Case report: Good response to CMOP regimen containing mitoxantrone hydrochloride liposome (PLM60) as induction chemotherapy in patients with angioimmunoblastic T-cell lymphoma.

Angioimmunoblastic T-cell lymphoma (AITL) is a highly aggressive subtype of peripheral T-cell lymphoma. The current prognosis with the first-line standard of care remains unsatisfactory, necessitating the exploration of more effective treatment options. We reported 5 cases of AITL receiving CMOP (mitoxantrone hydrochloride liposome, cyclophosphamide, vincristine, and prednisone). Cases 1 and 2 initially received CHOP as first-line induction therapy but switched to CMOP due to inadequate efficacy and cardiac adverse events. Cases 3, 4, and 5 were newly diagnosed and received CMOP. All patients achieved complete remission with acceptable cardiotoxicities and hematologic toxicities. After study treatment discontinuation, Cases 1 and 3 underwent autologous stem cell transplantation, and Cases 4 and 5 received oral maintenance agents. At the last follow-up, 4 patients remained in remission and 1 (Case 2) exhibited tumor recurrence. CMOP showed promise as a potential treatment option for AITL patients. Further research is essential to identify its efficacy and safety.

Polyadenosine diphosphate-ribose polymerase inhibitors: advances, implications, and challenges in tumor radiotherapy sensitization.

Polyadenosine diphosphate-ribose polymerase (PARP) is a key modifying enzyme in cells, which participates in single-strand break repair and indirectly affects double-strand break repair. PARP inhibitors have shown great potential in oncotherapy by exploiting DNA damage repair pathways, and several small molecule PARP inhibitors have been approved by the U.S. Food and Drug Administration for treating various tumor types. PARP inhibitors not only have significant antitumor effects but also have some synergistic effects when combined with radiotherapy; therefore they have potential as radiation sensitizers. Here, we reviewed the advances and implications of PARP inhibitors in tumor radiotherapy sensitization. First, we summarized the multiple functions of PARP and the mechanisms by which its inhibitors exert antitumor effects. Next, we discuss the immunomodulatory effects of PARP and its inhibitors in tumors. Then, we described the theoretical basis of using PARP inhibitors in combination with radiotherapy and outlined their importance in oncological radiotherapy. Finally, we reviewed the current challenges in this field and elaborated on the future applications of PARP inhibitors as radiation sensitizers. A comprehensive understanding of the mechanism, optimal dosing, long-term safety, and identification of responsive biomarkers remain key challenges to integrating PARP inhibition into the radiotherapy management of cancer patients. Therefore, extensive research in these areas would facilitate the development of precision radiotherapy using PARP inhibitors to improve patient outcomes.

Regulatory Effect and Mechanism of Erythroblastic Island Macrophages on Anemia in Patients with Newly Diagnosed Multiple Myeloma.

Objective: To examine the clinical characteristics and anemia-related factors in patients with newly diagnosed multiple myeloma (NDMM), as well as the effect and mechanism of erythroblastic islands (EBIs) and EBI macrophages in NDMM patients with anemia. Methods: We collected and analyzed clinical data to find anemia-related factors. Using flow cytometry, the numbers and ratios of erythroblasts and EBI macrophages were determined. RNA sequencing (RNA-seq) was used to determine the differences of EBI macrophages in NDMM patients with or without anemia. Results: Based on the clinical characteristics of NDMM patients with anemia, MCV, abnormal levels of albumin, osteolytic lesions, and Durie-Salmon (DS) stage are risk factors for anemia. Patients with anemia have fewer erythroblasts, erythroblastic islands (EBIs), and EBI macrophages in their bone marrow than patients without anemia. RNA-seq analysis of EBI macrophages from the bone marrow of patients with and without anemia revealed that macrophages from patients with anemia are impaired and tend to promote the production of interleukin-6, which has been demonstrated to be an essential survival factor of myeloma cells and protects them from apoptosis. Conclusion: In NDMM patients with anemia, EBI macrophages are impaired, which causes anemia in those patients. Our finding highlights the significance of EBI macrophages in anemia in NDMM patients and provides a new strategy for recovery from anemia in these patients.

Human leukocyte antigen-DRB1 gene polymorphism and aplastic anemia: A meta-analysis.

BACKGROUND: The human leukocyte antigen-DRB1 (HLA-DRB1) gene plays key roles in mediating immune response and activating autoreactive T-cells during aplastic anemia (AA) etiology. However, inconsistency appeared in the associations between HLA-DRB1 polymorphism and AA. We aimed to comprehensively clarify their associations in the meta-analysis. METHODS: PubMed, Embase, Web of Science, Science Direct, SinoMed, WanFang Data, China National Knowledge Infrastructure, and Chongqing VIP Chinese Science Database were searched from January 2000 to June 2022. Statistical analysis was performed in STATA 15.0 and Comprehensive Meta-analysis Software 3.0. RESULTS: A total of 16 studies with 4428 patients were eventually analyzed. The results of the meta-analysis suggested that HLA-DRB1*0301 could decrease the risk of AA (odd ratio (OR) = 0.600, 95% CI: 0.427, 0.843). Besides, HLA-DRB1*0901 and HLA-DRB1*1501 were risk factors of AA (OR = 1.591, 95% CI: 1.045, 2.424; OR = 2.145, 95% CI: 1.501, 3.063; respectively). Sensitivity analysis showed heterogeneity among included studies. CONCLUSION: HLA-DRB1 polymorphisms could play roles in the occurrence of AA, however more population-based studies with larger sample sizes are required to certify our findings.

Low-dose decitabine plus bortezomib-dexamethasone therapy is well-tolerated and highly effective on first-relapsed multiple myeloma: a single-center phase 2 trial.

An open-label, single-center, phase 2 trial of a second-line therapy comprising low-dose decitabine (DAC) plus bortezomib (Bort) and dexamethasone (DXM) (Dvd) in relapsed and/or refractory multiple myeloma (RRMM) patients was conducted to screen available and inexpensive agents, aiming to work synergistically with other existing anti-melanoma drugs at reasonable prices, and effectively treat Bort and/or Len-refractory patients. Forty-seven patients were included according to the inclusion criteria, with only 1 withdrawal due to premature death. After 17.2 (range: 0.5-24.1) months of median follow-up, all the 46 cases had halted or completed DVd therapy per protocol, with an overall response rate (ORR) of 87.0%. Meanwhile, DVd was indicated to induce high, deep, and lasting responses, dependent of prior treatment or baseline characteristics. The results revealed that DVd is well-tolerated and highly effective in the treatment of first-relapsed RRMM (including those with Bort-refractory disease) patients.

Genipin protects against mitochondrial damage of the retinal pigment epithelium under hyperglycemia through the AKT pathway mediated by the miR-4429/JAK2 signaling axis.

Background: To investigate the protective effect and mechanism of genipin (GE) on mitochondrial damage in retinal pigment epithelial (RPE) cells induced by high glucose. Methods: Differential genes of GE in the treatment of diabetic retinopathy (DR) were screened by the Gene Expression Omnibus (GEO) database. Differential genes located in the AKT pathway were obtained. TargetScan, miRDB, and DIANA databases were used to predict the targeted microRNAs (miRNAs) of differential genes. A high-fat diet combined with streptomycin (STZ) intraperitoneal injection were used to establish a diabetic mouse model. Diabetic mice were treated with GE by intragastric administration. The functional and molecular changes of the retina were detected by electroretinogram (ERG) and reverse transcription-polymerase chain reaction (RT-PCR). ARPE-19 cells were cultured under hyperglycemic conditions with AKT and JAK2 inhibitors. MiR-4429 was knocked down/overexpressed to detect changes in cell function, activity, and mitochondrial function. The dual luciferase reporter assay confirmed the targeted binding of miR-4429 with JAK2. Results: Bioinformatics analysis finally yielded JAK2 as the research target gene. miR-4429 was predicted to be the targeted miRNA of JAK2 by online databases. The results of animal experiments showed that the retinal function of mice recovered after GE administration (P<0.05), the expression of AKT and miR-4429 in RPE cells was significantly increased (P<0.05), and the expression of JAK2 was significantly decreased (P<0.05). The results of cell experiments showed that the functions of cells and mitochondria recovered after the addition of GE under hyperglycemia (P<0.05). Cell and mitochondrial functions were decreased after the addition of AKT inhibitor (P<0.05). Overexpression of miR-4429 or inhibition of JAK2 increased cell activity and mitochondrial function (P<0.05). The results of the dual luciferase reporter assay showed that miR-4429 had a targeted binding site with JAK2. Conclusions: GE protects ARPE-19 cell functional activity, inflammatory responses, and mitochondrial damage by promoting the AKT signaling pathway and regulating the expression of the miR-4429/JAK2 signaling axis.

In vitro Dissolution Testing and Pharmacokinetic Studies of Silymarin Solid Dispersion After Oral Administration to Healthy Pigs.

We evaluated the pharmacokinetics of silymarin solid dispersion in pigs to determine whether silybin bioavailability would be increased over that of a silymarin premix. In vitro dissolution testing was conducted using dissolution apparatus 1 (baskets) at 100 rpm at 37 ± 0.5°C in pH 1.2 HCl, pH 6.8 phosphate, and pH 4.3 acetate buffers containing 0.5% Tween-80. In vivo pharmacokinetics were studied using 16 healthy pigs (Yorkshire × Landrace) that were randomly assigned to two groups. Silymarin as solid dispersion and premix dosage forms were administered directly by stomach tubes at 50 mg kg-1 silybin. In vitro dissolution of silybin for the premix was 35.02, 35.90, and 38.70% in these buffers, respectively. In contrast, silybin dissolution in solid dispersions was increased to 82.92, 87.48, and 99.70%, respectively. Silymarin solid dispersion administered at a single dose resulted in a peak concentration (Cmax) of 1,190.02 ± 246.97 ng ml-1 with the area under the curve (AUC0-∞) at 1,299.19 ± 67.61 ng ml-1 h. These parameters for the premix groups were 411.35 ± 84.92 ng ml-1 and 586.82 ± 180.99 ng ml-1 h, respectively. The Cmax and AUC0-∞ values for the solid dispersion were about twice that of the premix and were consistent with the in vitro dissolution data.

MALDI-TOF MS for rapid detection and differentiation between Tet(X)-producers and non-Tet(X)-producing tetracycline-resistant Gram-negative bacteria.

The extensive use of tetracycline antibiotics has led to the widespread presence of tetracycline-resistance genes in Gram-negative bacteria and this poses serious threats to human and animal health. In our previous study, we reported a method for rapid detection of Tet(X)-producers using MALDI-TOF MS. However, there have been multiple machineries involved in tetracycline resistance including efflux pump, and ribosomal protection protein. Our previous demonstrated the limitation in probing the non-Tet(X)-producing tetracycline-resistant strains. In this regard, we further developed a MALDI-TOF MS method to detect and differentiate Tet(X)-producers and non-Tet(X)-producing tetracycline-resistant strains. Test strains were incubated with tigecycline and oxytetracycline in separate tubes for 3 h and then analyzed spectral peaks of tigecycline, oxytetracycline, and their metabolite. Strains were distinguished using MS ratio for [metabolite/(metabolite+ tigecycline or oxytetracycline)]. Four control strains and 319 test strains were analyzed and the sensitivity was 98.90% and specificity was 98.34%. This was consistent with the results obtained from LC-MS/MS analysis. Interestingly, we also found that the reactive oxygen species (ROS) produced by tetracycline-susceptible strains were able to promote the degradation of oxytetracycline. Overall, the MALDITet(X)-plus test represents a rapid and reliable method to detect Tet(X)-producers, non-Tet(X)-producing tetracycline-resistant strains, and tetracycline-susceptible strains.

Study on the interaction mechanism between C-reactive protein and platelets in the development of acute myocardial infarction.

BACKGROUND: Myocardial infarction (MI) is the single most critical event in coronary disease. Platelets are involved in the processes of acute MI (AMI). They lack nuclear DNA but retain megakaryocyte mRNAs, hence, their transcriptome could provide information preceding coronary events. However, their mechanisms are not clear. In this study, we obtained a gene expression atlas of platelets from patients after their very first AMI, and our purpose was to clarify the mechanisms of platelet involvement in the occurrence of AMI through bioinformatics analyses and animal models of AMI in vivo. METHODS: We obtained a gene expression atlas of platelets from patients after their very first AMI from the Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) were retrieved using R language. Weighted gene co-expression network analysis (WGCNA) was implemented in order to construct a gene co-expression correlation network among DEGs. Animal models of AMI in vivo were constructed to confirm the results of the bioinformatics analysis. RESULTS: Gene integration analysis yielded 2,852 DEGs (P<0.05, |log2FC| >1). Bioinformatics analysis demonstrated a significant association between C-reactive protein (CRP) and Staphylococcus aureus infection (SAI) (P=0.015). Data from in vivo experiments showed that CRP increased significantly in AMI rats (P<0.001), and the expression of FCGR2B mRNA and HLA-DRB4 mRNA was elevated in response to the increase of CRP (P<0.001). CONCLUSIONS: From the results of this study, we speculate that in the development of AMI, the increase in CRP activates platelets and induces platelets to play an anti-inflammatory role.

miR-17-3p promotes the proliferation of multiple myeloma cells by downregulating P21 expression through LMLN inhibition.

Multiple myeloma (MM), a hematological malignancy, has a poor prognosis and requires an invasive procedure. Reports have implicated miRNAs in the diagnosis, treatment and prognosis of hematological malignancies. In our study, we evaluated the expression profiles of miR-17-3p in plasma and bone marrow mononuclear cells of monoclonal gammopathy of undetermined significance (MGUS) and MM patients and healthy subjects. The results showed that the plasma and mononuclear cell expression levels of miR-17-3p in MM patients were higher than those in MGUS patients and normal controls. In addition, the expression of miR-17-3p was positively correlated with diagnostic indexes, such as marrow plasma cell abundance and serum M protein level, and positively correlated with the International Staging System stage of the disease. Receiver operating characteristic curve analysis suggested that miR-17-3p might be a diagnostic index of MM. Moreover, miR-17-3p regulated cell proliferation, apoptosis and the cell cycle through P21 in MM cell lines and promoted MM tumor growth in vivo. Furthermore, we predicted and verified LMLN as a functional downstream target gene of miR-17-3p. Negatively regulated by miR-17-3p, LMLN inhibits MM cell growth, exerting a tumor suppressive function through P21. Taken together, our data identify miR-17-3p as a promising diagnostic biomarker for MM in the clinic and unveil a new miR-17-3p-LMLN-P21 axis in MM progression.