Research on the mechanism of prednisone in the treatment of ITP via VIP/PACAP-mediated intestinal immune dysfunction.

RATIONALE: Immune thrombocytopenia (ITP) is thought to be a result of immune dysfunction, which is treated by glucocorticoids such as prednisone. Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) have immunomodulatory properties, but their role in intestinal immune control is unclear. The major goal of this study was to look at the effects of prednisone on platelet, VIP, and PACAP levels in ITP mice, as well as the regulatory system that controls intestinal immunity. METHODS: Eighteen BALB/c mice were randomly divided into three groups: blank control group, model control group, and prednisone group, with six mice in each group. The ITP animal model control group and the prednisone group were injected with anti-platelet serum (APS) to replicate the ITP animal model. The prednisone group began prednisone intervention on the 8th day. Platelet count was dynamically measured before APS injection, on the 4th day of injection, on the 1st day of administration, on the 4th day of administration, and at the end of the experiment. After the experiment, the expression of p53 protein in mouse mesenteric lymph node lymphocytes was detected by immunohistochemistry. The changes in lymphocyte apoptosis rate in mouse mesenteric lymph nodes were detected by in situ terminal transferase labeling (TUNEL). The contents of VIP and PACAP in the mouse brain, colon, and serum were detected by enzyme-linked immunosorbent assay (ELISA). The contents of IFN-γ, IL-4, IL-10, IL-17A in the mouse spleen were detected by ELISA. RESULTS: ①Changes of peripheral platelet count: there was no significant difference in platelet count among the three groups before modeling; on the 4th day, the platelet count decreased in the model control group and prednisone group; on the 8th day, the number of platelets in model control group and prednisone group was at the lowest level; on the 12th day, the platelet count in prednisone group recovered significantly; on the 15th day, the platelet count in prednisone group continued to rise. ②Changes of VIP, PACAP: compared with the blank control group, VIP and PACAP in the model control group decreased significantly in the brain, colon, and serum. Compared with the model control group, the levels of VIP and PACAP in the brain, colon, and serum in the prednisone group were increased except for serum PACAP. ③Changes of mesenteric lymphocytes: the expression of p53 protein in the mesenteric lymph nodes of model control group mice was significantly higher than that of blank control group mice. After prednisone intervention, the expression of p53 protein decreased significantly.④Changes of cytokines in spleen: compared with blank control group, IFN- γ, IL-17A increased and IL-4 and IL-10 decreased in model control group. After prednisone intervention, IFN- γ, IL-17A was down-regulated and IL-4 and IL-10 were upregulated. CONCLUSIONS: Prednisone-upregulated VIP and PACAP levels decreased P53 protein expression and apoptosis rate in mesenteric lymph node lymphocytes and affected cytokine expression in ITP model mice. Therefore, we speculate that the regulation of intestinal immune function may be a potential mechanism of prednisone in treating ITP.

Characterizing patients with rare mucormycosis infections using real-world data.

BACKGROUND: Invasive mucormycosis (IM) is a rare and often life-threatening fungal infection, for which clinical and epidemiological understanding is lacking. Electronic health record (EHR) data can be utilized to elucidate large populations of patients with IM to address this unmet need. This study aimed to descriptively assess data on patients with IM using the Optum® EHR dataset. METHODS: US patient data from the Optum® deidentified EHR dataset (2007-2019) were analyzed to identify patients with IM. Patients with hematologic malignancies (HM), at high risk of IM, were selected and sorted by IM diagnosis (ICD9 117.7; ICD10 B46). Demographics, comorbidities/other diagnoses, and treatments were analyzed in patients with IM. RESULTS: In total, 1133 patients with HM and IM were identified. Most were between 40 and 64 years of age, Caucasian, and from the Midwest. Essential primary hypertension (50.31%) was the most common comorbidity. Of the 1133 patients, only 33.72% were prescribed an antifungal treatment. The most common antifungal treatments were fluconazole (24.27%) and posaconazole (16.33%), which may have been prophylactic, and any AmB (15.62%). CONCLUSIONS: A large population of patients with IM were identified, highlighting the potential of analyzing EHR data to investigate epidemiology, diagnosis, and the treatment of apparently rare diseases.

The hemostatic mechanism of "Treated the Spleen" therapy on immune thrombocytopenia based on the characteristics of vasoactive factors.

BACKGROUND: To explore the effect mechanism of "treat the spleen" therapy on immune thrombocytopenia (ITP) based on the characteristics of vasoactive factors. METHODS: The ITP mice model was established by passive immunomodeling. 120 successfully modeled BALB/c mice were randomly divided into 6 groups: normal group, model group, prednisone group, Guipi Decoction group, Jianpi Yiqi group, and Jianpi Shexue group. These mice were treated with medicine for 16 days. After treatment, the platelet (PLT) counts and the degree of bleeding were evaluated, and the serum ET-1, NO, NOS3, TXA2, PGI2, vWF, VCAM-1, and TM contents of the model mice were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: The PLT counts in peripheral blood of mice in each experimental group significantly decreased compared with that in the normal group (P<0.01). On the 8th day after commencing administration, compared with the model group, PLT counts of mice in each experimental group significantly increased (P<0.01). Before administration, all groups had different bleeding tendencies except for the normal group. On the 6th and 8th day of drug intervention, compared with the model group, the bleeding grade of treated groups was significantly decreased (P<0.01). The values of ET-1, vWF, and VCAM-1 in each experimental group significantly decreased compared with that in the normal group, while the TXA2 values were up-regulated compared with that in the normal and model groups (P<0.01). The values of NO and TM in each experimental group significantly decreased compared with that in the normal group (P<0.05). In addition to the Guipi Decoction group, the NOS3 values in each group were significantly decreased compared with that in the normal group (P<0.05). The PGI2 values of the "treat the spleen" groups were significantly decreased compared to the normal group (P<0.01). CONCLUSIONS: In addition to increasing the PLT counts in peripheral blood of ITP model mice to achieve a hemostatic effect, the "treat the spleen" recipes up-regulated the levels of TXA2 and VCAM-1, while down-regulating the levels of PGI2 and TM. Therefore, balancing the procoagulant and anticoagulant factors might be one of the effective mechanisms of hemostasis.

Jianpi Yiqi Shexue ameliorates immune thrombocytopenia related fatigue by regulating mitochondrial function.

BACKGROUND: Immune thrombocytopenia (ITP) is a heterogeneous autoimmune disease characterized by platelet destruction. In previous studies, Jianpi Yiqi Shexue (JPYQSX) was shown to increase the peripheral platelet (PLT) counts in patients with ITP. In addition, JPYQSX also dramatically alleviated weakness and fatigue. This study aimed to investigate the effect of JPYQSX on ITP related fatigue and to illuminate the underlying mechanisms of its therapeutic effects. METHODS: Prednisone and different doses of JPYQSX were orally administered to mice with ITP. Post-treatment, all mice were subjected to a forced swimming test. In addition, blood samples were analyzed using an automated hematology analyzer. Spleen, liver, lungs, heart, kidneys, and colon tissues were collected to determine the expressions of reactive oxygen species (ROS), adenosine triphosphate (ATP), mitochondrial DNA (mtDNA), succinate dehydrogenase complex flavoprotein subunit A (SDHA), caseinolytic mitochondrial matrix peptidase proteolytic subunit (ClpP), and Lon peptidase 1 (Lonp1). RESULTS: Compared with the vehicle group, JPYQSX prolonged the forced swimming time, increased the PLT counts, and reduced the liver and spleen indices {calculated as follows: organ index (%) = [organ weight (mg)/body weight (g)] ×100%}. In addition, the levels of ROS were upregulated, while the ATP and mtDNA contents were downregulated in ITP model mice. Administration of JPYQSX restored the expression of these mitochondrial molecules to normal levels. Furthermore, JPYQSX also decreased the expressions of SDHA, ClpP, and Lonp1, which are closely related to mitochondrial activity. CONCLUSIONS: These findings suggest that JPYQSX prevents antiplatelet sera-mediated platelet destruction in ITP mice and ameliorates fatigue possibly through its effect on mitochondrial function. This study revealed JPYQSX as a potential alternative approach for ITP therapy.

Meta-analysis of the clinicopathological significance of miRNA-145 in breast cancer.

Low expression of tumor suppressor microRNA (miRNA) and high expression of carcinogenic miRNA promote the occurrence and progression of human cancer. Most studies show that miR-145 is a tumor suppressor miRNA, and is closely related to the clinicopathology of breast cancer. However, the results are still inconsistent. Therefore, we conducted a meta-analysis on the basis of eligible studies to summarize the possible correlation between miR-145 and the clinicopathology and prognosis of breast cancer. Using PubMed, Embase, Web of Science, Wanfang and CNKI, we searched all published papers written in either English or Chinese on miR-145 expression in breast cancer from 1990 to November 2019 for meta-analysis. We used standardized mean difference (SMD) to evaluate the differential expression of miR-145 in breast cancer tissues and adjacent normal tissues or normal breast tissues. We found that miR-145 expression was significantly lower in breast cancer tissues than that in adjacent normal tissues (SMD = -2.93, P<0.0001) and in healthy women (SMD = -0.52, P=0.009). miR-145 expression was lower in breast cancer patients with ER-positive (SMD = 0.65, P<0.001), HER-2-positive (SMD = -1.04, P<0.001), compared with their counterparts, respectively. In addition, breast cancer patients with low expression of miR-145 had larger tumor diameters (SMD = -1.97, P<0.001) and lymph node metastasis (SMD = -1.75, P<0.001) that are unfavorable prognostic factors. Conclusion: Low miR-145 is observed in breast cancer, which is closely related to molecular subtypes and unfavorable factors of breast cancer. These findings indicate that miR-145 is tumor suppressor miRNA, and may be a potential diagnostic and prognostic marker in breast cancer.

Chinese herbal medicine for opioid induced constipation in cancer patients: Protocol for a systematic review.

BACKGROUND: Opioid induced constipation (OIC) is a symptom that is commonly encountered in cancer pain management. Chinese herbal medicine (CHM) has been widely used to improve OIC in China. Many clinical trials indicate that CHM could improve OIC. In this systematic review, we aim to evaluate the effectiveness and safety of CHM for OIC in cancer patients. METHODS: We will search the following electronic databases for randomized controlled trials to evaluate the effectiveness and safety of CHM for OIC in cancer patients: CENTRAL, EMBASE, MEDILINE, CINAHL and China National Knowledge Infrastructure. Each database will be searched from inception to June 2018. The entire process will include study selection, data extraction, risk of bias assessment and meta-analyses. RESULTS: This proposed study will evaluate the effectiveness and safety of CHM for OIC. The outcomes will include change in bowel movements, quality of life and adverse events. CONCLUSIONS: This proposed systematic review will evaluate the existing evidence on the effectiveness and safety of CHM for OIC in cancer patients. DISSEMINATION AND ETHICS: The results of this review will be disseminated through peer-reviewed publication. Because all of the data used in this systematic review and meta-analysis has been published, this review does not require ethical approval. Furthermore, all data will be analyzed anonymously during the review process.

Incidence and risk of hematologic toxicities with hypomethylating agents in the treatment of myelodysplastic syndromes and acute myeloid leukopenia: A systematic review and meta-analysis.

BACKGROUND: Hypomethylating agents (HMAs) are believed to have reliable efficacy in treating myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Meanwhile, the adverse events of HMAs have become an increasing concern. There is, however, no systematic meta-analysis available to evaluate overall hematologic toxicities for HMAs. In this meta-analysis, we aim to determine the risk of hematologic toxicities in patients treated with HMAs. METHODS: Relevant studies were identified from PubMed, Embase, Cochrane Library, and the Clinical Trials. gov databases incepted to February 2018. All phase II and III trials meeting the inclusion criteria included adequate safety data. We calculated the relative risk (RR) of high-grade hematologic toxicities (HTEs) with corresponding 95% CI using Review Manager. The incidences of HTEs were also evaluated by R. Heterogeneity was calculated and reported mainly via I analyses. RESULTS: A total of 2337 MDS or AML patients from 14 studies were identified in this meta-analysis. The overall incidences of high-grade hematologic toxicities in patients who received HMAs were: 27% of the patients with anemia, 45% with neutropenia, 38% with thrombocytopenia, and 25% with febrile neutropenia, respectively. There was a significantly increased RR of neutropenia and thrombocytopenia using HMAs, in comparison with conventional care regimens (CCR) based on the drug type (decitabine vs azacitidine). CONCLUSIONS: We conclude that the use of HMAs are associated with an increased risk of neutropenia and thrombocytopenia in MDS or AML patients, and our results also demonstrate that HMAs exposure does not significantly increase the risk of high-grade anemia, leukopenia, or febrile neutropenia compared with CCR.

Metabolomics analysis of salvage chemotherapy on refractory acute myeloid leukemia patients.

Acute myeloid leukemia (AML) is a group of hematological malignancies causing high mortality around the world. However, the treatment of AML is still one of the most formidable challenges. In this study, we employed a well-established global metabolic profiling platform, which combined ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) with gas chromatography mass spectrometry (GC-MS) to investigate the metabolic alterations associated with salvage chemotherapy on 10 refractory acute myeloid leukemia (RAML) patients. A total of 390 metabolites were identified from 20 serum samples obtained from all 10 patients before and post salvage chemotherapy. The metabolomics profile was found to be very heterogeneous across the RAML patients. The results showed very subtle metabolic differences upon one-time chemotherapy treatment for an individual patient. Only 9 metabolites including imidazole lactate, glycerol 3-phosphate, three fatty acids, and four lysolipids in the blood serum were significantly changed before and post chemotherapy, suggesting their important roles during the development of RAML. This study may not only provide new insight into the metabolomics features in RAML patients, but also have relevance to improve the treatment and outcome of RAML.

Efficacy and Safety of the Combination Treatment of Rituximab and Dexamethasone for Adults with Primary Immune Thrombocytopenia (ITP): A Meta-Analysis.

Objective. To conduct a meta-analysis, assessing the efficacy and safety of the combination treatment of dexamethasone and rituximab for adults with ITP (primary immune thrombocytopenia). Methods. Randomized controlled trials that compared rituximab and dexamethasone combination treatment to dexamethasone monotherapy in the treatment of adults with ITP were collected by searching Pubmed, Embase, Cochrane, China National Knowledge (CNKI), Wanfang database, and Sino Med. We conducted pooled analyses on OR (overall response) rate, CR (complete response) rate, PR (partial response) rate, SR (sustained response) rate, R (relapse) rate, change in Treg cell count (mean [SD]), and AE (adverse event). GRADE pro scale was used to assess the quality of the evidence. Publication bias was assessed with Egger's test method. Results. A total of 11 randomized controlled trials were eligible for inclusion. The overall efficacy estimates favored combination arm in terms of OR rate at month 3, CR rate at week 4 and month 3, SR rate, and Treg cell count at week 2. Subgroup analysis showed that females obtained a higher OR rate than males did at week 4. No significant difference was found in pooled analysis of relapse rate between combination arm and monotherapy arm. The comparison of serious AE and other AEs showed no significant difference either. A total of 19 outcomes were assessed by GRADE pro software, of which 79% (15/19) was scaled as moderate-to-high level. Publication bias existed in studies on OR at week 4 (P=0.025), CR at week 4 (P=0.017), infection (P=0.006), and rash (P=0.028) of the AEs. Conclusion. Dexamethasone combined with rituximab can provide a better long-term response in the treatment of adults with ITP and will not increase the risk of adverse effects.

[Hemostatic Effect of Spleen-invigorating, Qi-replenishing and Blood-containing Formula on Simvastatin-induced Zebrafish Hemorrhage Model].

OBJECTIVE: To investigate the hemostatic effect of spleen-invigorating, qi-replenishing and blood-containing formula on simvastatin-induced zebrafish hemorrhage model, and to compare with the effect of clearing heat and cooling blood formula. METHODS: Zebrafishes from breed A B line were treated with 0.5 µmol/L simvastatin for 24 hours to establish zebrafishes hemorrhage model. Under strict blinded experimental conditions, the above mentioned zebrafishes were then treated with experimental drug of different concentrations at the maximum non-lethal dose. The intervention effect of spleen-invigorating, qi-replenishing and blood-containing formula was comprehensively assessed by examining the main observational parameters, such as bleeding reduction rate and hemostasis rate while referring to additional parameters, such as blood flow, improvement rate of blood flow, velocity of movement, improvement rate of motion, which are characteristics of spleen qi deficiency. RESULTS: When the hemostatic effect of experimental drug B1 at the concentrations of 500 and 1 000 µg/ml, zebrafish bleeding rates were 30% and 15%, the hemostatic rate was 60% and 80%, respectively; when the experimental drug B2 at concentration of 500 and 1 000 µg/ml, Zebrafish bleeding rates were 45% and 40%, the hemostatic rate was 40% and 47%, respectively, showing that experimental drug B1 was superior to B2 in terms of decreasing bleeding rate and improving hemostatic effect in zebrafish. In the equal concentration, the experimental drug B1 was superior to B2 in terms of increasing and improving the blood flow of hemorrhagic zebrafish. Promotion and improvement of motion: in equal concentration, experimental drug B1 was superior to B2 in terms of promoting the motion velocity and increasing the improving rate of motion in zebrafish. CONCLUSION: The spleen-invigorating, qi-replenishing and blood-containing formula displays a good hemostatic effect on simvastatin-induced hemorrhage of zebrafish. It also boosts the blood flow and motion velocity in hemorrhagic zebrafish, therefore, providing an experimental basis for the treatment of syndrome of spleen failing to control blood by spleen-invigorating, qi-replenishing and blood-containing formula.

Effect of Compound Zhebei Granule () combined with chemotherapy on surface markers of leukemia stem cell in patients with acute myeloid leukemia.

OBJECTIVE: To observe the effects of Compound Zhebei Granule (, CZBG) combined with chemotherapy on surface markers of leukemia stem cell (LSC) in the bone marrow of patients with acute myeloid leukemia (AML). METHODS: Seventy-eight patients with AML received bone marrow aspiration and the percentages of CD34(+) CD123(+) and CD33(+) CD123(+) cells were tested using flow cytometry method. A total of 24 refractory or relapsed AML patients were enrolled and treated with one cycle of standard chemotherapy combined with CZBG. Bone marrow samples were obtained before and after treatment, and the percentages of CD34(+) CD123(+) and CD33(+) CD123(+) cells were examined by flflow cytometry. RESULTS: Compared with refractory or relapsed AML patients, patients achieved remission had a significant lower percentage of CD34(+) CD123(+) cells(P<0.01) and CD33(+) CD123(+) cells (P<0.01), indicating that controlling the LSC percentage may be important for patients with AML to achieve sustainable remission. Compared with those before treatment, the expression levels of CD34(+) CD123(+) were significantly decreased after CZBG combined with chemotherapy treatment (P<0.01). The percentages of CD34(+) CD123(+) cells and CD33(+) CD123(+) in patients achieving complete remission after CZBG combined with chemotherapy treatment were both significantly lower than those in patients with nonremission (P<0.01). CONCLUSION: CZBG combining chemotherapy could reduce the percentages of CD34(+) CD123(+) and CD33(+) CD123(+) LSC, which might improve the clinical efficacy of refractory or relapsed AML.