of such transfusions, T-cell expansion data, immunophenotype, cytokine profiles and clinical response in children with post-transplant relapsed acute leukaemia who received T-replete, HLA-mismatched CBT and pooled granulocytes within a phase I/II trial (ClinicalTrials.Gov NCT05425043). All patients received the transfusion schedule without significant clinical toxicity. Nine of ten patients treated had detectable measurable residual disease (MRD) pre-transplant. Nine patients achieved haematological remission, and eight became MRD negative. There were five deaths: transplant complications (n = 2), disease (n = 3), including two late relapses. Five patients are alive and in remission with 12.7 months median follow up. Significant T-cell expansion occurred in nine patients with a greater median lymphocyte count than a historical cohort between days 7-13 (median 1.73 × 109 /L vs. 0.1 × 109 /L; p < 0.0001). Expanded T-cells were predominantly CD8+ and effector memory or TEMRA phenotype. They exhibited markers of activation and cytotoxicity with interferon-gamma production. All patients developed grade 1-3 cytokine release syndrome (CRS) with elevated serum IL-6 and interferon-gamma.

The role of granulocyte-macrophage colony-stimulating factor in head and neck cancer.

OBJECTIVE: To review the molecular mechanisms and biological roles of granulocyte-macrophage colony-stimulating factor (GM-CSF) in head and neck squamous cell carcinoma, highlighting its potential clinical applications. DESIGN: The search terms "granulocyte-macrophage colony-stimulating factor", "GM-CSF", "CSF2″ and "head and neck squamous cell carcinoma" or "head and neck cancer" were queried in the PubMed/MEDLINE and Scopus databases. RESULTS: Despite of being a widely expressed cytokine, the number of studies investigating the specific roles of GM-CSF in head and neck cancer was limited. Most of them investigated GM-CSF in conjunction with other cytokines. When studied alone, conflicting findings were observed in head and neck squamous cell carcinoma. GM-CSF has been shown to induce angiogenesis and local tumor invasion. Additionally, it has also been implicated in immune evasion. On the other hand, GM-CSF stimulated the differentiation of dendritic cells, which are responsible for presenting tumor antigens, and for the regulation of T cell function. Even with these paradoxical effects, there are few studies investigating the potential of GM-CSF as adjuvant therapy in head and neck cancer. CONCLUSION: The effects of GM-CSF in head and neck cancer may be pro- or antitumor. Understanding how one arm and not the other is activated is essential to assess the applicability and the safety of this cytokine as a therapeutic agent.

Peripheral low-density granulocytes after colorectal cancer surgery in predicting recurrence.

BACKGROUND: Low-density granulocytes (LDGs) have been shown to be increased in the peripheral blood of patients with inflammatory and malignant diseases. This study evaluated LDGs in patients who underwent radical surgery for colorectal cancer (CRC) and their impact on survival. METHODS: Patients who underwent radical colectomy between 2017 to 2021 were screened for enrolment in the study. Peripheral blood was obtained in the operating room before and after surgery and cells were recovered from the mononuclear layer after density gradient preparations. The ratio of CD66b(+) LDG to CD45(+) leukocytes was determined with flow cytometry, and the association of the ratios with patient outcomes was examined. The main outcome of interest was recurrence-free survival (RFS). RESULTS: Out of 228 patients treated, 176 were enrolled, including 108 colonic and 68 rectal cancers. Overall, 38 patients were stage I, 30 were stage II, 72 were stage 3, and 36 were stage IV. The number of LDGs was markedly increased immediately after surgery and the proportion of LDGs correlated positively with operating time (r = 0.2806, P < 0.001) and intraoperative blood loss (r = 0.1838, P = 0.014). Purified LDGs produced high amounts of neutrophil extracellular traps after short-term culture and efficiently trapped tumour cells in vitro. The proportion of postoperative LDGs was significantly higher in 13 patients who developed recurrence (median 9 (range 1.63-47.0)) per cent versus median 2.93 ((range 0.035-59.45) per cent, P = 0.013). When cut-off values were set at 4.9 per cent, a higher proportion of LDGs was strongly and independently associated with decreased RFS (P = 0.005). In patients with stage III disease, adjuvant chemotherapy significantly improved RFS of patients with high ratios of LDGs, but not low LDGs. CONCLUSION: LDGs are recruited to circulating blood by surgical stress early in the postoperative interval after colectomy for colonic cancer and their postoperative proportion is correlated with recurrence.

Activated granulocytes and inflammatory cytokine signaling drive T-cell lymphoma progression and disease symptoms.

Peripheral T-cell lymphomas (PTCLs), especially angioimmunoblastic and follicular TCLs, have a dismal prognosis because of the lack of efficient therapies, and patients' symptoms are often dominated by an inflammatory phenotype, including fever, night sweats, weight loss, and skin rash. In this study, we investigated the role of inflammatory granulocytes and activated cytokine signaling on T-cell follicular helper-type PTCL (TFH-PTCL) disease progression and symptoms. We showed that ITK-SYK-driven murine PTCLs and primary human TFH-PTCL xenografts both induced inflammation in mice, including murine neutrophil expansion and massive cytokine release. Granulocyte/lymphoma interactions were mediated by positive autoregulatory cytokine loops involving interferon gamma (CD4+ malignant T cells) and interleukin 6 (IL-6; activated granulocytes), ultimately inducing broad JAK activation (JAK1/2/3 and TYK2) in both cell types. Inflammatory granulocyte depletion via antibodies (Ly6G), genetic granulocyte depletion (LyzM-Cre/MCL1flox/flox), or IL-6 deletion within microenvironmental cells blocked inflammatory symptoms, reduced lymphoma infiltration, and enhanced mouse survival. Furthermore, unselective JAK inhibitors (ruxolitinib) inhibited both TCL progression and granulocyte activation in various PTCL mouse models. Our results support the important role of granulocyte-driven inflammation, cytokine-induced granulocyte/CD4+ TCL interactions, and an intact JAK/STAT signaling pathway for TFH-PTCL development and also support broad JAK inhibition as an effective treatment strategy in early disease stages.

Multiparameter flow cytometry in the evaluation of myelodysplasia: Analytical issues: Recommendations from the European LeukemiaNet/International Myelodysplastic Syndrome Flow Cytometry Working Group.

Multiparameter flow cytometry (MFC) is one of the essential ancillary methods in bone marrow (BM) investigation of patients with cytopenia and suspected myelodysplastic syndrome (MDS). MFC can also be applied in the follow-up of MDS patients undergoing treatment. This document summarizes recommendations from the International/European Leukemia Net Working Group for Flow Cytometry in Myelodysplastic Syndromes (ELN iMDS Flow) on the analytical issues in MFC for the diagnostic work-up of MDS. Recommendations for the analysis of several BM cell subsets such as myeloid precursors, maturing granulocytic and monocytic components and erythropoiesis are given. A core set of 17 markers identified as independently related to a cytomorphologic diagnosis of myelodysplasia is suggested as mandatory for MFC evaluation of BM in a patient with cytopenia. A myeloid precursor cell (CD34+ CD19- ) count >3% should be considered immunophenotypically indicative of myelodysplasia. However, MFC results should always be evaluated as part of an integrated hematopathology work-up. Looking forward, several machine-learning-based analytical tools of interest should be applied in parallel to conventional analytical methods to investigate their usefulness in integrated diagnostics, risk stratification, and potentially even in the evaluation of response to therapy, based on MFC data. In addition, compiling large uniform datasets is desirable, as most of the machine-learning-based methods tend to perform better with larger numbers of investigated samples, especially in such a heterogeneous disease as MDS.

A case of ulcerative colitis-related postoperative enteritis treated with granulocyte and monocyte apheresis.

A 46-year-old man, receiving continuous steroid therapy for refractory ulcerative colitis with an insufficient response to anti-tumor necrosis factor-α therapy, presented with left buttock pain. He was diagnosed with steroidal left femoral head necrosis, and total proctocolectomy with permanent ileostomy was performed. At 6 months postoperatively, the patient developed general fatigue, abdominal pain, and severe ileostomy diarrhea. Computed tomography revealed continuous intestinal edema from the descending duodenal leg to the upper jejunum. Gastrointestinal endoscopy revealed deep ulcers, coarse mucosa, and duodenal erosion. Based on clinical progress, findings, and pathology, the patient was diagnosed with ulcerative colitis-related postoperative enteritis. Although 5-aminosalicylic acid treatment was initiated, his symptoms persisted, bloody diarrhea from colostomy was observed. Subsequently, granulocyte and monocyte apheresis treatment was added. Symptoms and endoscopic findings improved with granulocyte and monocyte apheresis. Azathioprine was introduced as maintenance therapy, and no sign of recurrence was observed. Although ulcerative colitis-related postoperative enteritis has no definitive treatment, granulocyte and monocyte apheresis may be considered for initial treatment.

Low-density granulocytes in systemic autoimmunity and autoinflammation.

A body of evidence has re-energized the interest on the role neutrophils in inflammatory and autoimmune conditions. For decades, neutrophils have been considered a homogenous population. Nevertheless, accumulating evidence suggests that neutrophils are more versatile and heterogeneous than initially considered. The notion of neutrophil heterogeneity has been supported by the identification of low-density granulocytes (LDGs) in systemic lupus erythematosus (SLE) and other systemic autoimmune and autoinflammatory conditions. Transcriptomic, epigenetic, proteomic, and functional analyses support that LDGs are a distinct subset of proinflammatory neutrophils implicated in the pathogenesis of SLE and other autoimmune diseases. Importantly, it remains incompletely characterized whether LDGs detected in other inflammatory/autoimmune conditions display the same phenotype that those present in SLE. A shared feature of LDGs across diseases is their association with vascular damage, an important contributor to morbidity and mortality in chronic inflammatory conditions. Additionally, the lack of specific markers to identify LDGs in circulation or in tissue, makes it a challenge to elucidate their role in the pathogenesis of inflammatory and autoimmune conditions. In this review, we aim to examine the evidence on the biology and the putative pathogenic role of LDGs in systemic autoimmune diseases.

Possible Risk Factors for Bone Marrow Fibroplasia in Patients with Polycythemia Vera / 中国实验血液学杂志

OBJECTIVE@#To understand the biological characteristics of polycythemia vera (PV) patients with myeloid fibroplasia, and further analyze the risk factors affecting myeloid fibroplasia in PV patients, so as to provide ideas for predicting the occurrence of myeloid fibroplasia in PV patients.@*METHODS@#Forty patients with PV in the Department of Hematology, Xiyuan Hospital of China Academy of Chinese Medical Sciences were collected and divided into two groups, with (hyperplasia group) and without (Non-proliferative group) hyperplasia of bone marrow fibers. The differences of basic clinical characteristics, blood routine, biochemistry, bone marrow cells, coagulation function and other indicators between the two groups were compared, and the independent risk factors affecting the proliferation of bone marrow fibrous tissue in PV patients were further analyzed by multivariate regression.@*RESULTS@#Compared with Non-proliferative group, the JAK2 mutation rate (95% vs 70%，P=0.037), eosinophilic cell count (0.19 vs 0.11, P=0.047) and eosinophilic percentage (1.84 vs 1.27, P=0.001) in PV patients with hyperplasia were significantly increased, triglycerides (1.55 vs 1.91, P=0.038) and low-density lipoprotein (1.50 vs 3.08, P=0.000) were significantly reduced, bone marrow hematopoietic volume (0.85 vs 0.6, P=0.001), granulocyte/erythrocyte ratio (3.40 vs 1.89, P=0.033), lymphocyte/erythrocyte ratio (0.60 vs 0.42, P=0.033), and granulocyte+lymphocyte/erythrocyte ratio (3.72 vs 2.37, P=0.026) were significantly increased, thrombin time (18.84 vs 18.12, P=0.043) was significantly prolonged. Multivariate regression analysis results showed that peripheral blood eosinophil ≥2% and low-density lipoprotein ≤2 mmol/L were independent risk factors for bone marrow fibrous tissue hyperplasia in PV patients (P<0.05).@*CONCLUSION@#Increased proportion of peripheral blood eosinophils and decreased low density lipoprotein are risk factors for bone marrow fibrous tissue hyperplasia in PV patients.

Nuclear Proteomics of Induced Leukemia Cell Differentiation.

Studies of induced granulocytic differentiation help to reveal molecular mechanisms of cell maturation. The nuclear proteome represents a rich source of regulatory molecules, including transcription factors (TFs). It is important to have an understanding of molecular perturbations at the early stages of the differentiation processes. By applying the proteomic quantitative profiling using isobaric labeling, we found that the contents of 214, 319, 376, 426, and 391 proteins were altered at 3, 6, 9, 12, and 72 h, respectively, compared to 0 h in the HL-60 cell nuclear fraction under all-trans-retinoid acid (ATRA) treatment. From 1860 identified nuclear proteins, 231 proteins were annotated as proteins with transcription factor (TF) activity. Six TFs (RREB1, SRCAP, CCDC124, TRIM24, BRD7, and BUD31) were downregulated and three TFs EWSR1, ENO1, and FUS were upregulated at early time points (3-12 h) after ATRA treatment. Bioinformatic annotation indicates involvement of the HL-60 nuclear proteome in DNA damage recognition in the RUNX1-triggered pathway, and in the p53-regulation pathway. By applying scheduled multiple reaction monitoring using stable isotopically labeled peptide standards (MRM/SIS), we found a persistent increase in the content of the following proteins: PRAM1, CEPBP, RBPJ, and HIC1 in the HL-60 cell nuclear fraction during ATRA-induced granulocytic differentiation. In the case of STAT1, CASP3, PARP1, and PRKDC proteins, a transient increase in their content was observed at early time points (3-12 h) after the ATRA treatment. Obtained data on nuclear proteome composition and dynamics during granulocytic differentiation could be beneficial for the development of new treatment approaches for leukemias with the mutated p53 gene.

Generalized Pustular Psoriasis in Pregnancy: Current and Future Treatments.

Generalized pustular psoriasis (GPP) is a rare, severe neutrophilic skin disease characterized by sudden widespread eruption of sterile pustules with or without systemic symptoms. GPP may be life threatening in cases with severe complications such as cardiovascular failure, acute respiratory distress syndrome, and serious infections. Impetigo herpetiformis (IH) is a GPP that is induced and exacerbated by pregnancy and occurs most frequently during the last trimester. IH may result in poor or fatal neonatal outcomes, including placental insufficiency, fetal abnormalities, stillbirth, and early neonatal death. Most patients have prompt remission in the postpartum period; however, earlier appearance and more severe symptoms are observed during subsequent pregnancies. Appropriate treatment and close monitoring of the mother and fetus are vital for the management of patients with IH. Particular attention is required for the management of patients with IH to avoid an influence on the fetus. However, data regarding treatments for GPP in pregnant women are sparse. Over the last decade, many patients with IH have been treated with cyclosporine, corticosteroids, tumor necrosis factor-α inhibitors, interleukin (IL)-17 and IL-12/23 inhibitors, and granulocyte and monocyte adsorption apheresis (GMA). GMA may be an important option for patients with IH as it is presently one of the safest available therapeutic options, but there have been no reports to fully confirm its safety in pregnant patients with GPP. Alternatively, based on recent advances in the understanding of the role of the IL-36 axis in the pathogenesis of GPP, biologic agents that target the IL-36 pathway may demonstrate promising efficacy in IH.

Neutrophil granulocytes influence on extracellular matrix in cancer progression.

One in three persons will develop cancer in their lifetime (Siegel RL, Miller KD, Fuchs HE, Jemal A. CA Cancer J Clin 71: 7-33, 2021) and the majority of these patients will die from the spread of cancer throughout their body-a process known as metastasis. Metastasis is strongly regulated by the tumor microenvironment (TME) comprising cellular and noncellular components. In this review, we will focus on the role of neutrophils regulating the extracellular matrix (ECM), enabling ECM remodeling and cancer progression. In particular, we highlight the role of neutrophil-secreted proteases (NSP) and how these promote metastasis.