Recombinant human granulocyte-colony stimulating factor and differential expression of cerebral cortical proteins in the subacute stage of cerebral ischemia/reperfusion

Recombinant human granulocyte-colony stimulating factor （hG-CSF） has been shown to protect the nervous system after brain ischemia. However, the neuroprotective mechanism of hG-CSF remains unclear. The present study established a rat model of cerebral ischemia/reperfusion and subcutaneously injected recombinant hG-CSF after reperfusion for 2 hours. Cerebral cortical protein was extracted following 14 days of reperfusion and subjected to two-dimensional electrophoresis. In brain ischemic rats, 56 different protein spots were screened, including 17 that were upregulated and 17 that were downregulated, compared with the sham-surgery group. Matrix assisted laser desorption ionization/time of flight mass spectrometry was used to determine peptide mass fingerprinting. Following a National Center for Biotechnology Information database search and confirmation with the Swiss-Prot database, 19 spots were identified as known proteins. Following hG-CSF treatment, 35 different protein spots were found, including 16 that were downregulated and 19 that were upregulated. Six were known proteins, including dihydropyrimidinase-associated protein 2, glial fibrillary acidic protein, endomucin, Rho GDP dissociation inhibitor, Rab GDP dissociation inhibitor and guanine-nucleotide-binding protein. Results indicate that hG-CSF is involved in neuroprotection after brain ischemia, possibly by regulating the expression of various neural regeneration-associated proteins at the subacute stage.

Does granulocyte-colony stimulating factor administration induce damage or repair response in schistosomiasis?

AIM:To introduce Granulocyte-colony stimulating factor (G-CSF) as a new therapeutic modality for schistosomiasis through stem cell mobilization,immunomodulation or fibrosis remodeling. METHODS:In this study,a 5 d course of human recombinant G-CSF (100 μg/kg sc) was applied to Schis-tosoma mansoni-infected mice at different stages of disease (5 d before infection as well as 3,5 and 7 wk post-infection). The animals were sacrificed at 10 d as well as 4,6 and 8 wk post infection. Mice were examined for:(1) Total leukocyte count which is an accepted surrogate marker for the stem cell mobilization into the circulation; (2) Egg count in intestine and liver tissue to assess the parasitic load; and (3) Histopathological changes in Hx/E and Masson trichrome stained sections as well as collagen content in Sirius redstained liver sections to determine the severity of liver fibrosis. RESULTS:Mice developed leukocytosis. The egg load and the number of granulomas were not affected by the G-CSF treatment but there was an obvious change in the composition of granulomas towards an increased cellularity. Moreover,fibrosis was significantly decreased in treated groups compared to untreated animals (collagen content either preinfection or at 3 and 5 wk post infection:5.8 ± 0.5,4.7 ± 0.5,4.0 ± 0.7 vs 8.2 ± 0.9; P ≤ 0.01). CONCLUSION:Although G-CSF did not cause direct elimination of the parasite,it enhanced granulomatous reaction and reduced the fibrosis. Further investigation of the underlying mechanisms of these two actions is warranted.

Current management of chemotherapy-induced neutropenia in adults:key points and new challenges

Chemotherapy-induced neutropenia(CIN)is a potentially fatal and common complication in myelosuppressive chemotherapy.The timing and grade of CIN may play prognostic and predictive roles in cancer therapy.CIN is associated with older age,poor functional and nutritional status,the presence of significant comorbidities,the type of cancer,previous chemotherapy cycles,the stage of the disease,specific chemotherapy regimens,and combined therapies.There are many key points and new challenges in the management of CIN in adults including:(1)Genetic risk factors to evaluate the patient’s risk for CIN remain unclear.However,these risk factors urgently need to be identified.(2)Febrile neutropenia(FN)remains one of the most common reasons for oncological emergency.No consensus nomogram for FN risk assessment has been established.(3)Different assessment tools[e.g.,Multinational Association for Supportive Care in Cancer(MASCC),the Clinical Index of Stable Febrile Neutropenia(CISNE)score model,and other tools]have been suggested to help stratify the risk of complications in patients with FN.However,current tools have limitations.The CISNE score model is useful to support decision-making,especially for patients with stable FN.(4)There are still some challenges,including the benefits of granulocyte colony stimulating factor treatment and the optimal antibiotic regimen in emergency management of FN.In view of the current reports,our group discusses the key points,new challenges,and management of CIN.

Dynamic changes in growth factor levels over a 7-day period predict the functional outcomes of traumatic brain injury

Traumatic brain injury（TBI） can result in poor functional outcomes and death, and overall outcomes are varied. Growth factors, such as angiopoietin-1（Ang-1）, vascular endothelial growth factor（VEGF）, and granulocyte-colony stimulating factor（G-CSF）, play important roles in the neurological functions. This study investigated the relationship between serum growth factor levels and long-term outcomes after TBI. Blood samples from 55 patients were collected at 1, 3 and 7 days after TBI. Blood samples from 39 healthy controls were collected as a control group. Serum Ang-1, G-CSF, and VEGF levels were measured using ELISA. Patients were monitored for 3 months using the Glasgow Outcome Scale-Extended（GOSE）. Patients having a GOSE score of 〉 5 at 3 months were categorized as a good outcome, and patients with a GOSE score of 1-5 were categorized as a bad outcome. Our data demonstrated that TBI patients showed significantly increased growth factor levels within 7 days compared with healthy controls. Serum levels of Ang-1 at 1 and 7 days and G-CSF levels at 7 days were significantly higher in patients with good outcomes than in patients with poor outcomes. VEGF levels at 7 days were remarkably higher in patients with poor outcomes than in patients with good outcomes. Receiver operating characteristic analysis showed that the best cut-off points of serum growth factor levels at 7 days to predict functional outcome were 1,333 pg/mL for VEGF, 447.2 pg/mL for G-CSF, and 90.6 ng/mL for Ang-1. These data suggest that patients with elevated levels of serum Ang-1, G-CSF, and decreased VEGF levels had a better prognosis in the acute phase of TBI（within 7 days）. This study was registered with the Chinese Clinical Trial Registry（registration number： ChiCTR1800018251） on September 7, 2018.

Soluble factors secreted by human Wharton’s jelly mesenchymal stromal/stem cells exhibit therapeutic radioprotection: A mechanistic study with integrating network biology

BACKGROUND Human Wharton’s jelly-derived mesenchymal stromal/stem cells(hWJ-MSCs)have gained considerable attention in their applications in cell-based therapy due to several advantages offered by them.Recently,we reported that hWJ-MSCs and their conditioned medium have significant therapeutic radioprotective potential.This finding raised an obvious question to identify unique features of hWJ-MSCs over other sources of stem cells for a better understanding of its radioprotective mechanism.AIM To understand the radioprotective mechanism of soluble factors secreted by hWJMSCs and identification of their unique genes.METHODS Propidium iodide staining,endogenous spleen colony-forming assay,and survival study were carried out for radioprotection studies.Homeostasis-driven proliferation assay was performed for in vivo lymphocyte proliferation.Analysis of RNAseq data was performed to find the unique genes of WJ-MSCs by comparing them with bone marrow mesenchymal stem cells,embryonic stem cells,and human fibroblasts.Gene enrichment analysis and protein-protein interaction network were used for pathway analysis.RESULTS Co-culture of irradiated murine splenic lymphocytes with WJ-MSCs offered significant radioprotection to lymphocytes.WJ-MSC transplantation increased the homeostasis-driven proliferation of the lymphocytes.Neutralization of WJ-MSC conditioned medium with granulocyte-colony stimulating factor antibody abolished therapeutic radioprotection.Transcriptome analysis showed that WJ-MSCs share several common genes with bone marrow MSCs and embryonic stem cells and express high levels of unique genes such as interleukin(IL)1-α,IL1-β,IL-6,CXCL3,CXCL5,CXCL8,CXCL2,CCL2,FLT-1,and IL-33.It was also observed that WJ-MSCs preferentially modulate several cellular pathways and processes that handle the repair and regeneration of damaged tissues compared to stem cells from other sources.Cytokine-based network analysis showed that most of the radiosensitive tissues have a more complex network for the elevated cytokines.CONCLUSION Systemic infusion of WJ-MSC conditioned media will have significant potential for treating accidental radiation exposed victims。

Pathogenesis of Neuropsychiatric Syndromes of Systemic Lupus Erythematosus

The pathogenesis of neuropsychiatric syndromes of systemic lupus erythematosus (NPSLE) is multifactorial and can involve various inflammatory cytokines, autoantibodies such as anti-neuronal antibodies, anti-ribosomal P antibodies, anti-NR2 glutamate receptor binding antibodies, anti-Sm antibodies, anti-U1-RNP antibodies and anti-phospholipid antibodies, and immune complexes (IC). Disruption of the blood-brain barrier (BBB) is integral to the neuropathology of SLE. Recently the possibility has been reported that aforementioned autoantibodies in the circulation may be strongly associated with disruption of the BBB. Each of these mechanisms might contribute to the pathogenesis of focal NPSLE (for example, cerebrovascular disease, movement disorders, myelopathy, seizures and cranial neuropathy) or diffuse NPSLE (for example, acute confusional state, psychosis and cognitive dysfunction) to varying degrees. In this review we focus on how the aforementioned autoantibodies, the BBB, IC and cytokines as well as chemokines are associated with the appearance of NPSLE.

Clinical practice guidelines for acute-on-chronic liver failure: are we ready for reaching global consensus?

The concept of acute-on-chronic liver failure(ACLF)has gained increasing awareness during the last decade.It considers liver cirrhosis as a systemic disease where precipitating events lead to a sudden deterioration,decompensation and extrahepatic organ failures.Disease severity is determined by the number and types of organ failures and patients with ACLF have a distinct and worse prognosis than patients with acute decompensation but not fulfilling ACLF criteria(1-3).