BATF promotes extramedullary infiltration through TGF-ß1/Smad/MMPs axis in acute myeloid leukemia.

Acute myeloid leukemia (AML) is one of the most prevalent types of leukemia and is challenging to cure for most patients. Basic Leucine Zipper ATF-Like Transcription Factor (BATF) has been reported to participate in the development and progression of numerous tumors. However, its role in AML is largely unknown. In this study, the expression and prognostic value of BATF were examined in AML. Our results demonstrated that BATF expression was upregulated in AML patients, which was significantly correlated with poor clinical characteristics and survival. Afterward, functional experiments were performed after knocking down or overexpressing BATF by transfecting small interfering RNAs and overexpression plasmids into AML cells. Our findings revealed that BATF promoted the migratory and invasive abilities of AML cells in vitro and in vivo. Moreover, the target genes of BATF were searched from databases to explore the binding of BATF to the target gene using ChIP and luciferase assays. Notably, our observations validated that BATF is bound to the promoter region of TGF-ß1, which could transcriptionally enhance the expression of TGF-ß1 and activate the TGF-ß1/Smad/MMPs signaling pathway. In summary, our study established the aberrantly high expression of BATF and its pro-migratory function via the TGF-ß1-Smad2/3-MMP2/9 axis in AML, which provides novel insights into extramedullary infiltration of AML.

The Application Value of CICARE Communication Mode Combined with Detailed Nursing on the Related Factors of Poor Prognosis of Patients After Gastric Cancer Resection.

Objective: To explore the independent risk factors for poor prognosis in patients with gastric cancer after resection and analyze the clinical application value of (connect-introduce-communicate-ask-respond-exit) CICARE communication mode combined with detailed nursing for such patients. Methods: 96 patients who underwent gastric cancer resection in our hospital from January 2019 to October 2019 were analyzed. They were divided into the good prognosis and poor prognosis group according to the postoperative adverse prognosis. The factors related to poor prognosis were analyzed by univariate and multivariate analysis. Another 106 patients who underwent gastric cancer resection from January 2020 to October 2021 were randomly divided into study and control group, with 53 patients in each group. The control group received routine nursing, and study group received CICARE communication mode combined with detailed nursing. Adverse mood changes were compared between the two groups before and after nursing. The changes of pain before surgery and 6 and 12 h after surgery were compared between the two groups as well as nursing satisfaction rate. Results: Univariate and multivariate results showed that body mass index (BMI) ≥ 28.00 kg/m2, length of hospital stay≥10 d, and preoperative complications≥2 were independent risk factors for poor prognosis after gastric cancer resection (P < .05). Compared with the control group, the incidence of postoperative adverse reactions in the study group was significantly reduced (P < .05). The bad mood of the two groups was alleviated compared with that before nursing, but the study group was significantly better than control (P < .05). The pain degree in both groups decreased with time, the study group was significantly lower than that in control (P < .05). Nursing satisfaction of the study group was significantly higher than that of control (P < .05). Conclusion: BMI ≥ 28.00 kg/m2, length of hospital stay≥10 d, and preoperative complications ≥ 2 types can cause postoperative adverse reactions in patients with gastric cancer resection. CICARE detailed nursing based on the above risk factors can effectively reduce postoperative complications and relieve postoperative pain and adverse emotions of patients, which has high clinical application value.

Single-Cell Profiling Reveals Sustained Immune Infiltration, Surveillance, and Tumor Heterogeneity in Infiltrative Basal Cell Carcinoma.

Infiltrative basal cell carcinoma (iBCC) is a particularly aggressive subtype of basal cell carcinoma that tends to progress and recur after surgery, and its malignancy is closely related to the tumor microenvironment. In this study, we performed a comprehensive single-cell RNA analysis to profile 29,334 cells from iBCC and adjacent normal skin. We found active immune collaborations enriched in iBCC. Specifically, SPP1+CXCL9/10high macrophage 1 had strong BAFF signaling with plasma cells, and T follicular helper-like cells highly expressed the B-cell chemokine CXCL13. Heterogeneous proinflammatory SPP1+CXCL9/10high macrophage 1 and angiogenesis-related SPP1+CCL2high macrophage 1 were identified within the tumor microenvironment. Interestingly, we found an upregulation of major histocompatibility complex I molecules in fibroblasts in iBCC compared with those in adjacent normal skin. Moreover, MDK signals derived from malignant basal cells were markedly increased, and their expression was an independent factor in predicting the infiltration depth of iBCC, emphasizing its role in driving malignancy and remodeling the tumor microenvironment. In addition, we identified differentiation-associated SOSTDC1+IGFBP5+CTSV+ malignant basal subtype 1 and epithelial-mesenchymal transition-associated TNC+SFRP1+CHGA+ malignant basal subtype 2 cells. The high expression of malignant basal 2 cell markers was associated with the invasion and recurrence of iBCC. Altogether, our study helps to elucidate the cellular heterogeneity in iBCC and provides potential therapeutic targets for clinical research.

Signatures of EMT, immunosuppression, and inflammation in primary and recurrent human cutaneous squamous cell carcinoma at single-cell resolution.

Rationale: The recurrence of cutaneous squamous cell carcinoma (cSCC) after surgery is associated with the reprogramming of the tumor microenvironment (TME), and remains a key factor affecting its outcomes. Methods: We employed single-cell RNA sequencing (scRNA-seq) to examine the dynamic changes in epithelial cells, T cells, myeloid cells, and fibroblasts between primary and recurrent cSCC. Cell clustering, cell trajectory, cell-cell communication, and gene set enrichment analysis were used to investigate the TME heterogeneity between primary and recurrent cSCC. Gene expression differences were monitored by IHC staining. Results: We examined the immunosuppressed microenvironment in recurrent cSCC, which exhibited a T cell-excluded and SPP1+ tumor-associated macrophages (TAMs)-enriched status. In recurrent cSCC, CD8+ T cells showed high exhaustion and low inflammatory features, while SPP1+ TAMs displayed global pro-tumor characteristics, including decreased phagocytosis and inflammation and increased angiogenesis. Furthermore, the subgroups of SPP1+ TAMs harbored distinct functions. SPP1+ CD209high TAMs showed features of phagocytosis, while SPP1+ CD209low TAMs tended to have a high angiogenic ability. A subpopulation of tumor-specific keratinocytes (TSKs) showed significant epithelial-mesenchymal transition (EMT) features in recurrent cSCC, probably due to their active communication with IL7R + cancer-associated fibroblasts (CAFs). Moreover, we found that the pleiotropic growth factor/cytokine Midkine (MDK) could provoke different cell-cell interactions in cSCC with distinctive staging. In primary cSCC, MDK was highly expressed in fibroblasts and could promote their proliferation and block the migration of tumor cells, while in recurrent cSCC, the high expression of MDK in TSKs promoted their proliferation and metastasis. Conclusion: Our study provides insights into the critical mechanisms of cSCC progression, which might facilitate the development of a powerful approach for the prevention and treatment of cSCC recurrence.

Combination of Tumor Mutational Burden and DNA Damage Repair Gene Mutations with Stromal/Immune Scores Improved Prognosis Stratification in Patients with Lung Adenocarcinoma.

Background: Both the tumor environment and the genomic landscape of lung cancer may shape patient responses to treatments, including immunotherapy, but their joint impacts on lung adenocarcinoma (LUAD) prognosis are underexplored. Methods: RNA sequencing data and whole-exome sequencing results were downloaded from the TCGA database, and only LUAD-related data were included in this study. Based on gene expression data, the ESTIMATE algorithm was used to estimate stromal and immune scores, and CIBERSORT analysis was used for quantification of the relative abundances of immune cells. Somatic mutations were used for calculating tumor mutation burden (TMB). Specific mutations in genes involved in DNA damage repair (DDR) pathways were identified. The individual and joint associations of stromal and immune score, TMB, and DDR gene mutations with 5-year survival were analyzed by the Kaplan-Meier method and multivariate Cox model. Results: LUAD patients with a high (>highest 25%) stromal or immune score had prolonged survival as compared to those with a low (highest 25%) and low (

The role of the tumor microbe microenvironment in the tumor immune microenvironment: bystander, activator, or inhibitor?

The efficacy of cancer immunotherapy largely depends on the tumor microenvironment, especially the tumor immune microenvironment. Emerging studies have claimed that microbes reside within tumor cells and immune cells, suggesting that these microbes can impact the state of the tumor immune microenvironment. For the first time, this review delineates the landscape of intra-tumoral microbes and their products, herein defined as the tumor microbe microenvironment. The role of the tumor microbe microenvironment in the tumor immune microenvironment is multifaceted: either as an immune activator, inhibitor, or bystander. The underlying mechanisms include: (I) the presentation of microbial antigens by cancer cells and immune cells, (II) microbial antigens mimicry shared with tumor antigens, (III) microbe-induced immunogenic cell death, (IV) microbial adjuvanticity mediated by pattern recognition receptors, (V) microbe-derived metabolites, and (VI) microbial stimulation of inhibitory checkpoints. The review further suggests the use of potential modulation strategies of the tumor microbe microenvironment to enhance the efficacy and reduce the adverse effects of checkpoint inhibitors. Lastly, the review highlights some critical questions awaiting to be answered in this field and provides possible solutions. Overall, the tumor microbe microenvironment modulates the tumor immune microenvironment, making it a potential target for improving immunotherapy. It is a novel field facing major challenges and deserves further exploration.

Blockade of HSP70 by VER-155008 synergistically enhances bortezomib-induced cytotoxicity in multiple myeloma.

Proteasome inhibitor bortezomib is one of the most effective drugs currently available for the treatment of multiple myeloma (MM). However, the intrinsic and acquired resistance to bortezomib can limit its effectiveness. The activation of heat shock response has been characterized as a potential resistance mechanism protecting MM cells from bortezomib-induced cell death. In this study, in response to bortezomib therapy, we discovered that HSP70 is one of the most substantially upregulated heat shock proteins. In order to further explore approaches to sensitizing bortezomib-based treatment for MM, we investigated whether targeting HSP70 using a specific inhibitor VER-155008 combined with bortezomib could overcome the acquired resistance in MM. We found that HSP70 inhibitor VER-155008 alone significantly decreased MM cell viability. Moreover, the combination of VER-155008 and bortezomib synergistically induced MM cell apoptosis markedly in vitro. Notably, the combined treatment was found to increase the cleavage of PARP, an early marker of chemotherapy-induced apoptosis. Importantly, the reduction of anti-apoptotic Bcl-2 family member Bcl-2, Bcl-xL, and Mcl-1 and the induction of pro-apoptotic Bcl-2 family member BH3-only protein NOXA and Bim were confirmed to be tightly associated with the synergism. Finally, the ER stress marker CHOP (CCAAT-enhancer binding protein homologous protein), which can cause transcriptional activation of genes involved in cell apoptosis, was markedly induced by both VER-155008 and bortezomib. Taken together, our finding of a strong synergistic interaction between VER-155008 and bortezomib may support for combination therapy in MM patients in the future.

High Expression Levels of Long Noncoding RNA Small Nucleolar RNA Host Gene 18 and Semaphorin 5A Indicate Poor Prognosis in Multiple Myeloma.

BACKGROUND: The aim of this study was to detect the expression of long noncoding RNA small nucleolar RNA host gene 18 (SNHG18) andsemaphorin 5A (SEMA5A) genes in multiple myeloma (MM) patients and to explore the correlation of the expression of these genes with the clinical characteristics and prognosis of MM patients. METHODS: Forty-seven newly diagnosed MM, 18 complete remission MM, 13 refractory/relapse MM, and 22 iron deficiency anemia (serving as control) samples were extracted at the Department of Hematology, Second Affiliated Hospital of Xian Jiaotong University between January 2015 and December 2016. The clinical features of the MM patients are summarized. Real-time quantitative PCR was performed to analyze the relative expression levels of the SNHG18 and SEMA5Agenes. The clinical characteristics and overall survival (OS) of the MM patients were statistically analyzed while measuring different levels of SNHG18 and SEMA5Agene expression. At the same time, the correlation between the expression of SNHG18 and SEMA5A was also analyzed. RESULTS: The analysis confirmed that SNHG18 and its possible target gene SEMA5A were both highly expressed in newly diagnosed MM patients. After analyzing the clinical significance of SNHG18 and SEMA5A in MM patients, we found that the expression of SNHG18 and SEMA5A was related to the Durie-Salmon (DS), International Staging System (ISS), and Revised International Staging System (R-ISS) classification systems, and the Mayo Clinic Risk Stratification for Multiple Myeloma (mSMART; p < 0.05). Moreover, we observed a significant difference in OS between the SNHG18/SEMA5A high expression group and the low expression group. We found a positive correlation between SNHG18 and SEMA5A expression (r = 0.709, p < 0.01). Surprisingly, the expected median OS times of both the SNHG18 and SEMA5Ahigh expression groups were significantly decreased, which was in contrast to those of both the SNHG18 and SEMA5Alow expression groups and the single-gene high expression group (p < 0.05). CONCLUSION: High expression of both SNHG18 and SEMA5A is associated with poor prognosis in patients with MM.

Serum platelet factor 4 is a promising predictor in newly diagnosed patients with multiple myeloma treated with thalidomide and VAD regimens.

OBJECTIVE: Frequent loss of expression of platelet factor 4 (PF4) in multiple myeloma (MM) was revealed in several previous researches. The predictive analysis of serum PF4 level in newly diagnosed MM has not been well elucidated. This study is to assess if serum PF4 could be a prognostic factor in predicting treatment response and survival of MM treated with thalidomide and VAD regimens. METHODS: Sera of 122 MM were gained pre- and post-treatment of chemotherapy and oral thalidomide. Serological PF4 measurements were performed by ELISA. Kaplan-Meier method was employed for survival analysis. Log rank test was used significance analysis. Multivariate analysis of overall survival used Cox-regression. RESULTS: Our data showed that the median serum PF4 concentration was negatively associated with MM response and a significant correlation between serum PF4 level and unfavorable clinical features (ß2-microglobulin, ISS stage, del17p and creatinine). MM with lower serum PF4 concentration at diagnosis were prone to gain complete remission and very good partial remission after two courses of chemotherapy. Besides del17p, ß2-microglobulin, treatment response, the low serum PF4 concentration was an independent variable associated with a poor overall survival by univariate analysis and multivariate analysis. CONCLUSIONS: We speculate serum PF4 is a promising response and prognostic factor in newly diagnosed MM treated with thalidomide and VAD regimens.

Focusing on long non-coding RNA dysregulation in newly diagnosed multiple myeloma.

AIMS: Multiple myeloma (MM) is an incurable hematological cancer with a higher rate of relapse. Alterations in the function of long non-coding RNAs (lncRNAs) promote the progression and metastasis of cancer. We carry out this study to explore the expression profile of differently expressed lncRNAs in newly diagnosed MM. MAIN METHODS: The Bone marrows we analyzed were obtained from five MM and five IDA patients (serving as controls). Arraystar Human LncRNA Array V4.0 was used to profile expression of lncRNAs and mRNAs. Gene ontology (GO) and pathway analysis were utilized to understand the biological roles of differently expressed genes, while Database for Annotation, Visualization and Integrated Discovery (DAVID) was used for constructing the lncRNA-mRNA co-expression network. Quantitative polymerase chain reaction (qRT-PCR) was performed to confirm the expressions of dysregulated lncRNAs. KEY FINDINGS: Bioinformatic analysis of the lncRNA expression identified >3000 dysregulated lncRNAs (difference ≥ 2-fold) in MM samples. GO and pathway analysis revealed that ECM-receptor and cell cycle pathway-related genes were significantly associated with MM. Four dysregulated lncRNAs were confirmed by qRT-PCR. Among them, the expression of ST3GAL6-AS1, LAMA5-AS1and RP11-175D17.3wereassociated with stage and risk status of MM. On the basis of GEO public database analysis, LAMA5-AS1 was related with an overall survival rate of MM patients. SIGNIFICANCE: These results reveal the feasible functions of lncRNAs in pathogenesis of MM. Further studies are required to explore whether these lncRNAs could serve as candidate therapeutic targets and new molecular biomarkers for MM.

Working memory and the identification of facial expression in patients with left frontal glioma.

Patients with brain tumors may have cognitive dysfunctions including memory deterioration, such as working memory, that affect quality of life. This study was to explore the presence of defects in working memory and the identification of facial expressions in patients with left frontal glioma. This case-control study recruited 11 matched pairs of patients and healthy control subjects (mean age ± standard deviation, 37.00 ± 10.96 years vs 36.73 ± 11.20 years; 7 male and 4 female) from March through December 2011. The psychological tests contained tests that estimate verbal/visual-spatial working memory, executive function, and the identification of facial expressions. According to the paired samples analysis, there were no differences in the anxiety and depression scores or in the intelligence quotients between the 2 groups (P > .05). All indices of the Digit Span Test were significantly worse in patients than in control subjects (P < .05), but the Tapping Test scores did not differ between patient and control groups. Of all 7 Wisconsin Card Sorting Test (WCST) indexes, only the Preservative Response was significantly different between patients and control subjects (P < .05). Patients were significantly less accurate in detecting angry facial expressions than were control subjects (30.3% vs 57.6%; P < .05) but showed no deficits in the identification of other expressions. The backward indexes of the Digit Span Test were associated with emotion scores and tumor size and grade (P < .05). Patients with left frontal glioma had deficits in verbal working memory and the ability to identify anger. These may have resulted from damage to functional frontal cortex regions, in which roles in these 2 capabilities have not been confirmed. However, verbal working memory performance might be affected by emotional and tumor-related factors.

[Correlation of HSP90 mRNA expression with migration ability of human multiple myeloma cells].

This study was aimed to investigate the correlation of heat shock protein 90 (HSP90) expression with migration ability of human multiple myeloma cells. The HSP90 mRNA expression and migration change of human multiple myeloma cell line (U266) were detected by RT-PCR and Transwell chamber respectively after treatment of U266 cells with final concentration 50, 100, 150, 200 nmol/L of bortezomib (proteosome inhibitor) for 4 hours. The results indicated that along with the increasing of bortezomib concentration, the expression level of HSP90alpha mRNA in U266 cells was enhanced, while no obvious increase of HSP90beta mRNA expression was observed in spite of statistical difference as a whole (p<0.05), but with the increasing of drug concentration in cells, their migration ability gradually decreased (p<0.05). It is concluded that the correlation of HSP90 expression with migration ability of human multiple myeloma cells exists.

[Mechanism of C-reactive protein on proliferation of multiple myeloma U266 cells].

This study was purposed to investigate the mechanism of C-reactive protein (CRP) on proliferation of U266 cells. The human multiple myeloma cell line U266 was incubated with human CRP (0, 5, 10, 20 mg/L) for 24 hours, then the proliferation level of U266 cells was detected by using blood analyser. The mRNA expressions of survivin and HSP90alpha were examined by RT-PCR. The results showed that the proliferation ratio was increased, as compared with the control group (p<0.05); furthermore, the mRNA levels of survivin and HSP90alpha were up-regulated in proportion to the increased CRP concentrations. There was significant correlation between expression of survivin and HSP90alpha (r=0.737, p<0.0001) in incubated cells. It is concluded that CRP can stimulate the proliferation of MM cells directly by up-regulating the expression of survivin and HSP90alpha in MM cells. CRP can be regarded as a potential target for MM treatment.