Accumulation of circulating myeloid-derived suppressor cell subsets: predicting poor clinical efficacy and prognosis through T cell suppression in non-Hodgkin's lymphoma.

Myeloid-derived suppressor cells (MDSC) are implicated in the regulation of immune responses closely associated with poor clinical outcomes in cancer. However, the MDSC subtypes in non-Hodgkin's Lymphoma (NHL) has not been systematically investigated. So we investigated the percentage of MDSC subsets in 78 newly diagnosed NHL patients by flow cytometry. The results showed that all MDSC subsets increased in NHL patients compared to healthy donors. Notably, MDSC, M-MDSC, and CD14+CD66b+MDSC significantly increased in NHL patients compared to those with lymphadenitis. PMN-MDSC, e-MDSC and IPI were independent risk factors for poor clinical efficacy and were involved in constructing the nomogram for predicting clinical efficacy. Progression-free survival (PFS) was significantly shorter in patients with high level of MDSC subsets, and PMN-MDSC emerged as an independent prognostic factor for PFS. PMN-MDSC, e-MDSC and IPI were involved in constructing the nomogram for predicting PFS. Patients with a higher percentage of MDSC, PMN-MDSC, e-MDSC, and CD14+CD66b+MDSC experienced a shorter OS compared to those with lower percentages. In addition, research on mechanisms found that T cell function was suppressed and mediated by the expansion of MDSC via involving Arg-1 and IL-10 in vitro and in vivo. In conclusion, our study demonstrates that the increased circulating MDSC subsets predict poor clinical efficacy and prognosis in NHL, potentially involving T cell suppression through MDSC subsets expansion. These findings indicate the potential of MDSC subsets as comprehensive diagnostic, prognostic biomarkers, and therapeutic targets for NHL.

Prognostic value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography at diagnosis in untreated multiple myeloma patients: a systematic review and meta-analysis.

Multiple myeloma is a clonal B-lymphocyte tumor of terminally differentiated plasma cells. 18F-FDG PET/CT can provide valuable data for the diagnosis, restaging, and evaluate prognosis of multiple myeloma (MM). This meta-analysis aimed to evaluate the prognostic value of pre-treatment 18F-FDG PET/CT at diagnosis in MM patients. Related researches came from Embase, PubMed, and Cochrane Library databases through a systematic search, and the last one was updated on April 26, 2021. Cochran Q test and I-squared statistics were used to test for heterogeneity among the studies analyzed. The fixed model and random model were used to combine results when appropriate. Stata 12.0 was used to perform statistical analysis, and p < 0.05 was considered statistically significant. A total of 16 articles with 2589 patients were included in this study. Our results indicated PET/CT has an excellent prognostic role in MM, that higher SUVmax, more FL and EMD were associated with poor OS and PFS. SUVmax: OS (HR 1.89, 95% CI 1.47-2.44), PFS (HR 1.34, 95% CI 1.18-1.51); Fl: OS (HR 2.65, 95% CI 1.83-3.79), PFS (HR 1.61, 95% CI 1.40-1.86); EMD: OS (HR 2.11, 95% CI 1.41-3.16), PFS (HR 2.18, 95% CI 1.69-2.81). Furthermore, similar results were observed in most subgroup analyzes. Conclusion Pre-treatment 18F-FDG PET/CT examination has prognostic value for myeloma patients and has guiding significance for clinical treatment.

Identification of biomarkers for early diagnosis of multiple myeloma by weighted gene co-expression network analysis and their clinical relevance.

BACKGROUND: Multiple myeloma is an incurable hematologic malignancy, its early diagnosis is important. However, the biomarker for early diagnosis is limited; hence more need to be identified. The present study aimed to explore the easily tested new biomarker in multiple myeloma by weighted gene co-expression network analysis (WGCNA). METHODS: Differentially expressed genes (DEGs) were screened using GSE47552. WGCNA was used to screen hub genes. Subsequently. Hub genes of multiple myeloma were obtained by intersection of DEGs and WGCNA. We used the T-test to screen highly expressed genes. Then, the diagnostic value of key genes was evaluated by the receiver operating characteristic (ROC) curve. Finally, expression levels of key genes were tested and proved by RT-PCR. RESULTS: 278 DEGs were screened by Limma package. Three modules were most significantly correlated with multiple myeloma. 238 key genes were screened after the intersection of WGCNA with DEGs. In addition, SNORNA is rarely studied in multiple myeloma, and ROC curve analysis in our prediction model showed that SNORA71A had a good prediction effect (p = 0.07). The expression of SNORA71A was increased in samples of multiple myeloma (P = 0.05). RT-PCR results showed that SNORA71A was upregulated in 51 patient specimens compared to the healthy group (P < 0.05). Linear correlation analysis showed that creatinine was positively correlated with SNORA71A (r = 0.49 P = 0.0002). CONCLUSIONS: This study found that SNORA71A was up-regulated and associated with the clinical stages in multiple myeloma; it suggests that SNORA71A could be used as a novel biomarker for early diagnosis and a potential therapeutic target in multiple myeloma.

Integrated bioinformatics analysis reveals dynamic candidate genes and signaling pathways involved in the progression and prognosis of diffuse large B-cell lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a highly heterogeneous malignancy with varied outcomes. However, the fundamental mechanisms remain to be fully defined. AIM: We aimed to identify core differentially co-expressed hub genes and perturbed pathways relevant to the pathogenesis and prognosis of DLBCL. METHODS: We retrieved the raw gene expression profile and clinical information of GSE12453 from the Gene Expression Omnibus (GEO) database. We used integrated bioinformatics analysis to identify differentially co-expressed genes. The CIBERSORT analysis was also applied to predict tumor-infiltrating immune cells (TIICs) in the GSE12453 dataset. We performed survival and ssGSEA (single-sample Gene Set Enrichment Analysis) (for TIICs) analyses and validated the hub genes using GEPIA2 and an independent GSE31312 dataset. RESULTS: We identified 46 differentially co-expressed hub genes in the GSE12453 dataset. Gene expression levels and survival analysis found 15 differentially co-expressed core hub genes. The core genes prognostic values and expression levels were further validated in the GEPIA2 database and GSE31312 dataset to be reliable (p < 0.01). The core genes' main KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichments were Ribosome and Coronavirus disease-COVID-19. High expressions of the 15 core hub genes had prognostic value in DLBCL. The core genes showed significant predictive accuracy in distinguishing DLBCL cases from non-tumor controls, with the area under the curve (AUC) ranging from 0.992 to 1.00. Finally, CIBERSORT analysis on GSE12453 revealed immune cells, including activated memory CD4+ T cells and M0, M1, and M2-macrophages as the infiltrates in the DLBCL microenvironment. CONCLUSION: Our study found differentially co-expressed core hub genes and relevant pathways involved in ribosome and COVID-19 disease that may be potential targets for prognosis and novel therapeutic intervention in DLBCL.

Tumor Endothelial Marker 8 Promotes Proliferation and Metastasis via the Wnt/ß-Catenin Signaling Pathway in Lung Adenocarcinoma.

Tumor endothelial marker 8 (TEM8), also known as ANTXR1, was highly expressed in cancers, and was identified as a biomarker for early diagnosis and prognosis in some cancers. However, the clinical role and molecular mechanisms of TEM8 in lung adenocarcinoma (LUAD) are still unclear. The present study aimed to explore its clinical value and the molecular mechanisms of TEM8 underlying the progression of LUAD. Our study found the elevation of TEM8 in LUAD cell lines and tissues. What's more, we observed that the TEM8 expression level was associated with tumor size, primary tumor, and AJCC stage, and LUAD patients with high TEM8 expression usually have a poor prognosis. Then, we conducted a series of experiments by the strategy of loss-of-function and gain-of-function, and our results suggested that the knockdown of TEM8 suppressed proliferation, migration, and invasion and induced apoptosis in LUAD whereas overexpression of TEM8 had the opposite effect. Molecular mechanistic investigation showed that TEM8 exerted its promoting effects mainly through activating the Wnt/ß-catenin signaling pathway. In short, our findings suggested that TEM8 played a crucial role in the progression of LUAD by activating the Wnt/ß-catenin signaling pathway and could serve as a potential therapeutic target for LUAD.

Integrative analysis of hub genes and key pathway in two subtypes of diffuse large B-cell lymphoma by bioinformatics and basic experiments.

BACKGROUND: The germinal center B-cell (GCB) and activated B-cell (ABC) subtypes of diffuse large B-cell lymphoma (DLBCL) have a significant difference in prognosis. This study aimed to identify potential hub genes, and key pathways involved in them. METHODS: Databases including Gene Expression Omnibus (GEO), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and STRING were accessed to obtain potential crucial genes and key pathways associated with the GCB and ABC. Then qRT-PCR and Western blot experiments were performed to verify the most clinically significant gene and pathway. RESULTS: Three cohort datasets from the GEO database were analyzed, including 195 GCB and 169 ABC samples. We identified 1113 differentially expressed genes (DEGs) between the GCB and ABC subtypes. The DEGs were mainly enriched in biological processes (BP). The KEGG analysis showed enrichment in cell cycle and Wnt signaling pathways. We selected the top 10 genes using the STRING database and Cytoscape software. We used 5 calculation methods of the cytoHubba plugin, and found 3 central genes (IL-10, CD44, CCND2). CCND2 was significantly related to the prognosis of DLBCL patients. Besides, our experimental results demonstrated a significantly higher expression of CCND2 in the ABC-type cell line than in the GCB-type; it was proportional to the expression of key proteins in the Wnt signaling pathway. CONCLUSION: CCND2 overexpression and Wnt pathway activation might be the main reasons for the poor prognosis of ABC-DLBCL.

Anti-CD19 CAR-T cell therapy bridge to HSCT decreases the relapse rate and improves the long-term survival of R/R B-ALL patients: a systematic review and meta-analysis.

Chimeric antigen receptor (CAR) T cell therapy improves the remission rate of refractory/relapsed B-acute lymphoblastic leukemia (R/R B-ALL) patients, but the relapse rate remains high. Recent studies suggest patients who underwent post-chimeric antigen receptor T cell therapy hematopoietic stem cell transplantation (post- HSCT) would achieve durable remission and better survival, but this remains controversial. To this end, we conducted a meta-analysis to assess the role of post-HSCT in R/R B-ALL. The Cochrane Library, Embase, and PubMed were used to identify relevant studies; the latest search update was on July 05, 2020. We used the Cochran Q test and I-squared statistics to test for heterogeneity among the studies analyzed. The fixed model and random model were used to combine results when appropriate. We performed all statistical analyses with Stata 12, and P < 0.05 was considered statistically significant. We included 18 studies with 758 patients in the meta-analysis. Our results indicated that post-HSCT was associated with lower relapse rate (RR: 0.40, 95% CI: 0.32-0.50, P = 0.000), better overall survival (HR: 0.37, 95% CI: 0.19-0.71, P = 0.003), better leukemia-free survival (HR: 0.20, 95% CI: 0.10-0.40, P = 0.000). However, post-HSCT did not influence OS in Caucasians, and CAR-T cells with CD28 co-stimulation factor bridged to HSCT did not influence OS. Post-HSCT decreased the relapse rate and improved the long-term survival of R/R B-ALL patients. R/R B-ALL patients would benefit from post-HSCT after CAR-T cell therapy.

Long non-coding RNA HOTAIR regulates myeloid differentiation through the upregulation of p21 via miR-17-5p in acute myeloid leukaemia.

Long non-coding RNA HOTAIR has been reported to play a key role in regulating various biological processes in various cancers. However, the roles and mechanisms of HOTAIR in acute myeloid leukaemia (AML) are still unclear and need to be investigated. In this study, we induced differentiation of four AML cell lines by all-trans retinoic acid (ATRA) and found HOTAIR was significantly upregulated in the process. Chromatin immunoprecipitation (ChIP) assays indicated that C/EBPß upregulated HOTAIR during ATRA induced differentiation in HL-60 cells. By gain- and loss-of-function analysis, we then observed that HOTAIR expression was positively correlated with ATRA-induced differentiation and negatively regulated G1 phase arrest in HL-60 cells. In addition, we found that HOTAIR promoted ATRA-induced differentiation via the regulation of the cell cycle regulator p21 via miR-17-5p. Moreover, we detected the expression of HOTAIR in 84 de novo AML patients, HOTAIR was found significantly downregulated in the AML patients compared to the iron deficiency anaemia (IDA) control group, negatively correlated with the platelet level in M2 patients. In all, our data suggest that HOTAIR may be subtype-specific in AML-M2 patients, also HOTAIR regulates AML differentiation by C/EBPBß/HOTAIR/miR-17-5p/p21 pathway. The findings of the present study provide a novel insight into the mechanism of lncRNA-mediated differentiation and indicate that HOTAIR may be a promising therapeutic target for leukaemia, especially for AML with M2 type.Abbreviation: AML: acute myeloid leukaemia; APL: acute promyelocytic leukaemia; ATRA: all-trans retinoic acid; CCK8: cell Counting Kit-8; CDKs: cyclin-dependent kinases ; CeRNA: competing endogenous RNAs; ChIP: chromatin immunoprecipitation; CHX: cycloheximide; FAB: French-American-British; FCM: flow cytometry; HOTAIR: HOX transcript antisense RNA; IDA: iron-deficiency anemia; lncRNA: long non-coding RNA; 3'UTR: 3'untranslated region; MT: Mutation type; WT: Wild type; qRT-PCR: Quantitative real-time PCR.

Renal dysfunction among adult HIV/AIDS patients on antiretroviral therapy at a tertiary facility in Ghana.

BACKGROUND: Kidney diseases have emerged as significant cause of morbidity and mortality in HIV subject on antiretroviral therapy (ART). In Ghana, routine follow up of HIV positive clients is by estimation of serum creatinine and urea levels. Glomerular Filtration Rate (GFR) is not routinely calculated and proteinuria is not routinely checked. This study sought to investigate the kidney profiles of adult HIV/AIDS patients being managed on ART at the Cape Coast Teaching Hospital (CCTH), Ghana. METHODS: A hospital-based analytical cross sectional study with a retrospective component was conducted using systematic sampling method to recruit HIV/AIDS who visited the ART clinic. A total of 440 participants of both sexes aged 18 years and above, confirmed as HIV/AIDS positive and on ART were involved in this study. Blood and urine samples were collected from all subjects and the levels of serum creatinine and urea and proteinuria were estimated and eGFR calculated using the Modification of Diet in Renal Disease (MDRD) equations. Data analyses were performed using Stata version 13 software (Stata Corp, Texas USA). RESULTS: The mean age (years) of participants was 45.5 years (±11.6) with 288 (65.4%) being on Tenofovir based ART regimen. The mean eGFR was found to decrease from 112.4 ml/min/1.73 m at baseline, to 103.4 ml/min/1.73 m after 6 months on ART and to a mean of 99.4 ml/min/1.73 m at recruitment into this study. Factors which were found to be associated with having eGFR < 60 included age, gender and CD4 count though not statistically significant. Patients > 45 years had the highest odds with OR 2.0 (95% CI: 0.8-5.1), females had higher odds with OR 1.5 (95% CI: 0.5-5.2), and those with CD4 count > 350 had OR of 0.4 (95% CI 0.2-1.3). A total of 30.9% of the participants had proteinuria at recruitment. TDF based ART regimen had no statistically significant effect on serum creatinine and urea levels. CONCLUSION: Estimated GFR decreased after 6 months among patients on ART despite normal serum creatinine and urea levels. This finding suggests that clients in care at HIV/ART clinics in Ghana may benefit from routine estimation of GFR and proteinuria.

Preoperative Anaemia and Associated Postoperative Outcomes in Noncardiac Surgery Patients in Central Region of Ghana.

INTRODUCTION: Several studies suggest that preoperative anaemia (PA) is associated with adverse postoperative outcomes, but little is known about these outcomes in the Central Region of Ghana. This study aims to determine the prevalence of PA among noncardiac surgical patients and its implications for their postoperative outcomes. METHODS: This study was designed as an observational study; data including demographics and clinical and laboratory results were collected from the patients' records and through interviews. RESULTS: A total of 893 inpatient surgical cases undergoing elective and emergency operations, aged 15 years and above with mean age of 44.2 ± 17.0 yrs, were enrolled. The prevalence of PA was 54.3%, mostly microcytic with or without hypochromia (57.2%). The prevalence was higher in females than males (p ≤ 0.001). Preoperative anaemia was significantly associated with prolonged length of hospital stay (OR: 2.12 (95% CI: 1.49-3.10)). Allogeneic blood transfusion significantly prolonged the length of hospital stay (OR 4.48 (95% CI: 2.67-7.51)). 15.5% of the anaemic patients received oral iron supplements compared to 2.2% of nonanaemic patients (p ≤ 0.001). CONCLUSION: Preoperative anaemia is common among noncardiac surgical patients. It is independently and significantly associated with prolonged hospital stay leading to the use of increased healthcare resources. It is also the main predictor for perioperative allogeneic blood transfusions and the use of haematinics.

A Preliminary Study of the Suitability of Archival Bone Marrow and Peripheral Blood Smears for Diagnosis of CML Using FISH.

Background. FISH is a molecular cytogenetic technique enabling rapid detection of genetic abnormalities. Facilities that can run fresh/wet samples for molecular diagnosis and monitoring of neoplastic disorders are not readily available in Ghana and other neighbouring countries. This study aims to demonstrate that interphase FISH can successfully be applied to archival methanol-fixed bone marrow and peripheral blood smear slides transported to a more equipped facility for molecular diagnosis of CML. Methods. Interphase FISH was performed on 22 archival methanol-fixed marrow (BM) and 3 peripheral blood (PB) smear slides obtained at diagnosis. The BM smears included 20 CML and 2 CMML cases diagnosed by morphology; the 3 PB smears were from 3 of the CML patients at the time of diagnosis. Six cases had known BCR-ABL fusion results at diagnosis by RQ-PCR. Full blood count reports at diagnosis were also retrieved. Result. 19 (95%) of the CML marrow smears demonstrated the BCR-ABL translocation. There was a significant correlation between the BCR-ABL transcript detected at diagnosis by RQ-PCR and that retrospectively detected by FISH from the aged BM smears at diagnosis (r = 0.870; P = 0.035). Conclusion. Archival methanol-fixed marrow and peripheral blood smears can be used to detect the BCR-ABL transcript for CML diagnosis.