Search

Introduction Cervical cancer has high mortality, high recurrence and poor prognosis. Although prognostic biomarkers such as clinicopathological features have been proposed, their accuracy and precision are far from satisfactory. Therefore, novel biomarkers are urgently needed for disease surveillance, prognosis prediction and treatment selection. Materials Differentially expressed genes (DEGs) between cervical cancer and normal tissues from three microarray datasets extracted from the Gene Expression Omnibus platform were identified and screened. Based on these DEGs, a six‐gene prognostic signature was constructed using cervical squamous cell carcinoma and endocervical adenocarcinoma data from The Cancer Genome Atlas. Next, the molecular functions and related pathways of the six genes were investigated through gene set enrichment analysis and co‐expression analysis. Additionally, immunophenoscore analysis and the QuartataWeb Server were employed to explore the therapeutic value of the six‐gene signature. Results We discovered 178 overlapping DEGs in three microarray datasets and established a six‐gene (APOC1, GLTP, ISG20, SPP1, SLC24A3 and UPP1) prognostic signature with stable and excellent performance in predicting overall survival in different subgroups. Intriguingly, the six‐gene signature was closely associated with the immune response and tumour immune microenvironment. The six‐gene signature might be used for predicting response to immune checkpoint inhibitors (ICIs) and the six genes may serve as new drug targets for cervical cancer. Conclusion Our study established a novel six‐gene (APOC1, GLTP, ISG20, SPP1, SLC24A3 and UPP1) signature that was closely associated with the immune response and tumour immune microenvironment. The six‐gene signature was indicative of aggressive features of cervical cancer and therefore might serve as a promising biomarker for predicting not only overall survival but also ICI treatment effectiveness. Moreover, three genes (UPP1, ISG20 and GLTP) within the six‐gene signature have the potential to become novel drug targets., Our study established a novel six‐gene (APOC1, GLTP, ISG20, SPP1, SLC24A3 and UPP1) signature that was closely associated with the immune response and the tumour immune microenvironment. The six‐gene signature was indicative of aggressive features of cervical cancer and therefore might serve as a promising biomarker for predicting not only overall survival but also immune checkpoint inhibitor treatment effectiveness. Moreover, three genes (UPP1, ISG20 and GLTP) within the six‐gene signature have the potential to become novel drug targets.

The low rate of durable response against relapsed and/or refractory multiple myeloma (RRMM) in recent studies indicates that chimeric antigen receptor T‐cell (CART) treatment is yet to be optimized. This study aims to investigate the safety and efficacy of sequential infusion of CD19‐CART and B‐cell maturation antigen (BCMA)‐CARTs for RRMM with a similar 3 + 3 dose escalation combined with a toxicity sentinel design. We enrolled 10 patients, among whom 7 received autologous infusion and 3 received allogeneic infusion. The median follow‐up time was 20 months. The most common grade 3/4 treatment‐emergent toxicities were hematological toxicities. Cytokine‐release syndrome (CRS) adverse reactions were grade 1/2 in 9 out of 10 subjects. No dose‐limited toxicity (DLT) was observed for BCMA‐CAR‐positive T cells ≤5 × 107/kg), while two patients with dose‐levels of 5–6.5 × 107/kg experienced DLTs. The overall response rate was 90% (five partial responses and four stringent complete responses). Three out of four patients with stringent complete responses to autologous CART had progression‐free survival for over 2 years. The three patients with allogeneic CART experienced disease progression within 2 months. These results evidence the sequential infusion's preliminarily tolerability and efficacy in RRMM, and present a simple and safe design applicable for the establishment of multiple CART therapy., We conducted a pilot study to assess the feasibility of the sequential infusion of CD19 and B‐cell maturation antigen (BCMA)‐specific chimeric antigen receptor T‐cell (CART) for relapsed and/or refractory multiple myeloma treatment with a similar 3 + 3 dose escalation design. Translational Significance: The favorable and persistent responses against RRMM were observed in those patients with a combined infusion of autologous CD19‐CART and BCMA‐CART. The emergence of intolerant adverse event (neurotoxicity and sever CRS) was associated with increased dose level of BCMA‐CARTs infusion.

Esophageal cancer is one of the leading causes of cancer‐related deaths worldwide. FAM225A is a novel lncRNA, only has been explored in nasopharyngeal carcinoma tumorigenesis. This study aims to investigate the regulatory mechanism of FAM225A in esophageal squamous cell carcinoma (ESCC). We discovered that FAM225A exhibited higher expression in ESCC. The silence of FAM225A attenuated cell viability, migration, and invasion, but facilitated cell apoptosis in ESCC. Exosome‐mediated transfer of lncRNA FAM225A could participate in ESCC progression. In addition, we found that miR‐206 bound to FAM225A. Moreover, we further demonstrated that FAM225A absorbed miR‐206 to upregulate NETO2 and FOXP1 expression, and FOXP1 acted as a transcription factor to enhance FAM225A expression. Eventually, it was revealed that the overexpression of NETO2 or FOXP1 rescued the effects of FAM225A repression on ESCC progression. Our results suggested that FAM225A upregulated NETO2 and FOXP1 expression by sponging miR‐206 to accelerate ESCC progression and angiogenesis. These results determined the biological role of lncRNA FAM225A in ESCC tumorigenesis, and FAM225A may be a promising biomarker for ESCC treatment., FAM225A up‐regulated NETO2 and FOXP1 expression by absorbing miR‐206 in ESCC. FOXP1 induced FAM225A expression to promote ESCC progression.

Purpose Anti‐CD19 chimeric antigen receptor T (CAR‐T) cell therapy has demonstrated remarkable efficacy for refractory and relapsed diffuse large B cell lymphoma (R/R DLBCL). However, this therapy failed in nearly 25% patients mainly due to antigen loss. The authors performed a phase Ⅱ trial by coadministration of anti‐CD19 and anti‐CD20 CAR‐T cells treatment for R/R DLBCL and evaluated its efficacy and toxicity. Methods Totally 21 patients with DLBCL were enrolled in this study. The patients were conditioned with fludarabine and cyclophosphamide before the infusion of anti‐CD19 and anti‐CD20 CAR‐T cells. Treatment response, toxicity, and persistence were monitored continuously. Results Of the 21 patients received the treatment, the objective response rate (ORR) is 81.0% (95% confidence interval [CI], 58.1%‐94.6%) with four cases of bulk (4/5) and one case of testis involvement; 52.4% (95% CI, 29.8%‐74.3%) had a complete response (CR). Peak levels of anti‐CD19 and anti‐CD20 CAR cells were associated with response (P = .007 and .002). Grade 3‐4 cytokine release syndrome (CRS) and neurologic events occurred in 28.5% and 9.5% patients, respectively. Median overall survival (OS) and progression‐free survival (PFS) were 8.1 and 5.0 months, respectively. The maximum standard uptake value (SUVmax) of CD4/CD8 ratio before and after infusion were associated with responses, and the total lesion glycolysis (TLG) before infusion correlates with cytokines level. Conclusions Coadministration of anti‐CD19 and CD20 CAR‐T cells therapy for DLBCL is feasible with manageable toxicity. Cytokine markers are related to toxicity and SUVmax could predict efficacy. This trial was registered at www.clinicaltrials.gov as NCT03207178., In this study, we confirmed that combination of anti‐CD19 and anti‐CD20 CAR‐T cells therapy strategy was efficient (81% ORR and 52.4% CR respectively) for R/R DLBCL, and that the toxicities was transient and manageable. To our knowledge, this is the first report that combination of anti‐CD19 and anti‐CD20 double‐target CAR‐T cell therapy for R/R DLBCL, and our data demonstrated the feasibility of combination of anti‐CD19 and anti‐CD20 CAR‐T cells therapy for R/R DLBCL.

Glucocorticoids (GC) are the foundation of the chemotherapy regimen in acute lymphoblastic leukemia (ALL). However, resistance to GC is observed more frequently than resistance to other chemotherapy agents in patients with ALL relapse. Moreover, the mechanism underlying the development of GC resistance in ALL has not yet been fully uncovered. In this study, we used bioinformatic analysis methods to integrate the candidate genes and pathways participating in GC resistance in ALL and subsequently verified the bioinformatics findings with in vitro cell experiments. Ninety‐nine significant common differentially expressed genes (DEGs) associated with GC resistance were determined by integrating two gene profile datasets, including GC‐sensitive and ‐resistant samples. Using Kyoto Encyclopedia of Genes and Genomes (KEGG) and REACTOME pathways analysis, the signaling pathways in which DEGs were significantly enriched were clustered. The GC resistance‐related biologically functional interactions were visualized as DEG‐associated Protein–Protein Interaction (PPI) network complexes, with 98 nodes and 127 edges. MYC, a node which displayed the highest connectivity in all edges, was highlighted as the core gene in the PPI network. Increased C‐MYC expression was observed in adriamycin‐resistant BALL‐1/ADR cells, which we demonstrated was also resistant to dexamethasone. These results outlined a panorama in which the solitary and scattered experimental results were integrated and expanded. The potential promising target of the candidate pathways and genes involved in GC resistance of ALL was concomitantly revealed., These results outlined a panorama in which the solitary and scattered experimental results were integrated and extended. The potential promising target of the candidate pathways and genes in GC resistant acute lymphoblastic leukemia was concomitantly revealed.

MicroRNAs (miRNAs) are noncoding single‐stranded RNAs, approximately 20‐24 nucleotides in length, known as powerful posttranscriptional regulators. miRNAs play important regulatory roles in cellular processes by changing messenger RNA expression and are widely involved in human diseases, including tumors. It has been reported in the literature that miRNAs have a precise role in cell proliferation, programmed cell death, differentiation, and expression of coding genes. MicroRNA‐124 (miR‐124) has reduced exparession in various human neoplasms and is believed to be related to the occurrence, development, and prognosis of malignant tumors. In our review, we focus on the specific molecular functions of miR‐124 and the downstream gene targets in major cancers, which provide preclinical evidence for the treatment of human cancer. Although some obstacles exist, miR‐124 is still attracting intensive research focus as a promising and effective anticancer weapon., miRNA‐124 is closely related to the cancer development and progression, and decreased in many cancer types. Increasing miRNA‐124 levels, inhibiting cancer cell proliferation, and affecting clinical outcome. miRNA‐124 has the potential to be a target for cancer treatment.

Long noncoding RNA (lncRNA) CDKN2B‐AS1 has been shown to play a crucial role in the development as well as in the prognosis of various human cancers, including cervical cancer. However, the underlying mechanisms need to be further explored between CDKN2B‐AS1 and cervical cancer. In the present study, RT‐PCR showed that the mRNA level of CDKN2B‐AS1 was significantly upregulated while the miR‐181a‐5p was downregulated in cervical cancer cell lines. In addition, the interference of CDKN2B‐AS1 by shRNA resulted in the suppression of cell proliferation, invasion, migration and promotion of apoptosis and senescence, and either CDKN2B‐AS1 overexpression or miR‐181a‐5p showed reversed results. Further studies demonstrated that CDKN2B‐AS1 could directly interact with miR‐181a‐5p, and that there was an inverse correlation between miR‐181a‐5p and CDKN2B‐AS1. In addition, we found that TGFβI was a target of miR‐181a‐5p and could be downregulated by CDKN2B‐AS1 knockdown. Moreover, the in vivo experiments further demonstrated the contribution of CDKN2B‐AS1 in cervical cancer including tumor growth, apoptosis inhibition and senescence inhibition, and CDKN2B‐AS1 knockdown could inhibit the aforementioned activities. In summary, our study demonstrated that the CDKN2B‐AS1/miR‐181a‐5p/TGFβI axis might play a vital role in cervical cancer development.

The study aimed to investigate the role of serum EBV‐VCA IgG in assessing gastric cancer (GC) risk and prognosis. A total of 1790 Northern Chinese participants with pathologically confirmed disease underwent EBV‐VCA IgG serologic testing using enzyme‐linked immunosorbent assay (ELISA), including 821 controls, 410 atrophic gastritis (AG) patients, and 559 GC patients. We found that positive EBV‐VCA IgG was significantly associated with GC and its precursor, conferring a 1.55‐ and 1.36‐fold increased risk of GC and AG, respectively (P = 0.001, 95% CI = 1.21‐1.99; P = 0.011, 95% CI = 1.07‐1.72, respectively). The risk effects were more remarkable in younger, female, and Helicobacter pylori‐negative individuals than in older, male, and H. pylori‐positive individuals. EBV‐VCA IgG‐positive subjects had a lower PGI/II ratio than EBV‐VCA IgG‐negative subjects (median 8.0 vs 8.8, P = 0.001), especially those in the H. pylori‐positive (median 6.1 vs 6.8, P = 0.027) and GC subgroups (median 6.4 vs 7.9, P = 0.020). In the intestinal GC subgroup, the survival of EBV‐VCA IgG‐positive patients was worse than that of EBV‐VCA IgG‐negative patients (P = 0.041, HR = 2.45, 95% CI = 1.04‐5.78). Our study suggests that EBV‐VCA IgG seropositivity has potential in predicting the risk of GC and its precursor as well as the prognosis of histologically classified GC., This is an innovative report about the role of serum EBV‐VCA IgG detection in assessing the risk of gastric cancer (GC) and its precursor as well as GC prognosis. And this is the first report about the relationship between EBV‐VCA IgG serology assay and gastric function status. Our study provides theoretical and experimental basis for evaluating the potential of serum EBV‐VCA IgG as a biomarker in prediction of GC risk and prognosis.

Multidimensional interactions of multiple factors are more important in promoting cancer initiation. Gene‐gene interactions between protein‐coding genes have been paid great attention, while rare studies refer to the interactions between encoding and noncoding genes. Our research group previously found encoding gene PGC polymorphisms could affect the susceptibility to atrophic gastritis (AG) and gastric cancer (GC). Interestingly, several SNPs in long noncoding RNA (lncRNA) genes, just adjacent to PGC, were found to be associated with AG risk and GC prognosis afterward. This study aims to explore the SNP interactions between PGC and its neighbor lncRNAs on the risk of AG and GC. Genotyping for seven PGC SNPs and seven lncRNA SNPs was conducted using Sequenom MassARRAY platform in a total of 2228 northern Chinese subjects, including 536 GC cases, 810 AG cases, and 882 controls. We found 15 pairwise PGC‐lncRNAs SNPs had interactions: Five pairs were associated with AG risk, and ten pairs were associated with GC risk. Moreover, two GC‐related interactions PGC rs6939861 with lnc‐C6orf‐132‐1 rs7749023 and rs7747696 survived the Bonferroni correction (P correction = 0.049 and 0.007, respectively). Several combinations showed obvious epistasis and cumulative effects on disease risk. Some three‐way interactions of SNPs with smoking and drinking could also be observed. Besides, a few interacting SNPs showed correlations with the expression levels of PGC protein and related lncRNAs in serum. Our study would provide research clues for further screening combination biomarkers uniting both protein‐coding and noncoding genes with the potential in prediction of the susceptibility to GC and its precursor.

Background The immune checkpoint protein programmed cell death ligand 1 (PD‐L1) binds to PD1 to promote tumor cell escape from the killing effect of the immune system. However, there are few studies on the regulatory mechanisms of PD‐L1 in tumors. Although PD‐L1 has been reported to undergo ubiquitination in some cancers, its regulatory mechanisms in oral squamous cell carcinoma (OSCC) are unclear. Therefore, we aimed to investigate this phenomenon. Methods We examined the expression and function of USP9X and PD‐L1 in human oral keratinocytes (HOK) and OSCC cell lines (HN4 and HN30) as the control and relevant cancer cells using western blotting, immunoprecipitation, immunohistochemistry (IHC), T‐cell‐mediated tumor cell killing assay, and liquid chromatography‐mass spectrometry. Results Programmed cell death ligand 1 was highly expressed in OSCC by the regulation of the ubiquitin‐proteasome pathway. Furthermore, we discovered that ubiquitin‐specific peptidase 9, X‐linked (USP9X) could be combined with PD‐L1 to induce its deubiquitination and stabilize its protein expression in OSCC. Conclusion Our data indicate that USP9X deubiquitinates and stabilizes PD‐L1. Suppressing the expression of USP9X blocks tumor cell growth. The results provide a theoretical basis for USP9X as a therapeutic target.

Although the molecular biology of GC has been well characterized, early diagnostic biomarkers and effective therapeutic options in gastric cancer are still under investigation. Here, we found that miR‐148b expression decreased in human gastric cancer tissues compared with matched adjacent nontumor tissues by q‐PCR analysis and in situ hybridization. Further investigation revealed that overexpression of miR‐148b limited glycolysis including glucose consumption, lactate production in gastric cancer cell lines BGC‐823 and MKN45. Bioinformatics prediction uncovered that a dedicated transporters solute carrier family 2 member 1 (SLC2A1), also called GLUT1, was the direct target of miR‐148b. The target effects were further confirmed by luciferase assay and western blot analysis. Besides, a reverse correlation was observed between relative SLC2A1 and miR‐148b expression in human GC tissues compared with matched adjacent nontumor tissues. Subsequently, SLC2A1 suppression by SLC2A1 siRNA or specific inhibitor restricted the reduced effects of glycolysis mediated by miR‐148b while SLC2A1 overexpression abrogated the effect of miR‐148b on glycolysis. Our findings provided new evidence of miR‐148b in GC development through restraining glycolysis, highlighting the role of miR‐148b as a new target for GC treatment.

Linc00152, located on chromosome 2p11.2, is a long intergenic non‐coding RNA molecule with 828 nucleotides that is highly expressed in many types of human tumor tissues, especially in malignant tumors of the digestive system. Linc00152 promotes the occurrence and development of tumors by increasing tumor cell proliferation, invasion, metastasis, and apoptosis. Additionally, linc00152 contributes to the carcinogenesis of several cancers, including gastric cancer, liver cancer, hepatocellular carcinoma, gallbladder cancer, clear cell renal cell carcinoma, and colorectal cancer, by disturbing various signaling pathways (eg PI3K/AKT, mTOR, IL‐1, and NOTCH 1 signaling pathways). High linc00152 expression levels are associated with chemoresistance as well as poor prognosis and shorter survival. Continual advances made in the relevant research have indicated that linc00152 may be useful as a new tumor molecular biomarker, applicable for tumor diagnosis, targeted therapy, and prognosis assessment. This review summarizes the progress in the research into the relationship between linc00152 and the occurrence and development of malignancies based on molecular functions, regulatory mechanisms, and clinical applications.