Azacitidine combined with venetoclax alleviates AML-MR with TP53 mutation in SDS: a case report and literature review.

Shwachman-Diamond syndrome (SDS) is an autosomal recessive genetic disease, which is prone to transform into myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). TP53 mutation is a driving factor involved in the transformation of SDS into MDS/AML, and in the evolution of MDS to AML. Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is the only curable approach, however, challenge remains regarding the balance between efficacy and the high risk from treatment-related toxicity and mortality to achieve temporary disease control before transplantation to gain time and opportunities for transplantation. At present, pre-transplant bridging therapy has emerged as one of the important options with improved efficacy, reduced tumor burden, and less treatment-related toxicity. Here we reported azacitidine combined with venetoclax was used as pre-transplant bridging regimen in a TP53-mutant AML-MR case developed from SDS. He achieved complete remission with incomplete recovery and proceeded to Allo-HSCT. We hope to provide some evidence and insight for in-depth research and clinical treatment by presenting this case.

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.

On the luminescence of Ce3+, Eu3+, and Tb3+ in novel borate LiSr4(BO3)3.

This paper reports on the photoluminescence (PL) and time-resolved properties of Ce(3+), Eu(3+), and Tb(3+) in novel LiSr(4)(BO(3))(3) powder phosphors. Ce(3+) shows an emission band peaking at 420 nm under 350-nm UV excitation. Energy transfer from Ce(3+) to Mn(2+) takes place in the co-doped samples. Eu(3+) shows red emission under near UV excitation. LiSr(4)(BO(3))(3):Eu(3+) phosphor could be a suitable candidate for phosphor-converted solid state lighting. The luminescence lifetime is 2.13 ms for Eu(3+) in LiSr(4)(BO(3))(3):0.001Eu(3+). As Eu(3+) concentration increasing, the decay curves deviate from exponential behavior. Tb(3+) shows the strongest (5)D(4)→(7)F(5) emission line at 540 nm. Decay curves of (5)D(4)→(7)F(5) and (5)D(3)→(7)F(5) emission with different Tb(3+) concentrations were also measured. Cross-relaxation process is discussed based on the decay curves.

Resuming Sensitivity of Tamoxifen-Resistant Breast Cancer Cells to Tamoxifen by Tetrandrine.

BACKGROUND: Tamoxifen is one of the medicines for adjuvant endocrine therapy of hormone-dependent breast cancer. However, development of resistance to tamoxifen occurs inevitably during treatment. This study aimed to determine whether sensitivity of tamoxifen-resistant breast cancer cells (TAM-R) could be reinstated by tetrandrine (Tet). METHODS: All experiments were conducted in TAM-R cells derived from the MCF-7 breast cancer cell line by long-term tamoxifen exposure. Cell growth, apoptosis, and autophagy were end-points that evaluated the effect of Tet (0.9 µg/ml, 1.8 µg/ml, and 3.75 µg/ml) alone or in combination with TAM (1 µM). Cell apoptosis was determined by an ELISA assay and autophagy was determined by fluorescent staining using the Enzo autophagy detection kit. Immunoblotting was used to evaluate markers for apoptosis, autophagy, and related signal pathway molecules. RESULTS: Growth of TAM-R cells was significantly inhibited by Tet. Combination of Tet with tamoxifen induced a greater inhibition on cell growth than tamoxifen alone, which was predominantly due to enhancement of pro-apoptotic effect of TAM by Tet. Autophagy was significantly inhibited in TAM-R cells treated with Tet plus TAM as shown by increased autophagosomes and the levels of LC3-II and p62. At 0.9 µg/ml, Tet increased the levels of both apoptosis and autophagy markers. Among them increase in p53 levels was more dramatic. CONCLUSIONS: Tet as a monotherapy inhibits TAM-R cells. Tet potentiates the pro-apoptotic effect of TAM via inhibition of autophagy.

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.

Utilizing network pharmacology to explore potential mechanisms of YiSui NongJian formula in treating myelodysplastic syndrome.

The study aims to explore potential mechanisms of YiSui NongJian formula (YSNJF) in treating myelodysplastic syndromes (MDS) by network pharmacology-based strategy. Active compounds and corresponding potential therapeutic targets of YSNJF were harvested by utilizing the database of TCMSP (Traditional Chinese Medicine Systems Pharmacology) and BATMAN-TCM (Bioinformatics Analysis Tool for Molecular mechanism of Traditional Chinese Medicine). MDS targets were adopted from GeneCard, KEGG (Kyoto Encyclopedia of Genes and Genomes), TTD (Therapeutic Target Database), DrugBank, and DisGeNet. Then a network of YSNJF- compounds-target-MDS network was harvested. The protein-protein interaction (PPI) network was then generated by the Sting database and subjected to Cytoscape software to harvest major and core targets network by topological analysis. Genes from the core targets network were further subjected to Gene Ontology (GO) and KEGG enrichment analysis to figure out potential targeting pathways. Finally, a compounds-targets-pathways network was generated by Cytoscape. A total of 210 active compounds and 768 corresponding potential therapeutic targets were harvested from ingredients of YSNJF. MDS was shown to have 772 potential treating targets with 98 intersected targets corresponding to 98 active compounds in YSNJF. Topological analysis revealed that 15 targets formed the core PPI network. Further, GO and KEGG enrichment analysis revealed that those core targets were mainly enriched on cell cycle- and immune-related pathways. The present study revealed that therapeutic effects of YSNJF on MDS might be achieved through regulating cell cycle- and immune-related pathways.

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.

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.