Primary pancreatic peripheral T-cell lymphoma: A case report.

BACKGROUND: Primary pancreatic lymphoma (PPL) is an exceedingly rare tumor with limited mention in scientific literature. The clinical manifestations of PPL are often nonspecific, making it challenging to distinguish this disease from other pancreatic-related diseases. Chemotherapy remains the primary treatment for these individuals. CASE SUMMARY: In this case study, we present the clinical details of a 62-year-old woman who initially presented with vomiting, abdominal pain, and dorsal pain. On further evaluation through positron emission tomography-computed tomography, the patient was considered to have a pancreatic head mass. However, subsequent endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) revealed that the patient had pancreatic peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). There was a substantial decrease in the size of the pancreatic mass after the patient underwent a cycle of chemotherapy comprised of brentuximab vedotin, decitabine, and oxaliplatin (brentuximab vedotin and Gemox). The patient had significant improvement in radiological findings at the end of the first cycle. CONCLUSION: Primary pancreatic PTCL-NOS is a malignant and heterogeneous lymphoma, in which the clinical manifestations are often nonspecific. It is difficult to diagnose, and the prognosis is poor. Imaging can only be used for auxiliary diagnosis of other diseases. With the help of immunostaining, EUS-FNA could be used to aid in the diagnosis of PPL. After a clear diagnosis, chemotherapy is still the first-line treatment for such patients, and surgical resection is not recommended. A large number of recent studies have shown that the CD30 antibody drug has potential as a therapy for several types of lymphoma. However, identifying new CD30-targeted therapies for different types of lymphoma is urgently needed. In the future, further research on antitumor therapy should be carried out to improve the survival prognosis of such patients.

Risk Factors for Systemic Inflammatory Response Syndrome After Percutaneous Transhepatic Cholangioscopic Lithotripsy.

Background: There is a lack of validated predictive models for the occurrence of systemic inflammatory response syndrome (SIRS) after percutaneous transhepatic cholangioscopic lithotripsy (PTCSL) for the treatment of hepatolithiasis. This is the first study to estimate the incidence of SIRS after PTCSL. Methods: A retrospective analysis of 284 PTCSL sessions for the treatment of hepatolithiasis at our institution between January 2019 and January 2023 was performed. The development of SIRS after PTCSL was the primary study endpoint. Independent risk factors for SIRS after PTCSL were identified using univariate and multivariate logistic regression analyses. A nomogram prediction model was constructed using these independent risk factors, and the predictive value was assessed using receiver operating characteristic (ROC) curves. Results: The incidence of SIRS after PTCSL was 20.77%. According to multivariate analysis, the number of PTCSL sessions (odds ratio [OR]=0.399, 95% confidence interval [CI]=0.202-0.786, p=0.008), stone location (OR=2.194, 95% CI=1.107-4.347, p=0.024), intraoperative use of norepinephrine (OR=0.301, 95% CI=0.131-0.689, p=0.004), intraoperative puncture (OR=3.476, 95% CI=1.749-6.906, P<0.001), preoperative gamma-glutamyltransferase (OR=1.002, 95% CI=1.001-1.004, p=0.009), and preoperative total lymphocyte count (OR=1.820, 95% CI=1.110-2.985, p=0.018) were found to be independent risk factors for the development of SIRS after PTCSL. These six independent risk factors were used to construct a nomogram prediction model, which showed satisfactory accuracy with an area under the ROC curve of 0.776 (95% CI: 0.702-0.850). Conclusion: The number of PTCSL sessions, stone location, intraoperative use of norepinephrine, intraoperative puncture, preoperative gamma-glutamyltransferase, and preoperative total lymphocyte count may predict the occurrence of SIRS after PTCSL. This prediction model may help clinicians identify high-risk patients in advance.

CD7-positive leukemic blasts with DNMT3A mutations predict poor prognosis in patients with acute myeloid leukemia.

Background: DNMT3A mutations can be detected in premalignant hematopoietic stem cells and are primarily associated with clonal hematopoiesis of indeterminate potential; however, current evidence does not support assigning them to a distinct European Leukemia Net (ELN) prognostic risk stratification. CD7 is a lymphoid antigen expressed on blasts in approximately 30% of acute myeloid leukemia (AML), and its role in AML remains unclear and depends on subgroup evaluation. This study investigated the prognostic value of DNMT3A mutation combined with CD7 expression in AML. Methods: We retrospectively analyzed the clinical data of 297 newly diagnosed non-M3 AML patients. According to the DNMT3A mutation and CD7 expression in AML cells, patients were divided into the DNMT3A-mutated/CD7-positive (CD7+), DNMT3A-mutated/CD7-negative (CD7-), DNMT3A-wild-type/CD7+, and DNMT3A-wild-type/CD7- groups. Results: The DNMT3A-mutated/CD7+ group had lower complete remission rates and higher relapse rates. Importantly, these patients had significantly shorter overall survival (OS) and relapse-free survival (RFS). Furthermore, multivariate analysis showed that CD7+ with DNMT3A mutation was an independent risk factor for OS and RFS. Conclusion: CD7+ with DNMT3A mutation predicts a poor prognosis in AML patients, and the immunophenotype combined with molecular genetic markers can help to further refine the current risk stratification of AML.

A blastic plasmacytoid dendritic cell neoplasm-like immunophenotype is negatively associated with CEBPA bZIP mutation and predicts unfavorable prognosis in acute myeloid leukemia.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive myeloid malignancy which characteristically expresses an atypical phenotype including CD123+, CD56+, and CD4+. We are aimed to investigate the clinical and prognostic characteristics of AML patients exhibiting BPDCN-like immunophenotype and provide additional insights for risk stratification of AML. A total of 241 newly diagnosed AML patients were enrolled in this retrospective study and categorized into BPDCN-like positive (n = 125)/negative (n = 116) groups, determined by the present with CD123+ along with either CD56+ or CD4+, or both. Subsequently, an analysis was conducted to examine the general clinical characteristics, genetic profiles, and prognosis of the two respective groups. Patients with BPDCN-like immunophenotype manifested higher frequencies of acute myelomonocytic leukemia and acute monoblastic leukemia. Surprisingly, the presence of the BPDCN-like immunophenotype exhibited an inverse relationship with CEBPA bZIP mutation. Notably, patients with BPDCN-like phenotype had both worse OS and EFS compared to those without BPDCN-like phenotype. In the CN-AML subgroups, the BPDCN-like phenotype was associated with worse EFS. Similarly, a statistically significant disparity was observed in both OS and EFS within the favorable-risk subgroup, while only OS was significant within the adverse-risk subgrouMoreover, patients possessing favorable-risk genetics without BPDCN-like phenotype had the longest survival, whereas those who had both adverse-risk genetics and BPDCN-like phenotype exhibited the worst survival. Our study indicated that BPDCN-like phenotype negatively associated with CEBPA bZIP mutation and revealed a significantly poor prognosis in AML. Moreover, the 2022 ELN classification, in combination with the BPDCN-like phenotype, may better distinguish between different risk groups.

Differential effects of recombinant human thrombopoietin on clinical outcomes in CD7-positive and CD7-negative acute myeloid leukaemia.

To investigate the effect of recombinant human thrombopoietin (rhTPO) application on the clinical outcomes of CD7-positive acute myeloid leukaemia (CD7 + AML) patients following chemotherapy, we retrospectively studied 159 newly diagnosed non-M3 AML patients. Patients were divided into the following four groups according to the expression of CD7 in AML blasts and the use of rhTPO after chemotherapy: the CD7 + rhTPO group (n = 41), the CD7 + non-rhTPO group (n = 42), the CD7 negative (CD7-) rhTPO group (n = 37), and the CD7- non-rhTPO group (n = 39). The complete remission rate was higher in the CD7 + rhTPO group than in the CD7 + non-rhTPO group. Importantly, patients in the CD7 + rhTPO group had significantly higher 3-year overall survival (OS) rates and event-free survival (EFS) rates than those in the CD7 + non-rhTPO group, whereas they did not differ statistically between the CD7- rhTPO and CD7- non-rhTPO groups. In addition, multivariate analysis showed that rhTPO was an independent prognostic factor for OS and EFS in CD7 + AML. In conclusion, rhTPO led to better clinical outcomes for patients with CD7 + AML, while it had no significant effect on those with CD7- AML.

Upregulated mitosis-associated genes CENPE, CENPF, and DLGAP5 predict poor prognosis and chemotherapy resistance of Acute Myeloid Leukemia.

BACKGROUND: Mitosis-associated genes are dysregulated in many types of cancers and play important roles in disease progression and chemotherapy resistance. However, their expression and functions in chemotherapy-resistant Acute Myeloid Leukemia (AML) are still largely undetermined. OBJECTIVE: This study aims to explore the roles of spindle assembly checkpoint (SAC) genes CENPE, CENPF, and DLGAP5 in chemotherapy-resistant AML. METHODS: RNA-sequencing (RNA-seq) was performed in patients with chemotherapy-resistant AML and chemotherapy-sensitive AML. AML mRNA data from 151 patients with recurrence were downloaded from TCGA. Integrated analysis of the differentially expressed genes (DEGs), GO and KEGG pathways. CENPE, CENPF, or DLGAP5 knockdown cell lines were used to analyse proliferation, apoptosis and cell cycle alterations. RESULTS: A total of 87 DEGs (48 upregulated and 39 downregulated) were obtained through gene analysis of R/R-AML and a total of 329 DEGs (202 upregulated and 127 downregulated) were obtained in refractory S-AML. Upregulated DEGs were mainly enriched in cell cycle (GO: 0007049, hsa04110) and mitotic cell cycle (GO: 0000278) processes and pathway. Venn diagram analysis identified the most upregulated DEGs (including CENPE, CENPF, and DLGAP5) in chemoresistant AML. The expression of CENPE, CENPF and DLGAP5 in R-AML (TCGA) was significantly higher than that of primary AML (GEO). The proliferation of K562 cells after CENPE and DLGAP5 knockdown was significantly decreased (P= 0.0001 and P= 0.0006). In THP-1 cells, the CCK-8 values after CENPE, CENPF and DLGAP5 knockdown were significantly decreased (P= 0.01, P= 0.0395 and P= 0.0362). Knockdown of CENPE, CENPF and DLGAP5 significantly increased cell apoptosis by regulating Caspase-9, BAX, TP-53 and bcl-2, and induced cell cycle arrested by regulating CDK1, CDK2, CDKN1A, and CyclinD1. CONCLUSIONS: In conclusion, the mitotic cell cycle-associated genes CENPE, CENPF, and DLGAP5 were upregulated in chemotherapy-resistant AML patients and might be useful for predicting poor prognosis.

The Prognostic Significance of C-Reactive Protein to Albumin Ratio in Newly Diagnosed Acute Myeloid Leukaemia Patients.

BACKGROUND: The ratio of C-reactive protein to albumin (CAR) is an inflammatory marker that has been demonstrated to be a simple and reliable prognostic factor in several solid tumours and chronic lymphocytic leukaemia (CLL). However, no studies have investigated the prognostic value of the CAR in patients with acute myeloid leukaemia (AML). OBJECTIVES AND METHODS: We retrospectively analysed 212 newly diagnosed non-M3 AML patients. Using the receiver operating characteristic curve (ROC) method, the optimal cut-off value for CAR was determined. We investigated the correlations of the pretreatment CAR levels with clinical characteristics, treatment response of induction chemotherapy, overall survival (OS) and event-free survival (EFS). We also assessed the prognostic value of the CAR compared with other inflammation-based prognostic parameters by the area under the curve (AUC). RESULTS: According to the ROC curve, the optimal cut-off value of CAR was 1.015. CAR was associated with age, C-reactive protein (CRP) levels, albumin levels, ferritin levels, bone marrow blast percentage, French-American-British (FAB) classification, immunophenotype and 2017 European Leukemia Net (2017 ELN) risk stratification. Importantly, we found that high CAR was a powerful indicator of a lower complete remission (CR) rate (p<0.001), worse OS (p<0.001) and worse EFS (p<0.001). Subgroup analysis showed that a high CAR was associated with shorter OS and EFS in patients with intermediate risk stratification or those aged ≤65 years or those without haematopoietic stem cell transplantation (HSCT). In the multivariate analysis, the CAR was an independent prognostic factor for OS and EFS. Furthermore, the predictive value of CAR for OS is superior to that of CRP, albumin and GPS in de novo AML patients aged ≤65 years old. CONCLUSION: CAR is a simple and effective prognostic marker in patients with AML. It could be an additional prognostic factor that help further precise the current risk stratification of non-M3 AML, particularly for patients in intermediate risk stratification and those aged ≤65 years and those who did not undergo HSCT.

Predictive factors for differentiating thrombohemorrhagic disorders in high-risk acute promyelocytic leukemia.

INTRODUCTION: Acute promyelocytic leukemia (APL) is often accompanied by potentially fatal coagulopathy, especially in high-risk APL. Bleeding, particularly severe bleeding is the leading cause of early death (ED). Meanwhile, thrombosis, the other major coagulopathic complication, is being increasingly recognized. However, predictors of thrombohemorrhagic disorders are still not well investigated. MATERIALS AND METHODS: In this study, we retrospectively studied 83 patients with high-risk APL and categorized them into severe bleeding, thrombosis and no evident events groups. RESULTS: Severe bleeding was observed in 15 patients, nearly half of whom died of hemorrhage, while thrombosis was observed in 12 patients. Risk factor analysis showed that high WBC (>58.76 × 109/L) (p = 0.001) and prolonged PT (>17.7 s) (p = 0.015) could be independent predictors for severe bleeding, while high WBC/D-dimer>5.12 (p = 0.002) and low D-dimer/FIB<5.14 (p = 0.03) could be independent predictors for thrombosis in high-risk APL patients. Moreover, there are significant differences in WBC/D-dimer and D-dimer/FIB between DIC and Non-DIC groups (p < 0.001). Notably, we found that the WBC/D-dimer was dramatically higher in the thrombotic group than in the other two groups at the time of admission or during the first week of induction therapy. CONCLUSIONS: High WBC and prolonged PT could predict severe bleeding in high-risk APL patients, while high WBC/D-dimer and low D-dimer/FIB could be independent predictors for thrombosis. For high-risk APL, WBC/D-dimer and D-dimer/FIB are also beneficial in the diagnosis of DIC. WBC/D-dimer might help early identification of thrombosis at the time of admission or during the first week of induction therapy.

Lin28A/CENPE Promoting the Proliferation and Chemoresistance of Acute Myeloid Leukemia.

The prognosis of chemoresistant acute myeloid leukemia (AML) is still poor, mainly owing to the sustained proliferation ability of leukemic cells, while the microtubules have a major role in sustaining the continuity of cell cycle. In the present study, we have identified CENPE, a microtubular kinesin-like motor protein that is highly expressed in the peripheral blood of patients with chemoresistant AML. In our in vitro studies, knockdown of CENPE expression resulted in the suppression of proliferation of myeloid leukemia cells and reversal of cytarabine (Ara-C) chemoresistance. Furthermore, Lin28A, one of the RNA-binding oncogene proteins that increase cell proliferation and invasion and contribute to unfavorable treatment responses in certain malignancies, was found to be remarkably correlated with CENPE expression in chemoresistance AML. Overexpression of LIN28A promoted the proliferation and Ara-C chemoresistance of leukemic cells. RIP assay, RNA pull-down, and dual luciferase reporter analyses indicated that LIN28A bound specifically to the promoter region GGAGA of CENPE. In addition, the impacts of LIN28A on cell growth, apoptosis, cell cycle progression, and Ara-C chemoresistance were reverted by the knockdown of CENPE. Hence, Lin28A/CENPE has enhanced the proliferation and chemoresistance of AML, and therefore, it could be a prospective candidate for AML treatment.

Acute promyelocytic leukemia with myelofibrosis: A case report and literature review.

RATIONALE: Acute promyelocytic leukemia (APL) with myelofibrosis (MF) is rare, and only 14 cases have been reported in the literature to date. PATIENT CONCERNS: A 42-year-old woman was admitted to the hospital with easy bruising and excessive bleeding. With the remission of the primary disease during treatment, the degree of fibrosis did not decrease, but worsened progressively. DIAGNOSIS: The woman was diagnosed with acute promyelocytic leukemia with secondary myelofibrosis. INTERVENTIONS: All-trans retinoic acid (ATRA) was discontinued after 6 months of complete remission of APL. Arsenic trioxide (ATO) was discontinued because of supraventricular tachycardia 9 months after complete remission of APL. OUTCOMES: After withdrawal of ATRA for 2 months, the degree of fibrosis was significantly alleviated, and after withdrawal of ATRA for 8 months and ATO for 5 months, bone marrow biopsy showed no reticular fiber deposition. LESSONS: In this case report and review of an additional 14 cases of APL with MF, we highlighted the importance of the degree of MF to be evaluated by bone marrow biopsy at the time of bone marrow aspiration when APL is suspected. If MF is present, the type of MF should be determined in a timely manner, and appropriate intervention measures should be taken accordingly.

CCNB2, CDC20, AURKA, TOP2A, MELK, NCAPG, KIF20A, UBE2C, PRC1, and ASPM May Be Potential Therapeutic Targets for Hepatocellular Carcinoma Using Integrated Bioinformatic Analysis.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly malignant, recurrent and drug-resistant tumor, and patients often lose the opportunity for surgery when they are diagnosed. Abnormal gene expression is closely related to the occurrence of HCC. The aim of the present study was to identify the differentially expressed genes (DEGs) between tumor tissue and non-tumor tissue of HCC samples in order to investigate the mechanisms of liver cancer. METHODS: The gene expression profile (GSE62232, GSE89377, and GSE112790) was downloaded from the Gene Expression Omnibus (GEO) and analyzed using the online tool GEO2R to identify differentially expressed genes (DEGs). Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed using the Database for Annotation, Visualization and Integrated Discovery. Protein-protein interaction (PPI) of these DEGs was analyzed based on the Search Tool for the Retrieval of Interacting Genes database and visualized by Cytoscape software. In addition, we used the online Kaplan-Meier plotter survival analysis tool to evaluate the prognostic value of hub genes expression. HPA database was used to reveal the differences in protein level of hub genes. RESULTS: A total of 50 upregulated DEGs and 122 downregulated DEGs were identified. Among them, ten hub genes with a high degree of connectivity were picked out. Overexpression of these hub genes was associated with unfavorable prognosis of HCC. CONCLUSION: Our study suggests that CCNB2, CDC20, AURKA, TOP2A, MELK, NCAPG, KIF20A, UBE2C, PRC1, and ASPM were overexpressed in HCC compared with normal liver tissue. Overexpression of these genes was an unfavorable prognostic factor of HCC patients. Further study is needed to explore the value of them in the diagnosis and treatment of HCC.

The Synergistic Antitumor Activity of Chidamide in Combination with Bortezomib on Gastric Cancer.

PURPOSE: The aim of this study was to investigate the antitumor effect of chidamide in combination with bortezomib on gastric cancer cell lines. MATERIALS AND METHODS: First, the sensitivity and IC50 values of chidamide and bortezomib in several gastric cancer cell lines (MGC-803, BGC-823, SGC-7901, and MKN45) were measured using the CCK-8 assay. Then, the relatively insensitive gastric cancer cell lines (MGC-803 and BGC-823) were treated with low concentrations of chidamide alone, bortezomib alone, or chidamide and bortezomib combination to detect the effects on cell proliferation, apoptosis, migration, and invasion. Finally, the inhibitory effect of the combined chidamide and bortezomib treatment on MGC-803 cells was verified in vivo through tumor formation experiments in nude mice. RESULTS: Compared with low-dose chidamide or bortezomib alone, the low-dose drug combination significantly inhibited the proliferation, migration, and invasion of MGC-803 and BGC-823 cells and induced apoptosis of the cells. The effects of the low-dose chidamide and bortezomib combination reduced the growth on gastric cancer in vivo were investigated by using a subcutaneous tumor mouse model. CONCLUSION: Our results suggest that the combination of chidamide and bortezomib can significantly reduce the proliferation, invasion, and migration of MGC-803 and BGC-823 cells, providing a framework for the clinical evaluation of combined therapies for gastric cancers.

Validation of the EUTOS Long-Term Survival Score in Chinese Chronic Myeloid Leukemia Patients Treated with Imatinib: A Multicenter Real-World Study.

PURPOSE: To validate the clinical efficacy of the recently developed EUTOS long-term survival (ELTS) score in a real-world setting. PATIENTS AND METHODS: A total of 479 chronic myeloid leukemia (CML) patients treated with frontline imatinib between January 2010 and December 2017 were enrolled in this retrospective study. The ELTS score was evaluated on the end-points including complete cytogenetic response (CCyR), progression-free survival (PFS), overall survival (OS) and CML-related death, and the efficiency of the ELTS score was further compared with the historical Sokal, Hasford, EUTOS scores. RESULTS: With a median follow-up of 69 months (range, 9-112 months), 462 evaluable patients were stratified into the ELTS low-risk (n = 230), ELTS intermediate-risk (n = 168) and ELTS high-risk (n = 64) groups. For the regular assessment indicators like CCyR, PFS and OS, the ELTS scoring system could effectively identify the corresponding risk groups, similarly with the results provided by previous scoring systems. With respect to the CML-related death, the ELTS score could accurately identify a high-risk group with a significantly higher risk of dying of CML, and the 5-year cumulative incidence occurred in the ELTS high-, intermediate-, and low-risk groups was 11% (95% CI: 3-19%), 5% (95% CI: 1-9%) and 2% (95% CI: 0-4%), respectively. Most notably, the ELTS score outperformed the Sokal, Hasford and EUTOS scores without statistical difference among different risk groups. CONCLUSION: The ELTS score could effectively predict the prognosis of imatinib-treated CML patients in real-life settings.

NDRG2 and TLR7 as novel DNA methylation prognostic signatures for acute myelocytic leukemia.

Acute myelocytic leukemia (AML) is an aggressive malignant tumor and typically fatal without treatment. Identification and development of novel biomarkers could be beneficial for the diagnosis and prognosis of AML patients. Here, we aimed to identify the accurate DNA methylation prognostic signatures for AML patients. The DNA methylation data of AML patients and corresponding clinical information were retrieved from The Cancer Genome Atlas database. CPG sites that correlates closely with the survival of the AML patients were identified and further combined into CPG sites pairs to screen the survival-related pairs. The prognostic signatures were identified by the C-index and forward search algorithms and validated by the verification group. Finally, the functional enrichment analysis was performed on these CPG sites. As a result, a total of 498 CPG sites associated with the overall survival of AML patients was obtained. A prognostic signature composed of 10 CPG sites pairs was obtained and validated. The functional enrichment analysis showed prognostic genes were mainly enriched in tumor protein processing, cell differentiation, blood leukocyte immunity, and platelet growth factor pathways. In summary, we identified two accurate prognostic methylation signatures (NDRG2 and TLR7), which would be served as a novel therapy target for AML.

Non-invasive bioluminescence imaging of HCoV-OC43 infection and therapy in the central nervous system of live mice.

Human coronaviruses (HCoVs) are important pathogens that cause upper respiratory tract infections and have neuroinvasive abilities; however, little is known about the dynamic infection process of CoVs in vivo, and there are currently no specific antiviral drugs to prevent or treat HCoV infection. Here, we verified the replication ability and pathogenicity of a reporter HCoV-OC43 strain expressing Renilla luciferase (Rluc; rOC43-ns2DelRluc) in mice with different genetic backgrounds (C57BL/6 and BALB/c). Additionally, we monitored the spatial and temporal progression of HCoV-OC43 through the central nervous system (CNS) of live BALB/c mice after intranasal or intracerebral inoculation with rOC43-ns2DelRluc. We found that rOC43-ns2DelRluc was fatal to suckling mice after intranasal inoculation, and that viral titers and Rluc expression were detected in the brains and spinal cords of mice infected with rOC43-ns2DelRluc. Moreover, viral replication was initially observed in the brain by non-invasive bioluminescence imaging before the infection spread to the spinal cord of BALB/c mice, consistent with its tropism in the CNS. Furthermore, the Rluc readout correlated with the HCoV replication ability and protein expression, which allowed quantification of antiviral activity in live mice. Additionally, we validated that chloroquine strongly inhibited rOC43-ns2DelRluc replication in vivo. These results provide new insights into the temporal and spatial dissemination of HCoV-OC43 in the CNS, and our methods provide an extremely sensitive platform for evaluating the efficacy of antiviral therapies to treat neuroinvasive HCoVs in live mice.

The synergistic antileukemic effects of eltrombopag and decitabine in myeloid leukemia cells.

BACKGROUND: Hypomethylating agents (HMAs), such as decitabine (DAC), are currently used as first-line therapy for patients with high-risk myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML) not eligible for standard chemotherapies. Exacerbation of thrombocytopenia is one of the prevalent complications after HMA treatment. Eltrombopag (EP), an oral thrombopoietin receptor agonist, can efficiently stimulate megakaryopoiesis and elevate platelet counts in MDS/AML patients. However, the significance of combining EP with HMAs in patients with high-risk MDS/AML has not been determined. PURPOSE: To explore the impacts and mechanisms of EP and/or DAC on leukemia cell growth and to explore whether EP exhibits antileukemic effects in the context of DAC treatment in human myeloid leukemia cell lines. METHODS: In our study, we assessed the anti-leukemic effect of EP in the context of DAC treatment by measuring cell proliferation, apoptosis, cell-cycle distribution, and intracellular reactive oxygen species (ROS) levels. RESULTS: Our results showed that the combination of EP and DAC had a more obvious antiproliferative effect than that of DAC as a single agent. EP mainly induced S or G0/G1 phase cell cycle arrest, and DAC arrested the cell cycle in the S or G2/M phase. The combination of EP and DAC had a synergistic effect on cell cycle arrest. Furthermore, single-agent treatment with EP or DAC induced a change in intracellular ROS levels, and the combination of EP and DAC had a synergistic effect on ROS levels, exacerbating leukemia cell death. CONCLUSION: Our study provides in vitro evidence of the synergistic antileukemic effect and potential mechanisms of the combination of DAC and EP on myeloid leukemia cells.

High-Throughput Screening and Identification of Potent Broad-Spectrum Inhibitors of Coronaviruses.

Coronaviruses (CoVs) act as cross-species viruses and have the potential to spread rapidly into new host species and cause epidemic diseases. Despite the severe public health threat of severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome CoV (MERS-CoV), there are currently no drugs available for their treatment; therefore, broad-spectrum inhibitors of emerging and endemic CoVs are urgently needed. To search for effective inhibitory agents, we performed high-throughput screening (HTS) of a 2,000-compound library of approved drugs and pharmacologically active compounds using the established genetically engineered human CoV OC43 (HCoV-OC43) strain expressing Renilla luciferase (rOC43-ns2Del-Rluc) and validated the inhibitors using multiple genetically distinct CoVs in vitro We screened 56 hits from the HTS data and validated 36 compounds in vitro using wild-type HCoV-OC43. Furthermore, we identified seven compounds (lycorine, emetine, monensin sodium, mycophenolate mofetil, mycophenolic acid, phenazopyridine, and pyrvinium pamoate) as broad-spectrum inhibitors according to their strong inhibition of replication by four CoVs in vitro at low-micromolar concentrations. Additionally, we found that emetine blocked MERS-CoV entry according to pseudovirus entry assays and that lycorine protected BALB/c mice against HCoV-OC43-induced lethality by decreasing viral load in the central nervous system. This represents the first demonstration of in vivo real-time bioluminescence imaging to monitor the effect of lycorine on the spread and distribution of HCoV-OC43 in a mouse model. These results offer critical information supporting the development of an effective therapeutic strategy against CoV infection.IMPORTANCE Currently, there is no approved therapy to treat coronavirus infection; therefore, broad-spectrum inhibitors of emerging and endemic CoVs are needed. Based on our high-throughput screening assay using a compound library, we identified seven compounds with broad-spectrum efficacy against the replication of four CoVs in vitro Additionally, one compound (lycorine) was found to protect BALB/c mice against HCoV-OC43-induced lethality by decreasing viral load in the central nervous system. This inhibitor might offer promising therapeutic possibilities for combatting novel CoV infections in the future.

Do Muscle Enzyme Changes Forecast Liver Injury in Polymyositis/Dermatomyositis Patients Treated with Methylprednisolone and Methotrexate?

BACKGROUND: Long-term use of hormones and immunosuppressive agents is necessary for treating polymyositis (PM)/dermatomyositis (DM) but may cause liver damage. At what point do the costs of treatment outweigh the benefits, and how will the breakeven point be determined? METHODS: Serum muscle enzyme changes in 93 PM/DM patients were analyzed over the course of hormone and immunosuppressive agent treatment. From the analysis, a forecasting method was developed to help anticipate possible drug-induced liver injury. RESULTS: Before treatment, CK levels were frequently elevated and showed correlation with ALT,AST,LDH and CK-MB levels (r=0.682, 0.766, 0.739 and 0.784, respectively). After treatment, all muscle enzyme levels were decreased except ALT (p>0.05). ALT level was positively correlated with CK level (r=0.681) in those patients whose CK level remained abnormal after treatment. Linear regression analysis yielded an equation(CK Level=12.66*ALT Level-136.23) that could predict potential liver damage. CONCLUSIONS: CK level was the most sensitive index of PM/DM and was highly correlated with other serum muscle enzyme levels. An equation capable of predicting potential liver damage according to the correlation of CK and ALT was produced.

Elevated plasma-soluble CD16 levels in porcine reproductive and respiratory syndrome virus-infected pigs: correlation with ADAM17-mediated shedding.

Soluble CD16 (sCD16) is closely correlated with chronic diseases in humans. Here, plasma sCD16 levels in pigs were increased by infection with porcine reproductive and respiratory syndrome virus (PRRSV) but not with porcine epidemic diarrhea virus, porcine circovirus type 2 and pseudorabies virus. Of interest, PRRSV attached to blood neutrophils and reduced surface CD16 expression on neutrophils. In vitro data confirmed that PRRSV caused CD16 shedding in neutrophils. Further analyses revealed that ADAM17 was involved in porcine CD16 shedding. Thus, our findings suggest that increase in sCD16 levels may be an indicator of PRRSV infection.