Human Colony-stimulating Factor Research Articles

ПОИСК ПОТЕНЦИАЛЬНЫХ МОЛЕКУЛЯРНЫХ МИШЕНЕЙ СОЕДИНЕНИЯ 9-ДИГИДРОАКРИДОНА

In this work, the molecular targets of a new compound with antitumor effect, a 9-dihydroacridone derivative, were determined. The study was carried out in a virtual software environment for receptor-oriented flexible docking Autodock 4.2. The ligands were prepared using the MGL Tools 1.5.6. Ligand optimization was performed using the Avogadro software. The crystallographic structures of the active site macromolecules of human folate receptors (FOLR2) and colony stimulating factor kinase 1 (CSF1R) from the Protein Data Bank (PDB ID: 4KN2 and 4R7I, respectively) were used. A new compound, 9-aminium-3,3-dimethyl-3,4-dihydroacridin-1(2Н)-one L-2-hydroxybutanediovatate (laboratory name LHT-17-19), was studied. LHT-17-19 formed a stable complex with the type III receptor of tyrosine kinase of the monocyte and macrophage colony-stimulating factor (CSF1R) and with the folate receptor FOLR2 with Affinity DG -10.2 kcal/M, EDoc -6.82 kcal/M, Ki 9.99 uM and 10.0 kcal/ M, Edoc -7.05 kcal/M, Ki 6.85 uM, respectively. In terms of the main indicators of affinity LHT-17-19 was not inferior to the reference drugs imatinib and pemetrexed. Receptor kinases CSF1R and FOLR2 can be considered as potential molecular targets for novel medication candidate 9-aminium-3,3-dimethyl-3,4-dihydroacridin-1(2H)-one L-2-hydroxybutanediovate.

The Efficacy of Plerixafor Plus Recombinant Human Granulocyte Colony-Stimulating Factor for Autologous Stem-Cell Mobilization and Transplantation for Patients with Lymphoma and Plasma Cell Diseases

Objective: Plerixafor is a small-molecule inhibitor of CXCR4. This study evaluates the efficacy of plerixafor combined with recombinant human granulocytic colony stimulating factor(G-CSF), in mobilizing hematopoietic stem cells for autologous stem-cell transplantation (ASCT) in patients with lymphoma and plasma cell diseases.Methods: A retrospective analysis was performed on 41 patients with Plerixafor combined with G-CSF admitted to the Department of Hematology, Nanfang Hospital, Southern Medical University,China from July 2019 to February 2021. Mobilization protocol: all patients were given G-CSF 10μg/kg d1-4 and Plerixafor 20mg (all patients weighed less than 83kg) 11 hours before collection on day 5 (night of day 4).Results: The median age of 41 patients was 52 years (25-66 years), the median body weight was 57kg (41-80kg), and the male to female ratio was 1.16:1(22/19). The patients of plerixafor used in combination with G-CSF include Multiple Myeloma 75.6%(31/41), Diffuse Large B Cell Lymphoma was 9.8%(4/41), Peripheral T Cell Lymphoma (4.9%, 2/41), Angioimmunoblastic T Cell Lymphoma (2.4% ,1/41), Systemic light chain (AL) amyloidosis (2.4% ,1/41), POEMS syndrome (2.4%,1/41), and plasma cell leukemia (2.4%, 1/41). Above the patients got partial remission（PR） before mobilization. 17 patients got complete remission（CR）, 4 patients got very good PR(VGPR) and ten got PR. There were 5 lymphoma patients with CR and 2 with PR. The majority of patients, 25, received first-line chemotherapy. 11 patients received second-line chemotherapy, and five received third-line myeloma therapy or above. The median cycle of chemotherapy was 4 (range 4-41). Twenty-two patients with multiple myeloma received treatment with lenalidomide regimens. 26 of all (63.4%) had optimum mobilization (CD34 positive cell count ≥5 × 10 6 cells/kg), and 36 (87.8%) had minimum mobilization (CD34 positive cell count ≥2 × 10 6 cells/kg). The minimum and optimum mobilization rate of first-line chemotherapy regimen was 92% and 72% respectively. The rate of the minimum mobilization of the second line chemotherapy was 100%, the optimum mobilization rate was 63.6%. The minimum and the optimum mobilization rate were 60% and 20% for the third line chemotherapy and above. The minimum mobilization rate was 94.7% and the optimum mobilization rate was 57.9% in patients receiving lenalidomide containing chemotherapy less than the 4 cycles. The minimum and optimum mobilization rate were 66.7% and 66.7% for patients with more than 4 cycles of lenalidomide chemotherapy. Thirty-four patients received autologous hematopoietic stem cell transplantation. Conditioning regimens was TBI (total-body irradiation) + CY (CTX)+ VP-16 or BUCY+ Me-CCNU protocol in lymphoma patients, and Melphala 200mg/m 2 in Multiple myeloma patients. A reduction of melphalan dose(140mg/m 2) in patients with severe renal failure, here defined as iohexol clerarance <30 ml/min, is suggested. Neutrophil engraftment was defined as neutrophil count ≥ 0.5 × 10 9/L for 3 days or ≥ 1.0 × 10 9/L for 1 day. Platelet engraftment was defined as platelet count ≥ 20 × 10 9/L without a transfusion from the preceding 7 days. All patients who received transplantation had successful neutrophil engraftment and 94.1% had successful platelet engraftment. The median time to engraftment was 10 days(9-13 days) for neutrophil and 11 days (9-48 days) for platelet. Using all available laboratory measurements and clinical information to determine graft failures, there were two platelet graft failures in at 1 month follow-up visit. However they had successful platelet engraftment after treatment with Eltrombopag or Avatrombopag(43 days, 48 days).Conclusions: The mobilized cells after G-CSF plus Plerixafor contained high numbers of hematopoietic stem cells, and engrafted very efficiently. G-CSF plus Plerixafor may be preferred for ASCT in patients with lymphoma and plasma cell diseases. DisclosuresNo relevant conflicts of interest to declare.

Proteolytic Shedding of Human Colony-Stimulating Factor 1 Receptor and its implication.

Both Colony‐stimulating factor 1 receptor (CSF1R) and triggering receptor expressed on myeloid cells‐2 (TREM2) are trans‐membrane receptors and are expressed in the brain primarily by microglia. Mutations in these two microglia‐expressed genes associated with neurodegenerative disease have recently been grouped under the term “microgliopathy”. Several literatures have indicated that CSF1R and TREM2 encounters a stepwise shedding and TREM2 variants impair or accelerate the processing. However, whether CSF1R variant affects the shedding of CSF1R remains elusive. Here, plasmids containing human CSF1R or TREM2 were transiently transfected into the human embryonic kidney (HEK) 293T cells. Using Western Blot and/or ELISA assay, we demonstrated that, similar to those of TREM2, an N‐terminal fragment (NTF) shedding of CSF1R ectodomain and a subsequent C‐terminal fragment (CTF) of CSF1R intra‐membrane were generated by a disintegrin and metalloprotease (ADAM) family member and by γ‐secretase, respectively. And the shedding was inhibited by treatment with Batimastat, an ADAM inhibitor, or DAPT or compound E, a γ‐secretase inhibitor. Importantly, we show that the cleaved fragments, both extracellular domain and intracellular domain of a common disease associated I794T variant, were decreased significantly. Together, our studies demonstrate a stepwise approach of human CSF1R cleavage and contribute to understand the pathogenicity of CSF1R I794T variant in adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). These studies also suggest that the cleaved ectodomain fragment released from CSF1R may be proposed as a diagnostic biomarker for ALSP.

伴PML隐匿断裂点t(15;17)(q22;q21)阴性急性早幼粒细胞白血病一例报告并文献复习

伴PML隐匿断裂点t(15;17)(q22;q21)阴性急性早幼粒细胞白血病一例报告并文献复习

Optimization of Buffer Additives for Efficient Recovery of hGM-CSF from Inclusion Bodies Using Response Surface Methodology.

Overexpression of human granulocyte-macrophage colony-stimulating factor (hGM-CSF) by Escherichia coli leads to formation of insoluble and inactive proteins, inclusion bodies. The aim of this study was to improve recovery of biologically active hGM-CSF from inclusion bodies. The effect of types, concentrations and pHs of denaturing agents and addition of reducing agents on the yield of inclusion bodies solubilization was evaluated. Next, various conditions were evaluated for refolding hGM-CSF using a two-step design of experiment (DOE) including primary screening by factorial design, and then optimization by response surface design. It was found that hGM-CSF inclusion bodies can be efficiently solubilized with 4 M urea and 4 mM β-mercaptoethanol, pH = 9. A response surface quadratic model was employed to predict the optimum refolding conditions and the accuracy of this model was confirmed by high value of R2 (0.99) and F-value of 0.64. DOE results revealed that sorbitol (0.235 M), imidazole (97 mM), and SDS (0.09%) would be the optimum buffer additives for refolding of hGM-CSF. Following refolding studies, the obtained protein was subjected to circular dichroism which confirmed correct secondary structure of the refolded hGM-CSF. The refolded hGM-CSF exhibited reasonable biological activity compared with standard protein. The approach developed in this work can be important to improve the refolding of other proteins with similar structural features.

Clinical observation of priming regimen with pegylated recombinant human granulocyte colony-stimulating factor for treatment of initial treatment elderly patients with acute myeloid leukemia

Objective To evaluate the efficacy and side effects of priming regimen with pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) in the treatment of initial treatment elderly patients with acute myeloid leukemia (AML). Methods Thirty-five elderly patients with early-stage AML (non-M3) who received pre-excitation chemotherapy in Yancheng Third People's Hospital from February 2015 to January 2019 were retrospectively analyzed. According to the different granulocyte colony-stimulating factor (G-CSF) in the chemotherapy regimen, 15 cases were in PEG-rhG-CSF group, 6 mg PEG-rhG-CSF was used alone on day 0 by subcutaneous injection; 20 cases were in recombinant human granulocyte colony-stimulating factor (rhG-CSF) group, 200 μg/m2 rhG-CSF was used per day from day 0 to day 13 by subcutaneous injection, rhG-CSF was suspended or continued according to the number of white blood cells. In addition, both groups were given priming regimen with cytarabine and arubicin, or cytarabine and harringtonine. The efficacy and adverse reactions of the two groups were compared. Results In the PEG-rhG-CSF group, there were 5 cases of complete remission, 6 cases of partial remission, 4 cases of non-remission, and 11 cases were effective. In the rhG-CSF group, there were 8 cases of complete remission, 7 cases of partial remission, 5 cases of non-remission, and 15 cases were effective. There was no significant difference in the efficacy between the two groups (χ 2= 0.012, P= 0.911). In terms of adverse reactions, the incidence of infectious fever, bone pain, duration of neutropenia, and duration of thrombocytopenia were not statistically significant (all P > 0.05). Conclusions In the pre-excitation chemotherapy for AML, the clinical efficacy and adverse effects of PEG-rhG-CSF are similar to rhG-CSF. However, the use of PEG-rhG-CSF can simplify the operation and reduce the pain and risk of local infection during chemotherapy. Key words: Leukemia, myeloid, acute; Polyethylene glycols; Granulocyte colony-stimulating factor; Priming regimen

Clinical efficacy of low-dose decitabine and homoharringtonine combined with CAG regimen in treatment of acute myeloid leukemia

Objective To evaluate the efficacy and safety of low-dose decitabine and homoharringtonine combined with CAG regimen (cytarabine, aclarubicin and recombinant human granulocyte colony-stimulating factor) (DHCAG regimen) in treatment of acute myeloid leukemia (AML). Methods Nineteen patients who were treated with DHCAG regimen in the 920th Hospital of Joint Logistics Support Force from July 2017 to June 2018 were retrospectively analyzed. Among them, 13 cases were newly diagnosed, 6 cases were ineffective or relapsed; 2 cases were elderly (≥60 years old); 15 cases had pulmonary infection before chemotherapy, and 4 cases had no lesions in the lungs when admitted to hospital. The remission rate and chemotherapy-related adverse reactions were analyzed. Results After 19 patients received one course of DHCAG regimen, 16 patients had complete remission, 1 patient had partial remission, 2 patients had no remission, and the overall response rate was 89.5% (17/19). Four patients with undetected lung disease before chemotherapy had no infection in the lungs after treatment. Among 15 patients with pulmonary infection before treatment, 1 patient died of pulmonary infection progress, the remaining 14 cases were grade 1-2 infection. 7 cases had bleeding, and 3 cases had nausea and vomiting, all of which were grade 1-2. Conclusion The remission rate of DHCAG regimen in treatment of AML is high, and its adverse reactions are tolerable. Key words: Leukemia, myeloid, acute; Drug therapy, combination; Decitabine; Homoharringtonine; CAG regimen

Recombinant human granulocyte- colony stimulating factor in women with unexplained recurrent pregnancy losses: a randomized clinical trial.

STUDY QUESTIONDoes administration of recombinant human granulocyte colony stimulating factor (rhG-CSF) in the first trimester improve pregnancy outcomes, among women with a history of unexplained recurrent pregnancy loss?SUMMARY ANSWERrhG-CSF administered in the first trimester of pregnancy did not improve outcomes among women with a history of unexplained recurrent pregnancy loss.WHAT IS KNOWN ALREADYThe only previous randomized controlled study of granulocyte colony stimulating factor in recurrent miscarriage in 68 women with unexplained primary recurrent miscarriage found a statistically significant reduction in miscarriage and improvement in live birth rates. A further four observational studies where G-CSF was used in a recurrent miscarriage population were identified in the literature, two of which confirmed statistically significant increase in clinical pregnancy and live birth rates.STUDY DESIGN, SIZE, DURATIONA randomized, double-blind, placebo controlled clinical trial involving 150 women with a history of unexplained recurrent pregnancy loss was conducted at 21 sites with established recurrent miscarriage clinics in the United Kingdom between 23 June 2014 and 05 June 2016. The study was coordinated by University of Birmingham, UK.PARTICIPANTS/MATERIALS, SETTING, METHODSOne hundred and fifty women with a history of unexplained recurrent pregnancy loss: 76 were randomized to rhG-CSF and 74 to placebo. Daily subcutaneous injections of recombinant human granulocyte – colony stimulating factor 130 μg or identical appearing placebo from as early as three to five weeks of gestation for a maximum of 9 weeks. The trial used central randomization with allocation concealment. The primary outcome was clinical pregnancy at 20 weeks of gestation, as demonstrated by an ultrasound scan. Secondary outcomes included miscarriages, livebirth, adverse events, stillbirth, neonatal birth weight, changes in clinical laboratory variables following study drug exposure, major congenital anomalies, preterm births and incidence of anti-drug antibody formation. Analysis was by intention to treat.MAIN RESULTS AND THE ROLE OF CHANCEA total of 340 participants were screened for eligibility of which 150 women were randomized. 76 women (median age, 32[IQR, 29–34] years; mean BMI, 26.3[SD, 4.2]) and 74 women (median age, 31[IQR, 26–33] years; mean BMI, 25.8[SD, 4.2]) were randomized to placebo. All women were followed-up to primary outcome, and beyond to live birth. The clinical pregnancy rate at 20 weeks, as well as the live birth rate, was 59.2% (45/76) in the rhG-CSF group, and 64.9% (48/74) in the placebo group, giving a relative risk of 0.9 (95% CI: 0.7–1.2; P = 0.48). There was no evidence of a significant difference between the groups for any of the secondary outcomes. Adverse events (AEs) occurred in 52 (68.4%) participants in rhG-CSF group and 43 (58.1%) participants in the placebo group. Neonatal congenital anomalies were observed in 1/46 (2.1%) of babies in the rhG-CSF group versus 1/49 (2.0%) in the placebo group (RR of 0.9; 95% CI: 0.1–13.4; P = 0.93).LIMITATIONS, REASONS FOR CAUTIONThis trial was conducted in women diagnosed with unexplained recurrent pregnancy loss and therefore no screening tests (commercially available) were performed for immune dysfunction related pregnancy failure/s.WIDER IMPLICATIONS OF THE FINDINGSTo our knowledge, this is the first multicentre study and largest randomized clinical trial to investigate the efficacy and safety of granulocyte human colony stimulating factor in women with recurrent miscarriages. Unlike the only available single center RCT, our trial showed no significant increase in clinical pregnancy or live births with the use of rhG-CSF in the first trimester of pregnancy.STUDY FUNDING/COMPETING INTEREST(S)This study was sponsored and supported by Nora Therapeutics, Inc., 530 Lytton Avenue, 2nd Floor, Palo Alto, CA 94301, USA. Darryl Carter was the co-founder and VP of research, Nora Therapeutics, Inc. and held shares in the company. He holds a patent for the use of recombinant human granulocyte colony stimulating factor to reduce unexplained recurrent pregnancy loss. Mark Joing, Paul Kwon and Jeff Tong were or are employees of Nora Therapeutics, Inc. No other potential conflict of interest relevant to this article was reported.TRIAL REGISTRATION NUMBEREUDRACT No: 2014-000084-40; ClinicalTrials.gov Identifier: NCT02156063TRIAL REGISTRATION DATE31 Mar 2014DATE OF FIRST PATIENT’S ENROLMENT23 Jun 2014

Effect of caffeic acid on radiotherapy-induced hypocytosis in patients with lung cancer

Objective To investigate the clinical effect of caffeic acid tablets on hypocytosis induced by radiotherapy in patients with lung cancer. Methods From January 2017 to October 2015, one hundred and twenty patients with lung cancer treated by radiotherapy in No.88 Hospital of PLA were selected and randomly divided into the observation group and the control group, 60 cases in each group.Patients in the observation group were treated by oral caffeic acid tablets 0.3 g/time, 3 times/d until the end of radiotherapy.The control group was treated with radiotherapy alone and did not take any blood raising drugs.When myelosuppression appeared, recombinant human granulocyte colony-stimulating factor Injection or recombinant human interleukin 11 was given till it turned to normal blood.The incidence rate of bone marrow suppression, number of white blood cells(WBC), platelet (PLT) and the efficacy of radiotherapy were observed. Results The incidence rate of bone marrow suppression of the observation group was 16.67%(10/60), which was significantly lower than that of the control group(63.33%(38/60)). The difference was statistically significant (χ2=27.22, P 0.05). Conclusion Caffeic acid tablet is effective in preventing leukocyte and thrombocytopenia caused by bone marrow suppression in patients with lung cancer after radiotherapy. Key words: Caffeic acid; Lung cancer; Radiotherapy; Leukocyte reduction; Thrombocytopenia

Recombinant human granulocyte macrophage colony-stimulating factor for the prevention and treatment of oral mucositis induced by concurrent chemoradiotherapy in patients with locally advanced nasopharyngeal carcinoma

Objective To observe the effect of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) on the prevention and treatment of oral mucositis induced by concurrent chemoradiotherapy in patients with locally advanced nasopharyngeal carcinoma. Methods A total of 64 patients with locally advanced nasopharyngeal carcinoma from April 2015 to April 2017 in the Second Affiliated Hospital of Xi'an Jiaotong University were enrolled. The patients were randomly divided into the observation group (32 cases) and the control group (32 cases) according to the random number table method. Both groups were treated with intensity modulated radiotherapy (IMRT) and synchronized with TP regimen (docetaxel + cisplatin) chemotherapy for 2 cycles. Both groups were treated with mouthwash at the beginning of radiotherapy to prevent oral mucositis. The observation group was given rhGM-CSF mouthwash, and the control group was given compound borax mouthwash. The oral mucositis and the oral pain during the treatment and the end of the treatment were evaluated by using American Radiation Oncology Group (RTOG)grading criteria and visual analogue scoring method (VAS) grading criteria. The time of onset of oral mucositis and the total time of radiotherapy in both groups was also recorded. Results All the patients were treated with concurrent chemoradiotherapy. The total radiotherapy time in the observation group was less than that in the control group [(46.4±1.6) vs. (48.2±3.2) d, t=-2.720, P=0.009]. The clinical total effective rate was 93.8% (30/32) in the observation group and 96.9% (31/32) in the control group respectively (χ 2=0.35, P = 0.554). The occurrence of grade 1, 2 and 3 oral mucositis in the observation group was (20.9±2.5), (29.3±2.4), and (34.5±1.8) d respectively, which was latter than that in the control group [(16.3±2.0), (24.2±2.2) and (31.0±2.2) d] respectively (t = 8.125, P = 0.000; t = 8.840, P = 0.000; t = 6.944, P = 0.001). During concurrent chemoradiotherapy, the incidence of grade 3 oral mucositis in the observation group was lower than that in the control group [31.2% (10/32) vs. 56.2% (18/32); Z = -2.197, P = 0.028]. At the end of concurrent chemoradiotherapy, the total incidence of grade 2 and grade 3 oral mucositis in the observation group was lower than that in the control group [53.1% (17/32) vs. 81.2% (26/32); Z = -2.708, P = 0.007]. The incidence of moderate and severe oral pain caused by oral mucositis in the observation group was lower than that in the control group [46.9% (15/32) and 6.2% (2/32) vs. 59.4% (19/32) and 15.6% (5/32), respectively; Z = -2.009, P = 0.045]. Conclusion rhGM-CSF mouthwash can delay the occurrence of oral mucositis, reduce the incidence of oral mucositis and oral pain to effectively prevent and treat oral mucositis induced by concurrent chemoradiotherapy in patients with locally advanced nasopharyngeal carcinoma, which is worthy of clinical application. Key words: Nasopharyngeal neoplasms; Radiotherapy; Antineoplastic combined chemotherapy protocols; Stomatitis; Granulocyte macrophage colony-stimulating factors, recombinant

Azathioprine-induced myelosuppression in a pemphigus patient with a heterozygous mutation in the NUDT15 gene

A 49-year-old male patient presented with repeated oral erosions for 1 year, as well as cutaneous erythema and blisters for 1 month. According to histopathological examination and detection of specific antibodies of pemphigus, the patient was diagnosed with pemphigus vulgaris. After the treatment with oral prednisone and azathioprine for 1 month, the white blood cell count and segmented neutrophilic granulocyte count both decreased. After withdrawal of azathioprine, the patient was subcutaneously injected with 150 μg recombinant human granulocyte colony-stimulating factor for 1 session. Then, the white blood cell count became normal. Genotyping test revealed that the patient carried a heterozygous mutation in the NUDT15 gene (JZ274) , and was homozygous for wild-type TPMT*2, TPMT*3C and ITPA genes. The patient was diagnosed with azathioprine-induced myelosuppression. Key words: Azathioprine; Pemphigus; Heterozygote; Bone marrow; NUDT15

Effect of recombinant human granulocyte-macrophage colony-stimulating factor on expression of metalloproteinases and tissue inhibitors of metalloproteinase in residual burn wounds

Objective To investigate the effect of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) on the expression of metalloproteinases (MMP)-1, MMP-2, MMP-13 and tissue inhibitors of metalloproteinase (TIMP)-1, TIMP-2 in residual burn wounds. Methods The study was a randomized and self-controlled clinical trial. Ten patients with residual burn wounds were selected. Two residual burn wounds with area of 16-25 cm2 were selected from every patient and were divided into combined group (with treatment of rhGM-CSF gel and mupirocin ointment) and control group (with treatment of mupirocin ointment) randomly. The wound healing rate at the 7th and 14th day after treatment and wound healing time were investigated. The wound tissue samples around the wounds before remedy and at the 7th and 14th day after remedy were obtained for evaluation of expression change of MMP-1, MMP-2, MMP-13, TIMP-1 and TIMP-2 by immunohistochemistry. Results The wound healing rate in combined group was (42±7)% and (86±6)% respectively at the 7th and 14th day after remedy, which was obviously higher than that in control group [ (35±8)%, t=16.927, P=0.000; (68±7)%, t=41.849, P=0.000]. The average wound healing time was (17.8±1.5) days in combined group, which was significantly shorter than that in control group [ (21.1±1.6) days, t=-21.604, P=0.000]. Before remedy, the differences of MMP-1, MMP-2, TIMP-1 and TIMP-2 measured of two groups were not significant. At the 7th and 14th day after remedy, the integral optical density (IA) of MMP-1 (2 128±157 and 1 644±157 respectively) and MMP-2 (1 834±130 and 1 493±105 respectively) in the combined group were significantly decreased compared with control group (MMP-1: 3 653±181 and 3 060±175; MMP-2: 2 350±121 and 2 064±109) respectively. The IA of TIMP-1 (855±120 and 1 187±125 respectively) and TIMP-2 (773±117 and 1 039±134 respectively) in the combined group were significantly increased compared with control group (TIMP-1: 590±111 and 846±101; TIMP-2: 614±91 and 808±124) respectively. The expression of MMP-13 was not measured in two groups before and after remedy. Conclusion The healing-promoting effect of rhGM-CSF on residual burn wounds may be in association with inhibiting the expression of MMP-1 and MMP-2 or inducing the expression of TIMP-1 and TIMP-2 in wound tissue. Key words: Burns; Granulocyte-macrophage colony-stimulating factor; Wound healing; Metalloproteinases

Effects of precautionary nursing on preventing adverse reaction of rhG-CSF injection in patients with femoral head necrosis

Objective To explore the effects of precautionary nursing on preventing adverse effects (i.e. fever, headache, nausea/vomit) of recombinant human granulocyte colony stimulating factor (rhG-CSF) injections in patients with femoral head necrosis. Methods Eighty patients with femoral head necrosis who received autologous stem cell transplantation and rhG-CSF in Zhejiang Provincial Hospital of TCM from June 2015 to March 2016 were selected into this study using convenience sampling. According to the random number table, the participants were divided into the intervention group (n=40) and the control group (n=40) . Based on the conventional nursing care, the intervention group received additional predictive and targeted nursing intervention. The incidence of adverse drug reaction was compared between two groups. Results The intervention group found significantly fewer cases that had headache (2 vs. 9 cases) , fever (4 vs. 13 cases) , and nausea/vomit (9 vs. 23 cases) compared with the control group (χ2=5.165, 6.050, 10.208; P<0.05) . Conclusions The precautionary nursing intervention can significantly relieve the adverse drug reaction of rhG-CSF and may benefit the stem cell transplantation in patients with femoral head necrosis. Key words: Femoral head necrosis; Stem cell transplantation; Complication; Recombinant human granulocyte colony stimulating factor injections; Precautionary nursing

High efficiency of peripheral blood hematopoietic stem cell mobilization in multiple myeloma: one case report and literature review

Objective To explore the influential factors of obtaining high proportion of CD34+ cells in patients with multiple myeloma (MM) peripheral blood hematopoietic stem cell (HSC) mobilization. Methods One patient with MM who was 64 years old and hospitalized in Department of Hematology, Hainan Branch of Chinese PLA General Hospital was enrolled into this study on January 2014. The patient achieved complete remission after four courses of bortezomib + doxorubicin hydrochloride liposome + dexamethasone induction regimens. Then peripheral blood HSC was mobilized with bortezomib + high dose cyclophosphamide + dexamethasone regimens in combination with recombinant human granulocyte colony-stimulating factor (rhG-CSF) and recombinant human thrombopoietin (rhTPO). Mobilization effect was reported with its relevant literature reviewed. Results The proportion of CD34+ cells in HSC graft was 6.80%. The number of mononuclear cells and CD34+ cells in harvest of single collection was 3.17×108/kg and 19.20×106/kg, respectively. Engraftment time of neutrophil and platelet was 10 days and 12 days after HSC transplantation, respectively. Conclusions Chemotherapy in combination with rhG-CSF and rhTPO is effective and safety for autologous HSC mobilization in MM patient. As this research is just a case report, it still needs many large sample and multi-center randomized controlled trials to confirm whether it can be widely used in MM patients. Key words: Multiple myeloma; Hematopoietic stem cell transplantation; Hematopoietic stem cell mobilization

Clinical analysis on malignant clonal hematopoiesis in severe aplastic anemia patients with immunosuppressive therapy

To investigate the clinical characteristics and risk factors of monosomy 7 malignant clonal evolution in patients with severe aplastic anemia (SAA) treated with combined immunosuppressive therapy (IST). The clinical data of SAA patients treated with IST who had monosomy 7 malignant clonal evolution from October 2004 to January 2012 were analyzed respectively. Six patients (4.2%) had monosomy 7 clonal evolutions. The median time to monosomy 7 was 36 (12-75) months after IST. All 6 patients were diagnosed myelodysplastic syndromes (MDS). Among them, 3 patients transformed to acute myeloid leukemia following MDS. The time was 24, 45 and 51 months after IST. The median following time was 42 (17-84) months. Four patients died during the following time. The median time from MDS to death was 9 (5-17) months. Among them, three patients died with infection, one died with cerebral hemorrhage. Six patients had the clinical characteristics that they had no response to IST after 6 months, high monocyte percentage in one month after IST combined with recombinant human granulocyte colony stimulating factor (rHu-GCSF) and agranulocytosis in 3 months after IST. Poor myeloid response to IST suggests malignant clonal hematopoiesis and poor prognosis in SAA patients.

Structure and Assembly Mechanism of the Signaling Complex Mediated by Human CSF-1

Human colony-stimulating factor 1 receptor (hCSF-1R) is unique among the hematopoietic receptors because it is activated by two distinct cytokines, CSF-1 and interleukin-34 (IL-34). Despite ever-growing insights into the central role of hCSF-1R signaling in innate and adaptive immunity, inflammatory diseases, and cancer, the structural basis of the functional dichotomy of hCSF-1R has remained elusive. Here, we report crystal structures of ternary complexes between hCSF-1 and hCSF-1R, including their complete extracellular assembly, and propose a mechanism for the cooperative human CSF-1:CSF-1R complex that relies on the adoption by dimeric hCSF-1 of an active conformational state and homotypic receptor interactions. Furthermore, we trace the cytokine-binding duality of hCSF-1R to a limited set of conserved interactions mediated by functionally equivalent residues on CSF-1 and IL-34 that play into the geometric requirements of hCSF-1R activation, and map the possible mechanistic consequences of somatic mutations in hCSF-1R associated with cancer.

Effect of recombinant human granulocyte colony-stimulating factor on Nogo receptor expression in the brain tissues of neonatal rats after hypoxic-ischemic brain damage

Objective To observe the different effects of 2 doses recombinant human granulocyte colony-stimulating factors(rhG-CSF)on Nogo receptor(NgR)expression in the brain tissue of neonatal rats after hypoxic-ischemic brain damage(HIBD)at different times in order to reveal the neuroprotective effects of rhG-CSF. Methods Seven-day neonatal Sprague-Dawley(SD)rats were randomly divided into 4 groups by drawing method: sham operation group, model group, low-dose rhG-CSF group and high-dose rhG-CSF group, 24 rats in each group.Then each group was divided into 4 subgroups(6 rats in each subgroup)and all rats were exterminated at different times after HIBD(1 d, 3 d, 7 d and 14 d). In the low-dose rhG-CSF group and high-dose rhG-CSF group, the rats were given daily doses of rhG-CSF 50 μg/kg, 100 μg/kg respectively for 7 days by subcutaneous injection immediately after the molding(total 7 injections). In model group, rats received an injection of same amount of 9 g/L saline.In sham operation group, rats received no special treatment.Brain tissues of rats from each group were collected at different time points.The expressions of NgR protein and NgR mRNA in the left brain tissue were detected by immunohistochemistry and real-time fluorescent quantitative polymerase chain reaction(PCR). Results Immunohistochemistry: NgR proteins were constitutively expressed in the cerebral cortex in sham operation group at each time point; compared with sham operation group, the expressions of NgR in model group were increased markedly at each time point (135.67±16.63, 173.98±17.82, 234.00±14.70, 319.59±25.22), and the differences were statistically significant(all P<0.01); compared with model group, the expressions of NgR in the cerebral cortex in low-dose rhG-CSF group (134.35±8.89, 109.04±12.62, 75.99±13.39)and high-dose rhG-CSF group (81.38±12.25, 80.14±10.50, 72.58±13.66) on the 3rd, 7th, 14th day were reduced significantly(all P<0.01). Compared with low-dose rhG-CSF group, the protein expressions of NgR in the high-does rhG-CSF group were decreased faster, and had the marked difference on the 3rd, 7th day (P<0.05). Real-time fluorescent quantitative PCR: compared with the sham operation group, the expressions of NgR mRNA increased gradually in the cerebral cortex in the model group (1.34±0.24, 1.88±0.27, 2.88±0.84, 4.26±0.86), the differences in NgR mRNA expression were statistically significant at different times(all P<0.05); compared with model group, the expressions of NgR mRNA in low-dose rhG-CSF group on the 7th (1.08±0.30), 14th day (0.93±0.26) and high-dose rhG-CSF group on the 3rd(0.61±0.10), 7th(0.56±0.28), 14th day (0.47±0.12) were significantly different(all P<0.05). The expressions of low-dose group and high-dose group were reduced gradually.The NgR mRNA expression reduced more quickly in the high-dose group than in the low-dose rhG-CSF group and had substantial difference between two groups in 3 days (P<0.05). Conclusions The findings suggest that rhG-CSF intervention can reduce the expressions of NgR in the brain tissues of neonatal rats after HIBD, and low-dose rhG-CSF also has neuroprotective effect, but it could be weaker than high-dose rhG-CSF. Key words: Recombinant human granulocyte colony-stimulating factor; Hypoxic ischemic brain damage; Nogo receptor

Significance of the expression of Toll-like receptor and costimulatory molecule of dendritic cells in the perip-heral blood in children with Henoch-Schönlein purpura

Objective To observe the expression of Toll-like receptor(TLR) on peripheral blood dendritic cells(DC) in children with Henoch-Schonlein purpura(HSP), and to investigate the pathogenesis of the abnormal expression of TLR in children with HSP. Methods Twenty hospitalized children with HSP in the Affiliated Hospital of Qingdao University Medical College from Dec.2011 to Jul.2012 were enrolled in the study(HSP group). Twenty age-metched healthy children were selected as a healthy control group.Peripheral venous blood was sampled under aseptic condition, peripheral blood mononuclear cells (PBMC) were isolated from density gradient centrifugation, and DC were generated by recombinat human granulocyte-macrophage colony-stimulating factor(GM-CSF), interleukin-4(IL-4) and tumor necrosis factor-α(TNF-α) in vitro.Expressions of CD83, CD86 and TLR2, TLR3, TLR4 in peripheral blood DC were examined by fluorescent activated cell sorter (FACS). Results 1.No significant distinction was found in the expression of the CD83 on peripheral blood DC between HSP group and healthy control group(t=0.80, P>0.05); in HSP group had remarkably increased expression of the CD86 on peripheral blood DC than that of the healthy control group(t=9.56, P<0.01).2.Expression rates of TLR2, TLR3, TLR4 on peripheral blood DC in the HSP group were higher than those in the healthy control group(t=11.79, 13.29, 9.45, all P<0.01).3.Expression rates of TLR2, TLR3 and TLR4 in HSP group had positive correlation with expression rates of CD86(r=0.84, P<0.01; r=0.53, P<0.05; r=0.66, P<0.05). Conclusions Expressions of TLR2, TLR3 and TLR4 on peripheral blood DC significantly increased and were positively correlated with expression of CD86.This implies that TLR and co-stimulatory molecules might parti-cipate in the pathogenesis of HSP by mediating signal transduction, leading to abnormity of cytokines, then inducing Th1/Th2 immune imbalance by showing the advantage of Th2 function. Key words: Henoch-Schonlein purpura; Dendritic cell; Toll-like receptor; CD86; Child

Clinical observation of the salvage therapy using pegylated recombinant human granulocyte colony stimulating factor for grade IV neutropenia induced by concurrent chemoradiotherapy

To investigate the efficacy and safety of pegylated recombinant human granulocyte colony stimulating factor (PEG-rhG-CSF) in the salvage therapy for the grade IV neutropenia induced by concurrent chemoradiotherapy, and to provide evidence for its clinical rational application. 114 malignant tumor patients suffered with grade IV neutropenia induced by concurrent chemoradiotherapy were treated in the following groups. In the P-50 group, 42 patients received a single subcutaneous injection of 50 µg/kg PEG-rhG-CSF. In the P-100 group, 30 patients received a single subcutaneous injection of 100 µg/kg PEG-rhG-CSF. In the P+R group, 22 patients received a single subcutaneous injection of 50 µg/kg PEG-rhG-CSF and multiple subcutaneous injections of 5 µg×kg(-1)×d(-1) rhG-CSF, until the absolute neutrophil count (ANC) ≥ 2.0×10(9)/L. In the R group, 20 patients received multiple subcutaneous injections of 5 µg×kg(-1)×d(-1) rhG-CSF, until ANC ≥ 2.0×10(9)/L. The P-50, P-100 and P+R groups were experimental groups, and the R group was defined as control group. In each group, the neutrophil proliferation rate and the neutrophil counts at different time points, the period of neutropenia symptom relief, and the rate of adverse reactions induced by above drugs were analyzed. Both neutrophil proliferation rates and neutrophil counts in the patients of experimental groups at different time points were significantly higher than those in the control group. In the experimental groups the period of the clinical effect began in 12-24 hours, and the conditions of neutropenia were improved in 36 hours. In the experimental groups, the period of the symptom relief such as fever and skeletal muscle pain was (30.00 ± 7.48) hours and (30.00 ± 5.10) hours, respectively, significantly shorter than (72.00 ± 17.89) hours and (59.00 ± 11.46) hours in the control group (P < 0.05). The adverse drug reaction rate was 26.1% in the experimental groups and 25.0% in the control group (P > 0.05). For the treatment of grade IV neutropenia induced by concurrent chemoradiotherapy, PEG-rhG-CSF is effective and safe. The recommend dose of this drug for the salvage therapy for those patients is a single hypodermal injection of 50 µg/kg. Usually it becomes effective in 12-24 hours.

Application effect of the acupoint injection of dexamethasone at Zusanli on improving the tolerance of ;chemotherapy in the patients with breast cancer

Objective To explore the effect of the preventive acupoint injection of dexamethasone at Zusanli on the degree of bone marrow suppression and a series of unwell symptoms in the patients with breast cancer after chemotherapy .Methods Eighty patients who met the inclusion criteria of the breast cancerafter chemotherapy were randomly divided into the control group and the observation group according to the random number table, each with 40 cases.The control group was taken oral medicine as Berbamine Hydrochloride Tablets and Leucogenum , and the observation group received the preventive acupoint injection of dexamethasone at Zusanli on the fifth days after chemotherapy , 5mg/d for 3d, on the basis of the control group .The degree of bone marrow suppression was compared , and the fatigue and appetite of patients were also evaluated by the brief fatigue scale（BFI） and visual analogue scale（VAS） in two groups.Results The levels of WBC, NE and HB in the observation group were respectively （4.73 ±2.11）×10^9/L, （2.13 ±0.61） ×10^9/L, （112.20 ±5.76）g/L on the seventh day after chemotherapy , and better than （3.21 ±0.85） ×10^9/L, （1.66 ±0.42） ×10^9/L, （107.90 ±5.72）g/L in the control group, and the differences were statistically significant （t=4.212, 4.026, 3.349, respectively;P＆lt;0.01）.The count of WBC was on the increase in the observation group on the seventh day after chemotherapy , and then decreased slowly , and the degree of decrease in the observation group was lower than that of control group , and the difference was found in the development trend between two groups （ F=53.19, P〈0.05）.The degree of fatigue and bone marrow suppression in the observation group on the seventh day after chemotherapy were better than those in the control group , and the differences were statistically significant （Z=-2.795, -3.307, respectively;P＆lt;0.01）.The appetite of patients in two groups gradually＆amp;nbsp;returned to normal , and there was a positive correlation the degree of fatigue and bone marrow suppression after chemotherapy （r =0.656, 0.682, respectively; P＆lt;0.05）.The cases of the more than Ⅲdegree of bone marrow suppression was 6 cases in the observation group , and 15 cases in the control groups , and these patients received the Recombinant human granulocyte colony-stimulating factor （rhG-CSF） treatment, and the difference was statistically significant （χ2 =5.230, P 〈0.05 ）.Conclusions The preventive acupoint injection of dexamethasone at Zusanli can reduce the degree of bone marrow suppression and the fatigue symptoms caused by bone marrow suppression after chemotherapy in the patients with breast cancer so as to improve their tolerance of chemotherapy . Key words: Dexamethasone; Acupoint,zusanli; Acupoint injection; Chemotherapy; Tolerance