Multi-omics and single cell characterization of cancer immunosenescence landscape.

Cellular senescence (CS) is closely related to tumor progression. However, the studies about CS genes across human cancers have not explored the relationship between cancer senescence signature and telomere length. Additionally, single-cell analyses have not revealed the evolutionary trends of malignant cells and immune cells at the CS level. We defined a CS-associated signature, called "senescence signature", and found that patients with higher senescence signature had worse prognosis. Higher senescence signature was related to older age, higher genomic instability, longer telomeres, increased lymphocytic infiltration, higher pro-tumor immune infiltrates (Treg cells and MDSCs), and could predict responses to immune checkpoint inhibitor therapy. Single-cell analysis further reveals malignant cells and immune cells share a consistent evolutionary trend at the CS level. MAPK signaling pathway and apoptotic processes may play a key role in CS, and senescence signature may effectively predict sensitivity of MEK1/2 inhibitors, ERK1/2 inhibitors and BCL-2 family inhibitors. We also developed a new CS prediction model of cancer survival and established a portal website to apply this model ( https://bio-pub.shinyapps.io/cs_nomo/ ).

Genomic landscape and distinct molecular subtypes of primary testicular lymphoma.

Primary testicular lymphoma (PTL) is a rare lymphoma predominantly occurring in the elderly male population. It is characterized by a limited response to treatment and a heightened tendency towards relapse. Histologically, approximately 90% of PTL cases are classified as diffuse large B-cell lymphomas (DLBCL). Genetic features of PTL were delineated in a limited scope within several independent studies. Some of the articles which analyzed the genetic characterization of DLBCL have incorporated PTL samples, but these have been constrained by small sample sizes. In addition, there have been an absence of independent molecular typing studies of PTL. This report summarizes the common mutational features, copy number variations (CNVs) and molecular typing of PTL patients, based on whole-exome sequencing (WES) conducted on a cohort of 25 PTL patients. Among them, HLA, CDKN2A and MYD88 had a high mutation frequency. In addition, we found two core mutational characteristics in PTL including mutation in genes linked to genomic instability (TP53 and CDKN2A) and mutation in immune-related genes (HLA, MYD88, CD79B). We performed molecular typing of 25 PTL patients into C1 subtype with predominantly TP53 mutations and C2 subtype with predominantly HLA mutations. Notably, mutations in the TP53 gene predicted a poor outcome in most types of lymphomas. However, the C1 subtype, dominated by TP53 mutations, had a better prognosis compared to the C2 subtype in PTL. C2 subtype exhibited a worse prognosis, aligning with our finding that the mechanism of immune escape in PTL was primarily the deletions of HLA rather than PD-L1/PD-L2 alterations, a contrast to other DLBCLs. Moreover, we calculated the tumor mutation burden (TMB) and identified that TMB can predict prognosis and recurrence rate in PTL. Our study underscores the significance of molecular typing in PTL based on mutational characteristics, which plays a crucial role in prognostication and guiding therapeutic strategies for patients.

Peroxiredoxin 1 promotes proliferation and inhibits differentiation of MC3T3-E1 cells via AKT1 / NF-κB signaling pathway.

OBJECTIVES: Osteoporosis is the most common metabolic bone disease worldwide. The decrease in bone mass is primarily accompanied by a decrease in the number and activity of osteoblasts. Peroxiredoxins (PRDXs) are proteins that detect extremely low peroxide levels and act as sensors that regulate oxidation signals, thereby regulating various cellular functions. This study aimed to evaluate the effects of PRDX1 and estrogen on the biological behavior of osteoblasts, including their proliferation and differentiation. METHODS: Ovariectomized (OVX) mice were used to establish a model of osteoporosis and perform morphological and immunohistochemical analyses. Prdx1 gene knockout and overexpression were performed in mouse MC3T3-E1 pre-osteoblasts to assess proliferation and osteogenic differentiation using the cell counting kit-8, quantitative reverse transcription polymerase chain reaction, western blotting (WB), Alizarin Red S staining, etc. RESULTS: The OVX mice exhibited osteoporosis and PRDX1 expression increased. In vitro experiments showed that during the osteogenic differentiation of osteoblasts, PRDX1 expression decreased, while the expression of COL1 and RUNX2 increased. After Prdx1 knockout, the proliferation of osteoblasts decreased; expression of Runx2, ALP, and COL1 increased; and mineralization increased. However, after Prdx1 overexpression, osteoblast proliferation was enhanced, whereas osteogenic differentiation and mineralization were inhibited. Estrogen inhibits the H2O2-induced decrease in osteoblastic differentiation and increase in PRDX1 expression. WB revealed that when LY294002 inhibited the AKT signaling pathway, the levels of p-AKT1, p-P65, and PRDX1 protein in MC3T3-E1 cells decreased. However, when pyrrolidine dithiocarbamate (PDTC) inhibited the NF-κB signaling pathway, the expression of p-AKT1 and PRDX1 did not change except for a significant reduction of p-P65 expression. Furthermore, PDTC reversed the decreased expression of RUNX2, ALP, and COL1 caused by PRDX1 overexpression. CONCLUSIONS: PRDX1 promotes the proliferation of osteoblasts and inhibits osteogenic differentiation. Estrogen regulated osteoblastic differentiation by affecting the expression of PRDX1 in osteoblasts, and the effect is related to the AKT1/NF-κB signaling pathway.

Genetic and prognostic analysis of blastoid and pleomorphic mantle cell lymphoma: a multicenter analysis in China.

Blastoid or pleomorphic mantle cell lymphoma (B/P-MCL) is characterized by high invasiveness and unfavorable outcomes, which is still a challenge for treating MCL. This retrospective study was performed to comprehensively analyze the clinical, genomic characteristics and treatment options of patients with B/PMCL from multicenter in China. Data were obtained from 693 patients with B/PMCL from three centers in China between April 1999 and December 2019. Seventy-four patients with BMCL (n = 43) or PMCL (n = 31) were included in the analysis. The median age of the cohort was 60.0 years with a male-to-female ratio of 2.89:1. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 44.1% and 46.0%, respectively. Mutations of TP53, ATM, NOTCH1, NOTCH2, NSD2, SMARCA4, CREBBP, KMT2D, FAT1, and TRAF2 genes were the most common genetic changes in B/P-MCL. Progression of disease within 12 months (POD12) could independently predict the poor prognosis of patients with blastoid and pleomorphic variants. Patients with POD12 carried a distinct mutation profile (TP53, SMARCA4, NSD2, NOTCH2, KMT2D, PTPRD, CREBBP, and CDKN2A mutations) compared to patients with non-POD12. First-line high-dose cytosine arabinoside exposure obtained survival benefits in these populations, and BTKi combination therapy as the front-line treatment had somewhat improvement in survival with no significant difference in the statistic. In conclusion, B/P-MCL had inferior outcomes and a distinct genomic profile. Patients with POD12 displayed a distinct mutation profile and a poor prognosis. New therapeutic drugs and clinical trials for B/P-MCL need to be further explored.

Traditional uses, botany, phytochemistry, and pharmacology of Lonicerae japonicae flos and Lonicerae flos: A systematic comparative review.

ETHNOPHARMACOLOGICAL RELEVANCE: Lonicerae japonicae flos (LJF) and Lonicerae flos (LF) belong to different genera of Caprifoliaceae with analogous appearances and functions. Historically, they have been used as herbal medicines to treat various diseases with confirmed wind-heat evacuation, heat-clearing, and detoxification effects. However, the Chinese Pharmacopoeia (2005 Edition) lists LJF and LF under different categories. AIM OF THE STUDY: Few studies have systematically compared the similarities and dissimilarities of LJF and LF concerning their research achievements. This systematic review and comparison of the traditional use, identification, and phytochemical and pharmacological properties of LJF and LF provides valuable insights for their further application and clinical safety. MATERIALS AND METHODS: Related document information was collected from databases that included Web of Science, X-MOL, Science Direct, PubMed, and the China National Knowledge Infrastructure. RESULTS: The chemical constituents and pharmacological effects of LJF and LF were similar. A total of 337 and 242 chemical constituents were isolated and identified in LJF and LF, respectively. These included volatile oils, cyclic ether terpenes, flavonoids, phenolic acids, triterpenoids, and their saponins. Additionally, LJF plants contain more iridoids and flavonoids than LF plants. The latter have a variety of triterpenoid saponins and significantly higher chlorogenic acid content than LJF plants. Pharmacological studies have shown that LJF and LF have various anti-inflammatory, antiviral, antibacterial, anti-endotoxic, antioxidant, anti-tumor, anti-platelet, myocardial protective, and hepatoprotective effects. CONCLUSIONS: This review was undertaken to explore whether LJF and LF should be listed separately in the Chinese Pharmacopoeia in terms of their disease prevention and treatment strategies. Although LJF and LF showed promising effects, their action mechanisms remains unclear. Specifically, their impact on gut microbiota, gastrointestinal tract, and blood parameters requires further investigation. These studies will provide the foundation for scientific utilization and clinical/non-clinical applications of LJF and LF, and the maximum benefits from their mutual use.

Prediction and prognostic potential of NR3C1 gene expression level in DLBCL patients.

Objective: Diffuse Large B-Cell Lymphoma (DLBCL) is a common and frequently occurring subtype of Non-Hodgkin Lymphoma (NHL). The effective treatment and prognosis of DLBCL are still urgently needed to be explored. This article aims to shed light on the connection between DLBCL survival and NR3C1 expression levels. Methods: First, we divided the 952 DLBCL patients into an NR3C1 high-expression group and an NR3C1 low-expression group and compared the baseline characteristics of the two groups. Second, we used multivariate analysis to predict the dependent variable for age, pathology, ECOG score, lactate dehydrogenase (LDH) ratio, and NR3C1 expression level. Finally, we analyzed the progression-free survival (PFS) and overall survival rate (OS) of DLBCL patients with high or low NR3C1 expression. Results: DLBCL patients with high NR3C1 expression had a better prognosis than those with low NR3C1 expression (OS, P < 0.0001). In DLBCL patients of CHOP therapy, high NR3C1 expression was associated with a good survival prognosis in OS (OS, P = 0.028). Conclusion: In multivariate analysis, NR3C1 high expression was an independent prognostic factor that predicted a longer OS of DLBCL (OS, P = 0.0003). NR3C1 is considered an independent predictor of DLBCL patients and can be used as a biomarker for the prognosis of DLBCL.

FAM46C-mediated tumor heterogeneity predicts extramedullary metastasis and poorer survival in multiple myeloma.

Cancers originate from a single cell according to Nowell's theory of clonal evolution. The enrichment of the most aggressive clones has been developed and the heterogeneity arises for genomic instability and environmental selection. Multiple myeloma (MM) is a multiple relapse plasma cell cancer generated from bone marrow. Although there were accumulating researches in multiple myeloma pathogenesis, the heterogeneity remains poorly understood. The participants enrolled in this study were 4 EMP+ (EMP, Extramedullary plasmacytoma) and 2 EMP- primarily untreated MM patients. Single cell RNA sequencing and analysis were conducted for the single cell suspension, which was sorted by flow cytometry from peripheral blood mononuclear cells or bone marrow cells. In our research, the results of single cell RNA sequencing show that FAM46C determines MM tumor heterogeneity predicting extramedullary metastasis by influencing RNA stability. Further, we integrated and analyzed 2280 multiple myeloma samples from 7 independent datasets, which uncover that FAM46C mediated tumor heterogeneity predicts poorer survival in multiple myeloma.

p53 directly downregulates the expression of CDC20 to exert anti-tumor activity in mantle cell lymphoma.

BACKGROUND: Cell cycle dysregulation characterized by cyclin D1 overexpression is common in mantle cell lymphoma (MCL), while mitotic disorder was less studied. Cell division cycle 20 homologue (CDC20), an essential mitotic regulator, was highly expressed in various tumors. Another common abnormality in MCL is p53 inactivation. Little was known about the role of CDC20 in MCL tumorigenesis and the regulatory relationship between p53 and CDC20 in MCL. METHODS: CDC20 expression was detected in MCL patients and MCL cell lines harboring mutant p53 (Jeko and Mino cells) and wild-type p53 (Z138 and JVM2 cells). Z138 and JVM2 cells were treated with CDC20 inhibitor apcin, p53 agonist nutlin-3a, or in combination, and then cell proliferation, cell apoptosis, cell cycle, cell migration and invasion were determined by CCK-8, flow cytometry and Transwell assays. The regulatory mechanism between p53 and CDC20 was revealed by dual-luciferase reporter gene assay and CUT&Tag technology. The anti-tumor effect, safety and tolerability of nutlin-3a and apcin were investigated in vivo in the Z138-driven xenograft tumor model. RESULTS: CDC20 was overexpressed in MCL patients and cell lines compared with their respective controls. The typical immunohistochemical marker of MCL patients, cyclin D1, was positively correlated with CDC20 expression. CDC20 high expression indicated unfavorable clinicopathological features and poor prognosis in MCL patients. In Z138 and JVM2 cells, either apcin or nutlin-3a treatment could inhibit cell proliferation, migration and invasion, and induce cell apoptosis and cell cycle arrest. GEO analysis, RT-qPCR and WB results showed that p53 expression was negatively correlated with CDC20 expression in MCL patients, Z138 and JVM2 cells, while this relationship was not observed in p53-mutant cells. Dual-luciferase reporter gene assay and CUT&Tag assay revealed mechanistically that CDC20 was transcriptionally repressed by p53 through directly binding p53 to CDC20 promoter from - 492 to + 101 bp. Moreover, combined treatment of nutlin-3a and apcin showed better anti-tumor effect than single treatment in Z138 and JVM2 cells. Administration of nutlin-3a/apcin alone or in combination confirmed their efficacy and safety in tumor-bearing mice. CONCLUSIONS: Our study validates the essential role of p53 and CDC20 in MCL tumorigenesis, and provides a new insight for MCL therapeutics through dual-targeting p53 and CDC20.

High trophinin-associated protein expression predicts good survival in acute myeloid leukemia with normal cytogenetics.

BACKGROUND: Nearly half of adult acute myeloid leukemia (AML) patients were classified into cytogenetic normal acute myeloid leukemia (CN-AML). The expression level of Trophinin associated protein (TROAP) was proven to be associated with the prognosis of several cancers, but it is still unclear in the prognosis of patients with CN-AML. METHODS: We integrated CN-AML patient samples from 4 datasets to analyze the relationship between TROAP expression and the survival of CN-AML. In addition, we investigated 92 AML patients of The Cancer Genome Atlas (TCGA) database to analyze the relationship between TROAP expression and the survival of AML patients received chemotherapy. We investigated the relationship between the expression of TROAP and drug sensitivity in AML cell lines. RESULTS: CN-AML patients with high TROAP expression were related to good event-free survival (EFS) and overall survival (OS). In AML patients received chemotherapy, high TROAP expression was associated with good survival prognosis. Additionally, the expression of TROAP gene in leukemia stem cells (LSC) + group was lower. Among multiple drugs, the lower the expression of TROAP, the lower the IC50. CONCLUSION: TROAP could serve as an independent predictor of CN-AML patients and could act as a potential biomarker for the prognosis of CN-AML. TROAP expression levels were closely correlated with the drug sensitivity of multiple drugs.

The expression level of Neuronal Calcium Sensor 1 can predict the prognosis of cytogenetically normal AML.

Acute myeloid leukemia (AML) is malignant clonal expansion of myeloid blasts with high heterogeneity and numerous molecular biomarkers have been found to judge the prognosis in some specific classifications of AML. Furthermore, as for patients with cytogenetically normal acute myeloid leukemia (CN-AML), we need to find more new biomarkers to predict the patients' outcomes. Recently, the expression level of Neuronal Calcium Sensor 1 (NCS1) has been associated with the prognosis of breast cancer and hepatocellular carcinoma, but nothing related has been reported about hematological malignancies. Therefore, we make this study to explore the relationship between the NCS1 expression level and CN-AML. We analyzed the relation between survival and NCS1 RNA expression through 75 CN-AML patients from Cancer Genome Atlas (TCGA) database and 433 CN-AML patients (3 independent datasets) from Gene Expression Omnibus (GEO) database. Additionally, we compared the NCS1 RNA expression between 138 leukemia stem cells positive (LSCs+) samples and 89 leukemia stem cells negative (LSCs-) samples from 78 AML patients from GSE76004 dataset. In our study, CN-AML patients with high expression level of NCS1 have longer EFS or OS. In addition, the NCS1 expression level in leukemia stem cells was low (p = 0.00039). According to these findings, we concluded that the high expression of NCS1 can predict favorable prognosis in CN-AML patients. Furthermore, our work put forward that NCS1 expresses lower in LSCs+, which might be an important mechanism to explain the aggressiveness of AML.

The prognostic value of RASGEF1A RNA expression and DNA methylation in cytogenetically normal acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is a significantly heterogeneous malignancy of the blood. Cytogenetic abnormalities are crucial for the prognosis of AML. However, since more than half of patients with AML are cytogenetically normal AML (CN-AML), predictive prognostic indicators need to be further refined. In recent years, gene abnormalities are considered to be strong prognostic factors of CN-AML, already having clinical significance for treatment. In addition, the relationship of methylation in some genes and AML prognosis predicting has been discovered. RASGEF1A is a guanine nucleotide exchange factors of Ras and widely expressed in brain tissue, bone marrow and 17 other tissues. RASGEF1A has been reported to be associated with a variety of malignant tumors, examples include Hirschsprung disease, renal cell carcinoma, breast cancer, diffuse large B cell lymphoma, intrahepatic cholangiocarcinoma and so on [1, 2]. However, the relationship between the RASGEF1A gene and CN-AML has not been reported. METHODS: By integrating the Cancer Genome Atlas (TCGA) database 75 patients with CN-AML and 240 Gene Expression Omnibus (GEO) database CN-AML samples, we examined the association between RASGEF1A's RNA expression level and DNA methylation of and AML patients' prognosis. Then, we investigated the RASGEF1A RNA expression and DNA methylation's prognostic value in 77 patients with AML after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) as well as 101 AML patients after chemotherapy respectively. We investigated the association between sensitivity to Crenolanib and expression level of RASGED1A in patients by integrating 191 CN-AML patients from BeatAML dadataset. We integrated the expression and methylation of RASGEF1A to predict the CN-AML patients' prognosis and investigated the relationship between prognostic of AML patients with different risk classification and expression levels or methylation levels of RASGEF1A. RESULTS: We found that RASGEF1A gene high expression group predicted poorer event-free survival (EFS) (P< 0.0001) as well as overall survival (OS) (P< 0.0001) in CN-AML samples, and the identical results were found in AML patients receiving chemotherapy (P< 0.0001) and Allo-HSCT (P< 0.0001). RASGEF1A RNA expression level is an CN-AML patients' independent prognostic factor (EFS: HR = 5.5534, 95% CI: 1.2982-23.756, P= 0.0208; OS: HR = 5.3615, 95% CI: 1.1014-26.099, P= 0.0376). The IC50 (half maximal inhibitory concentration) of Crenolanib of CN-AML samples with RASGEF1A high expression level is lower. In addition, patients with high RASGEF1A methylation level had significant favorable prognosis (EPS: P< 0.0001, OS: P< 0.0001). Furthermore, the integrative analysis of expression and methylation of RASGEF1A could classify CN-AML patients into subgroups with different prognosis (EFS: P= 0.034, OS: P= 0.0024). Expression levels or methylation levels of RASGEF1A help to improve risk classification of 2010 European Leukemia Net. CONCLUSION: Higher RASGEF1A RNA expression and lower DNA methylation predicts CN-AML patients' poorer prognosis. The RASGEF1A high expression level from patients with CN-AML have better sensitivity to Crenolanib. The integrative analysis of RASGEF1A RNA expression and DNA methylation can provide a more accurate classification for prognosis. Lower RASGEF1A expression is a favorable prognostic factor for AML patients receiving chemotherapy or Allo-HSCT. 2010 European Leukemia Net's risk classification can be improved by RASGEF1A expression levels or methylation levels.

Simultaneous analysis of mutations and methylations in circulating cell-free DNA for hepatocellular carcinoma detection.

Cell-free DNA (cfDNA)-based liquid biopsy is a promising approach for the early detection of cancer. A major hurdle is the limited yield of cfDNA from one blood draw, limiting the use of most samples to one test of either mutation or methylation. Here, we develop a technology, Mutation Capsule Plus (MCP), which enables multiplex profiling of one cfDNA sample, including simultaneous detection of genetic and epigenetic alterations and genome-wide discovery of methylation markers. With this technology, we performed de novo screening of methylation markers on cfDNA samples from 30 hepatocellular carcinoma (HCC) cases and 30 non-HCC controls. The methylation markers enriched in HCC cfDNA were further profiled in parallel with a panel of mutations on a training cohort of 60 HCC and 60 non-HCC cases, resulting in an HCC detection model. We validated the model in an independent retrospective cohort with 58 HCC and 198 non-HCC cases and got 90% sensitivity with 94% specificity. Furthermore, we applied the model to a prospective cohort of 311 asymptomatic hepatitis B virus carriers with normal liver ultrasonography and serum AFP concentration. The model detected four of the five HCC cases in the cohort, showing 80% sensitivity and 94% specificity. These findings demonstrate that the MCP technology has potential for the discovery and validation of multiomics biomarkers for the noninvasive detection of cancer. This study also provides a comprehensive database of genetic and epigenetic alterations in the cfDNA of a large cohort of HCC cases and high-risk non-HCC individuals.

Identification of six hub genes in mantle cell lymphoma patients with BTKi resistance.

Background: Bruton tyrosine kinase inhibitor (BTKi) resistance is an unsolved problem in the treatment of relapse/recurrence (R/R) mantle cell lymphoma (MCL). Although salvage therapy following ibrutinib resistance has been attempted in recent years, the survival of resistant patients was significantly reduced. Once ibrutinib-treated patients relapse, the 1-year survival rate is only 22%. Acquired drug resistance and primary drug resistance were found to relate closely to genetic mutations. The hub genes identification and clinical data analysis of patients resistant to BTKi based on the Chinese MCL gene mutation profile are worthy of exploration. Methods: Based on 28 MCL patients' mutation data and clinical data, 6 hub genes were screened by a gene panel of 69 genes and univariate Cox prognostic analysis. Prognosis and responses to salvage therapy regimen were analyzed. Results: Patients with BTKi had less favorable clinical features at baseline. Chimeric antigen receptor T-cell (CAR-T) therapy yielded the best response among salvage treatments. The 6 hub genes were screened by a gene panel of 69 genes (GP79) which might be a potential predictor for MCL patients with BTKi resistance. Conclusions: The clinical characteristics of BTKi resistance in MCL patients were summarized, and 6 hub genes were identified to provide ideas and suggestions for further research.

Global characterization of megakaryocytes in bone marrow, peripheral blood, and cord blood by single-cell RNA sequencing.

Megakaryocytes (MK) are mainly derived from bone marrow and are mainly involved in platelet production. Studies have shown that MK derived from bone marrow may have immune function, and that MK from peripheral blood are associated with prostate cancer. Single-cell transcriptome sequencing can help us better understand the heterogeneity and potential function of MK cell populations in bone marrow (BM), peripheral Blood (PB), and cord blood (CB) of healthy and diseased people.We integrated more than 1.2 million single-cell transcriptome data from 132 samples of PB, BM, and CB from healthy individuals and patients from different dataset. We examined the MK (including MK and product of MK) by single-cell RNA sequencing data analysis methods and identification of MK-related protein expression by the Human Protein atlas. We investigate the relationship between the MK subtype and Non-Small Cell Lung Cancer (NSCLC) in 77 non-cancer and 402 NSCLC. We found that MK were widely distributed and the amount of MK in peripheral blood was more than that in bone marrow and there were specificity MK subtypes in peripheral blood. We found classical MK1 with typical MK characteristics and non-classical MK2 closely related to immunity which was the most common subtype in bone marrow and cord blood. Classical MK1 was closely related to Non-Small Cell Lung Cancer (NSCLC) and can be used as a diagnostic marker. MK2 may have potential adaptive immune function and play a role in tumor NSCLC and autoimmune diseases Systemic Lupus Erythematosus. MK have 14 subtypes and are widely distributed in PB, CB, and BM. MK subtypes are closely related to immunity and have potential to be a diagnostic indicator of NSCLC.

CXCL12/CXCR4 facilitates perineural invasion via induction of the Twist/S100A4 axis in salivary adenoid cystic carcinoma.

The activation of CXCL12/CXCR4 axis participated in the progression of multiple cancers, but potential effect in terms of perineural invasion (PNI) in SACC remained ambiguous. In this study, we identified that CXCL12 substantially expressed in nerve cells. CXCR4 strikingly expressed in tumour cells, and CXCR4 expression was closely associated with the level of EMT-associated proteins and Schwann cell hallmarks at nerve invasion frontier in SACC. Activation of CXCL12/CXCR4 axis could promote PNI and up-regulate relative genes of EMT and Schwann cell hallmarks both in vitro and in vivo, which could be inhibited by Twist silence. After overexpressing S100A4, the impaired PNI ability of SACC cells induced by Twist knockdown was significantly reversed, and pseudo foot was visualized frequently. Collectively, the results indicated that CXCL12/CXCR4 might promote PNI by provoking the tumour cell to differentiate towards Schwann-like cell through Twist/S100A4 axis in SACC.

Inhibition of DEC2 is necessary for exiting cell dormancy in salivary adenoid cystic carcinoma.

BACKGROUND: Patients were prone to have poor prognosis once dormant tumor cells being reactivated. However, the molecular mechanism of tumor cell dormancy remains poorly understood. This study aimed to investigate the function of DEC2 in the dormancy of salivary adenoid cystic carcinoma (SACC) in vitro and vivo. METHODS: The function of DEC2 in tumor dormancy of SACC was investigated in nude mice by establishing primary and lung metastasis model. Meanwhile, the interaction between hypoxia and SACC dormancy and the role of DEC2 were demonstrated through CoCl2 induced hypoxia-mimicking microenvironments. Furthermore, the expression of DEC2 was detected by immunohistochemical staining in primary SACC samples with and without recurrence. RESULTS: In the primary SACC, DEC2 overexpression inhibited cell proliferation, increased cell population arrested in G0/G1 phase, and participated in dormancy regulation, which limited tumor growth. Intriguingly, in the model of lung metastasis, the level of DEC2 was reduced significantly and resulted in dormancy exit and growth resumption of SACC cells. Then, we found that DEC2 may associate with hypoxia in contributing to tumor dormancy, which might provide a possible cue to explain the different roles of DEC2 in primary and metastasis lesions. And overexpression of DEC2 induced dormancy and promoted migration and invasion through activating EMT program. Finally, DEC2 positive expression was shown to be significantly correlated with recurrence and dormancy of SACC patients. CONCLUSIONS: These findings provide a novel insight into the role of DEC2 gene in tumor dormancy and metastasis.

Escalating health risk of thallium and arsenic from farmland contamination fueled by cement-making activities: A hidden but significant source.

Soil-to-vegetable migration of toxic metal(loid)s is a pivotal pathway of human exposure to chemical intoxication. Thallium (Tl) and arsenic (As) are highly toxic metal(loid)s but their co-occurrence in soils and vegetables remain poorly understood. Herein, the present study focuses on potential health risk arising from co-occurrence of TlAs in various common vegetables cultivated in different farmlands around an industrial area featured by cement production activities. The results reveal obvious co-contamination of Tl (2.28 ± 1.39 mg/kg) and As (102.0 ± 66.7 mg/kg) in soils. Fine particles bearing sulfide and other minerals associated with Tl and As are detected in fly ash from cement plant, which can be migrated by wind over a long distance with hidden but inevitable pollution. Bioaccumulation Factor (BCF) and Enrichment Factor (EF) show that taro and corn preferentially accumulate Tl especially in underground parts. Hazard Quotient (HQ) indicates that consumption of these vegetables may result in chronic poisoning and/or even carcinogenic risk. The study highlights that the pathway and high risk of co-contamination of TlAs in the nearby farmlands posed by cement-making activities should be highly concerned.

Fibroblasts in cancer dormancy: foe or friend?

Cancer dormancy is defined that the residual cancer cells could enter into a state of quiescence and patients remain asymptomatic for years or even decades after anti-tumor therapies. Fibroblasts, which represent a predominant cell type in tumor microenvironment, play a pivotal role in determining the ultimate fate of tumor cells. This review recapitulates the pleiotropic roles of fibroblasts which are divided into normal, senescent, cancer-associated fibroblasts (CAFs) and circulation CAFs in tumor dormancy, relapse, metastasis and resistance to therapy to help the treatment of cancer metastasis.

5-Hydroxymethylcytosine profiles of cfDNA are highly predictive of R-CHOP treatment response in diffuse large B cell lymphoma patients.

BACKGROUND: Although R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) remains the standard chemotherapy regimen for diffuse large B cell lymphoma (DLBCL) patients, not all patients are responsive to the scheme, and there is no effective method to predict treatment response. METHODS: We utilized 5hmC-Seal to generate genome-wide 5hmC profiles in plasma cell-free DNA (cfDNA) from 86 DLBCL patients before they received R-CHOP chemotherapy. To investigate the correlation between 5hmC modifications and curative effectiveness, we separated patients into training (n = 56) and validation (n = 30) cohorts and developed a 5hmC-based logistic regression model from the training cohort to predict the treatment response in the validation cohort. RESULTS: In this study, we identified thirteen 5hmC markers associated with treatment response. The prediction performance of the logistic regression model, achieving 0.82 sensitivity and 0.75 specificity (AUC = 0.78), was superior to existing clinical indicators, such as LDH and stage. CONCLUSIONS: Our findings suggest that the 5hmC modifications in cfDNA at the time before R-CHOP treatment are associated with treatment response and that 5hmC-Seal may potentially serve as a clinical-applicable, minimally invasive approach to predict R-CHOP treatment response for DLBCL patients.