Macrophage-coated tumor cluster aggravates hepatoma invasion and immunotherapy resistance via generating local immune deprivation.

Immune checkpoint inhibitors (ICIs) represent a promising treatment for hepatocellular carcinoma (HCC) due to their capacity for abundant lymphocyte infiltration. However, some patients with HCC respond poorly to ICI therapy due to the presence of various immunosuppressive factors in the tumor microenvironment. Our research reveals that a macrophage-coated tumor cluster (MCTC) signifies a unique spatial structural organization in HCC correlating with diminished recurrence-free survival and overall survival in a total of 572 HCC cases from 3 internal cohorts and 2 independent external validation cohorts. Mechanistically, tumor-derived macrophage-associated lectin Mac-2 binding protein (M2BP) induces MCTC formation and traps immunocompetent cells at the edge of MCTCs to induce intratumoral cytotoxic T cell exclusion and local immune deprivation. Blocking M2BP with a Mac-2 antagonist might provide an effective approach to prevent MCTC formation, enhance T cell infiltration, and thereby improve the efficacy of ICI therapy in HCC.

Intratumoral microbial heterogeneity affected tumor immune microenvironment and determined clinical outcome of HBV-related HCC.

BACKGROUND AND AIMS: The intratumoral microbiome has been reported to regulate the development and progression of cancers. We aimed to characterize intratumoral microbial heterogeneity (IMH) and establish microbiome-based molecular subtyping of HBV-related HCC to elucidate the correlation between IMH and HCC tumorigenesis. APPROACH AND RESULTS: A case-control study was designed to investigate microbial landscape and characteristic microbial signatures of HBV-related HCC tissues adopting metagenomics next-generation sequencing. Microbiome-based molecular subtyping of HCC tissues was established by nonmetric multidimensional scaling. The tumor immune microenvironment of 2 molecular subtypes was characterized by EPIC and CIBERSORT based on RNA-seq and verified by immunohistochemistry. The gene set variation analysis was adopted to explore the crosstalk between the immune and metabolism microenvironment. A prognosis-related gene risk signature between 2 subtypes was constructed by the weighted gene coexpression network analysis and the Cox regression analysis and then verified by the Kaplan-Meier survival curve.IMH demonstrated in HBV-related HCC tissues was comparably lower than that in chronic hepatitis tissues. Two microbiome-based HCC molecular subtypes, defined as bacteria- and virus-dominant subtypes, were established and significantly correlated with discrepant clinical-pathologic features. Higher infiltration of M2 macrophage was detected in the bacteria-dominant subtype with to the virus-dominant subtype, accompanied by multiple upregulated metabolism pathways. Furthermore, a 3-gene risk signature containing CSAG4 , PIP4P2 , and TOMM5 was filtered out, which could predict the clinical prognosis of HCC patients accurately using the Cancer Genome Atlas data. CONCLUSIONS: Microbiome-based molecular subtyping demonstrated IMH of HBV-related HCC was correlated with a disparity in clinical-pathologic features and tumor microenvironment (TME), which might be proposed as a biomarker for prognosis prediction of HCC.

Vasohibin 2 promotes lymphangiogenesis of lung squamous cell carcinoma through snail-dependent vascular endothelial growth factor-D (VEGF-D) signaling pathway.

Background: Tumor lymphatic metastasis is mostly dependent on lymphangiogenesis, which was less studied compared to angiogenesis and the molecular mechanisms involved remained unclear. Methods: We analyzed the mRNA expression profiles of 937 primary lung squamous cell carcinoma (LUSC) samples from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to explore the genes related to lymphatic metastasis in LUSC. We focused on vasohibin 2 (VASH2) and investigated its biological functions in LUSC proliferation, apoptosis, migration, invasion, as well as lymphangiogenesis capacity by forced over-expressing VASH2 in LUSC cell line H520 in vitro and in vivo. We also evaluated the anti-tumor efficacy of specific anti-VASH2 antibody in LUSC xenograft-bearing mice models. Results: Vasohibin2 (VASH2) was filtered out as a significant predictive factor of poor prognosis and lymphatic metastasis in LUSC patients both in public datasets and an independent Chinese LUSC cohort. VASH2 promoted the proliferation and invasion of LUSC cells in vitro and vivo. Forced over-expression of VASH2 in LUSC cells promoted the amplification and tube formation capacity of human umbilical vein endothelial cells (HUVECs) and human lymphatic endothelial cells (HLECs) via up-regulating vascular endothelial growth factor-D (VEGF-D), which could be reversed via Snail inhibition. Furthermore, blocking VASH2/VEGF-D signaling using specific antibodies dramatically inhibited tumor growth in mice by interfering with the proliferation of cancer cells and lymphangiogenesis in tumor tissues. Conclusions: In conclusion, VASH2 facilitated lymphangiogenesis and tumor growth in a Snail-dependent manner and might serve as a novel biomarker for early diagnosis and prognosis prediction, as well as a potential therapeutic target in LUSC.

ATP8B1 Knockdown Activated the Choline Metabolism Pathway and Induced High-Level Intracellular REDOX Homeostasis in Lung Squamous Cell Carcinoma.

The flippase ATPase class I type 8b member 1 (ATP8B1) is essential for maintaining the stability and polarity of the epithelial membrane and can translocate specific phospholipids from the outer membrane to the inner membrane of the cell. Although ATP8B1 plays important roles in cell functions, ATP8B1 has been poorly studied in tumors and its prognostic value in patients with lung squamous cell carcinoma (LUSC) remains unclear. By investigating the whole genomic expression profiles of LUSC samples from The Cancer Genome Atlas (TCGA) database and Tianjin Medical University Cancer Institute and Hospital (TJMUCH) cohort, we found that low expression of ATP8B1 was associated with poor prognosis of LUSC patients. The results from cellular experiments and a xenograft-bearing mice model indicated that ATP8B1 knockdown firstly induced mitochondrial dysfunction and promoted ROS production. Secondly, ATP8B1 knockdown promoted glutathione synthesis via upregulation of the CHKA-dependent choline metabolism pathway, therefore producing and maintaining high-level intracellular REDOX homeostasis to aggravate carcinogenesis and progression of LUSC. In summary, we proposed ATP8B1 as a novel predictive biomarker in LUSC and targeting ATP8B1-driven specific metabolic disorder might be a promising therapeutic strategy for LUSC.

Association of Total Thyroidectomy or Thyroid Lobectomy With the Quality of Life in Patients With Differentiated Thyroid Cancer With Low to Intermediate Risk of Recurrence.

IMPORTANCE: Owing to the good prognosis of differentiated thyroid cancer (DTC), guidelines recommend total thyroidectomy (TT) or thyroid lobectomy (TL) as surgical treatment for DTC with low to intermediate risk of recurrence. However, the association of these surgeries with the health-related quality of life (HRQOL) of patients with DTC with low to intermediate risk of recurrence is unclear. OBJECTIVE: To longitudinally compare the HRQOL of patients with DTC undergoing different surgeries. DESIGN, SETTING, AND PARTICIPANTS: This prospective observational longitudinal cohort study enrolled patients diagnosed with DTC with low to intermediate risk of recurrence at the First Affiliated Hospital, Sun Yat-sen University, China, from October 1, 2018, to September 31, 2019. Eligible patients were categorized into TL and TT groups according to the surgery they underwent. They were evaluated preoperatively and followed up at 1, 3, 6, and 12 months postoperatively using 3 HRQOL-related questionnaires (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, version 3.0; Hospital Anxiety and Depression Scale; and Thyroid Cancer-Specific Quality of Life Questionnaire); serum thyrotropin levels, complications, and patient satisfaction were also monitored. Data were analyzed to compare the HRQOL of patients undergoing different surgeries at different time points. EXPOSURES: Total thyroidectomy or TL. MAIN OUTCOMES AND MEASURES: The primary end point was HRQOL (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, version 3.0; Hospital Anxiety and Depression Scale; and Thyroid Cancer-Specific Quality of Life Questionnaire) at different time points, and the secondary end points were postoperative complications, thyrotropin level, and patient satisfaction. RESULTS: Of the 1060 eligible patients, 563 underwent TL (438 women [77.8%]; median [IQR] age, 38 [31-45] years), and 497 underwent TT (390 women [78.5%]; median [IQR] age, 38 [32-48] years). Compared with the TL group, including the 1- to 4-cm tumor subgroup, the TT group experienced more postoperative HRQOL problems at 1 and 3 months postoperatively. However, nearly all the differences disappeared at 6 and 12 months postoperatively. CONCLUSIONS AND RELEVANCE: Results of this study suggest that HRQOL of patients with DTC with low to intermediate risk of recurrence is not associated with the extent of surgery, and HRQOL may not be an important consideration when making surgical decisions. If better HRQOL is requested in the short term, TL may be preferred.

The mutation landscape of multiple cancer predisposition genes in Chinese familial/hereditary breast cancer families.

OBJECTIVE: Approximately 5%-10% of breast cancer (BC) patients display familial traits that are genetically inherited among the members of a family. The purpose of this study was to profile the germline mutations in 43 genes with different penetration rates and their correlations with phenotypic traits in Chinese familial BC families. METHODS: Ion Torrent S5™-based next generation sequencing was conducted on 116 subjects from 27 Chinese familial BC families. RESULTS: Eighty-one germline mutations in 27 BC predisposition genes were identified in 82.8% (96/116) of the cases. Among these, 80.8% of the mutated genes were related to DNA damage repair. Fourteen possible disease-causing variants were identified in 13 of 27 BC families. Only 25.9% (7/27) of the BC families exhibited hereditary deficiency in BRCA1/2 genes, while 22.2% of the BC families exhibited defects in non-BRCA genes. In all, 41.7% (40/96) of the mutation carriers had BRCA mutations, 88.5% (85/96) had non-BRCA mutations, and 30.2% (29/96) had both BRCA and non-BRCA mutations. The BC patients with BRCA mutations had a higher risk of axillary lymph node metastases than those without mutations (P < 0.05). However, the BC patients with non-BRCA mutations frequently had a higher occurrence of benign breast diseases than those without mutations (P < 0.05). CONCLUSIONS: In addition to BRCA1/2, genetic variants in non-BRCA DNA repair genes might play significant roles in the development of familial/hereditary BC. Therefore, profiling of multiple BC predisposition genes should be more valuable for screening potential pathogenic germline mutations in Chinese familial/hereditary BC.

Lin28A promotes the proliferation and stemness of lung cancer cells via the activation of mitogen-activated protein kinase pathway dependent on microRNA let-7c.

BACKGROUND: Among patients with lung cancer, metastatic and relapsed cases account for the largest proportion of disease-associated deaths. Tumor metastasis and relapse are believed to originate from cancer stem cells (CSCs), which have the capacity to be highly proliferative and invasive. In our previous studies, we established a conditional basement membrane extract-based (BME-based) 3-dimensional (3D) culture system to mimic the tumor growth environment in vivo and further amplified lung cancer stem cells (LCSCs) in our system. However, the molecular mechanisms of LCSC amplification and development in our 3D culture system have not been fully uncovered. METHOD: We established the conditional 3D culture system to amplify LCSCs in other lung cancer cell lines, followed by examining the expression of Lin28A and let-7 microRNAs in them. We also explored the expression of Lin28A and let-7 microRNAs in LCSCs from clinical lung cancer tissue samples and even analyzed the correlation of Lin28A/let-7c and patients' survival outcomes. We further constructed A549 cells either knockdown of Lin28A or overexpression of let-7c, followed by investigating stemness marker gene expression, and stemness phenotypes including mammosphere culture, cell migration and invasion in vitro, as well as tumorigenicity in vivo. RESULTS: Here, we observed that Lin28A/let-7c was dysregulated in LCSCs in both the 3D culture system and lung cancer tissues. Further, the abnormal expression of Lin28A/let-7c was correlated with poor survival outcomes. Via the construction of A549 cells with let-7c over-expression, we found that let-7c inhibited the maintenance of LCSC properties, while the results of Lin28A knockdown showed that Lin28A played a critical role in the enrichment and proliferation of LCSCs via mitogen-activated protein kinase (MAPK) signaling pathway. Importantly, we found that LCSCs with knockdown of Lin28A or over-expression of let-7c exhibited inhibited carcinogenesis and disrupted expansion in vivo. CONCLUSIONS: Our study uncovered the functions and mechanisms of the Lin28A/let-7c/MAPK signaling pathway in promoting the proliferation and cancer stemness of LCSCs, which might be a potential therapeutic target for reducing and even eliminating LCSCs in the future.

A hereditary ovarian cancer family with rare pathogenic splicing mutation: Implications for variant interpretation.

The BRCA1/2 gene is important for assessing the risk of familial/hereditary ovarian cancer (OC). This case is a patient with OC, and two of her immediate family members are cancer patients. We sequenced the coding and splicing regions of 42 OC susceptibility genes, and found a rare pathogenic splicing mutation BRCA1:c.132C > T (p.cys44 =) in 2 patients. Although the mutation is synonymous, software prediction and functional verification have shown that it affects alternative splicing and leads to frameshift mutations (c.131_134del). Chromosome microarray analysis of the tissue samples revealed the presence of a BRCA1 gene deletion with a fragment size of 1.42 Mb and an HRD score of 71. In addition, the proband showed a sensitive response to platinum treatment. This case suggests the clinical significance of OC susceptibility genes sequencing and HRD scoring in screening hereditary OC families.

Imbalance of TGF-ß1/BMP-7 pathways induced by M2-polarized macrophages promotes hepatocellular carcinoma aggressiveness.

The transforming growth factor-beta (TGF-ß) signaling pathway is the predominant cytokine signaling pathway in the development and progression of hepatocellular carcinoma (HCC). Bone morphogenetic protein (BMP), another member of the TGF-ß superfamily, has been frequently found to participate in crosstalk with the TGF-ß pathway. However, the complex interaction between the TGF-ß and BMP pathways has not been fully elucidated in HCC. We found that the imbalance of TGF-ß1/BMP-7 pathways was associated with aggressive pathological features and poor clinical outcomes in HCC. The induction of the imbalance of TGF-ß1/BMP-7 pathways in HCC cells could significantly promote HCC cell invasion and stemness by increasing inhibitor of differentiation 1 (ID1) expression. We also found that the microRNA (miR)-17-92 cluster, originating from the extracellular vesicles (EVs) of M2-polarized tumor-associated macrophages (M2-TAMs), stimulated the imbalance of TGF-ß1/BMP-7 pathways in HCC cells by inducing TGF-ß type II receptor (TGFBR2) post-transcriptional silencing and inhibiting activin A receptor type 1 (ACVR1) post-translational ubiquitylation by targeting Smad ubiquitylation regulatory factor 1 (Smurf1). In vivo, short hairpin (sh)-MIR17HG and ACVR1 inhibitors profoundly attenuated HCC cell growth and metastasis by rectifying the imbalance of TGF-ß1/BMP-7 pathways. Therefore, we proposed that the imbalance of TGF-ß1/BMP-7 pathways is a feasible prognostic biomarker and recovering the imbalance of TGF-ß1/BMP-7 pathways might be a potential therapeutic strategy for HCC.

Association of sleep duration with stroke, myocardial infarction, and tumors in a Chinese population with metabolic syndrome: a retrospective study.

BACKGROUND: Previous studies have suggested that abnormal sleep duration is associated with increased risk of metabolic syndrome (MetS). However, evidence on the association of sleep duration with stroke, myocardial infarction (MI) and tumors in populations with MetS is limited. METHODS: A total of 8968 participants (2754 with MetS at baseline) were recruited in this retrospective study between March 2012 and December 2012. The baseline characteristics and information on sleep duration were collected by self-reported questionnaires. In addition, physical examination and blood test were also performed. The outcome events in this study were new onset of stroke, MI and tumors during subsequent follow-up. Multivariate logistic regressions were adopted to investigate the relationships between sleep duration and outcome events among different sleep duration groups (< 6 h, 6-7 h, 7-8 h [reference], 8-9 h, and > 9 h per day) in participants with MetS. RESULTS: The mean self-reported total sleep duration was 7.8 ± 1.2 h. Compared with participants with MetS slept for 7-8 h per day, the adjusted odds ratios (ORs) for those slept for > 9 h in stroke, MI and tumors were 2.014 (95% confidence interval [CI]: 1.184-3.426, P = 0.010), 1.731 (95% CI: 0.896-3.344, P = 0.102) and 2.159 (95% CI: 0.991-4.704, P = 0.053), respectively, whereas the adjusted ORs for those slept for < 6 h in stroke, MI and tumors were 2.249 (95% CI: 0.973-5.195, P = 0.058), 1.213 (95% CI, 0.358-4.104, P = 0.756) and 1.743 (95% CI, 0.396-7.668, P = 0.462), respectively. CONCLUSIONS: Long sleep duration (> 9 h) significantly increased the risk of stroke but not MI and tumors in individuals with MetS compared with 7-8 h of sleep duration. Short sleep duration (< 6 h) was not associated with the increased risk of stroke, MI and tumors in individuals with MetS.

Cancer exosome-derived miR-9 and miR-181a promote the development of early-stage MDSCs via interfering with SOCS3 and PIAS3 respectively in breast cancer.

We previously identified that the development of early-stage myeloid-derived suppressor cells (eMDSCs) in breast cancer with high IL-6 (IL-6high) expression was correlated with the SOCS3 deficiency-dependent hyperactivation of the JAK/STAT signaling pathway. However, the regulatory mechanisms have not yet been elucidated. In this study, we aimed to investigate how the posttranscriptional regulation mediated by cancer exosome-derived miRNAs affected the JAK/STAT signaling pathway and the development of eMDSCs. Using miRNA microarray, we screened miR-9 and miR-181a which were exclusively upregulated in eMDSCs and inversely associated with SOCS3 expression. We found both miRNAs promoted the amplification of immature eMDSCs with the strong suppression on T-cell immunity in mice and humans. Furthermore, miR-9 and miR-181a promoted 4T1 tumor growth and immune escape via enhancing eMDSCs infiltration in situ. But miR-9 and miR-181a stimulated eMDSCs development by separately inhibiting SOCS3 and PIAS3, two crucial regulators in the negative feedback loop of the JAK/STAT signaling pathway. Elevated miR-9 and miR-181a in eMDSCs was derived from tumor-derived exosomes, and blocking the exosome release could fully attenuate the miRNA-mediated regulation on eMDSCs development. In summary, our findings indicated that tumor exosome-derived miR-9 and miR-181a activated the JAK/STAT signaling pathway via targeting SOCS3 and PIAS3, respectively, and thus promoted the expansion of eMDSCs which might provide potential therapeutic target for IL-6high breast cancer treatment.

Macrophages-induced long noncoding RNA H19 up-regulation triggers and activates the miR-193b/MAPK1 axis and promotes cell aggressiveness in hepatocellular carcinoma.

Dysregulation of long noncoding RNA (lncRNA) H19 has been implicated in hepatocellular carcinoma (HCC), but the concrete regulatory mechanism is lack of research. We mined gene expression profiles of 457 HCC samples from TCGA and TJMUCH cohorts and further validated in 64 FFPE HCC tissues. LncRNA H19 overexpression in situ was significantly correlated with poor prognosis of HCC patients, which induced EMT, promoted stemness and accelerated invasion of HCC cells in vitro. Co-expression network analysis indicated lncRNA H19 negatively correlated with miR-193b and positively correlated with MAPK1 gene, which implicated that lncRNA H19 served as a sponge molecule to hijack miR-193b and protect MAPK1. Forced overexpression of H19 attenuated miR-193b-mediated inhibition on multiple driver oncogenes (EGFR, KRAS, PTEN and IGF1R) and MAPK1 gene, thus triggered EMT and stem cell transformation in HCC. LncRNA H19 positively correlated with CD68 + TAMs in situ. TAMs-induced lncRNA H19 promotes HCC aggressiveness via triggering and activating the miR-193b/MAPK1 axis, mediates the crosstalk between HCC and immunological microenvironment, and causes poor clinical outcomes. LncRNA H19 is a valuable predictive biomarker and potential therapeutic target in HCC.

The Association between Resting Heart Rate and Urinary Albumin/Creatinine Ratio in Middle-Aged and Elderly Chinese Population: A Cross-Sectional Study.

OBJECTIVE: In general population, resting heart rate (RHR) is associated with cardiovascular disease. However, its relation to chronic kidney disease (CKD) is debated. We therefore investigated the relationship between RHR and urinary albumin/creatinine ratio (UACR, an indicator of early kidney injury) in general population at different levels of blood pressure and blood glucose. METHODS: We screened out 32,885 subjects from the REACTION study after excluding the subjects with primary kidney disease, heart disease, tumor history, related drug application, and important data loss. The whole group was divided into four groups (Q1: RHR ≤ 71, Q2: 72 ≤ RHR ≤ 78, Q3: 79 ≤ RHR ≤ 86, and Q4: 87 ≤ RHR) according to the quartile of average resting heart rate. The renal function was evaluated by UACR (divided by quartiles of all data in the center to which the subject belonged). Ordinary logistic regression was carried out to explore the association between RHR and UACR at diverse blood pressure and blood glucose levels. RESULTS: The subjects with higher RHR quartile tend to have a higher UACR, even multifactors were adjusted. After stratifying the subjects according to blood pressure and blood glucose, the positive relationship between RHR and UACR remained in the subjects with normal blood pressure and normal glucose tolerance, while in the hypertension (SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg) group and the diabetic mellitus (FPG ≥ 7.0 mmol/L and/or PPG ≥ 11.1 mmol/L) group, the relationship disappeared. In the subjects without hypertension, compared with the Q1 group, the UACR is significant higher in the Q3 group (OR: 1.11) and the Q4 group (OR: 1.22). In the subjects with normal glucose tolerance (NGT), compared with the Q1 group, the UACR is significantly higher in the Q3 group (OR: 1.13) and the Q4 group (OR: 1.19). CONCLUSIONS: The population with higher RHR tend to have a higher UACR in the normal blood pressure group and the normal glucose tolerance group.

Self-reported sleep duration and daytime napping are associated with renal hyperfiltration and microalbuminuria in an apparently healthy Chinese population.

BACKGROUND: Sleep duration affects health in various ways. The objective of the present study was to investigate the relationships among sleep duration, daytime napping and kidney function in a middle-aged apparently healthy Chinese population. METHODS: According to self-reported total sleep and daytime napping durations, 33,850 participants who were 38-90 years old and recruited from eight regional centers were divided into subgroups. Height, weight, waist circumference, hip circumference, blood pressure, biochemical indexes, fasting blood glucose (FBG), postprandial blood glucose (PBG), HbA1c, creatinine and urinary albumin-creatinine ratio (UACR) were measured and recorded for each subject. Microalbuminuria was defined as UACR ≥30 mg/g, chronic kidney disease (CKD) was defined as eGFR <60 ml/min, and hyperfiltration was defined as eGFR ≥135 ml/min. Multiple logistic regression was applied to investigate the association between sleep and kidney function. RESULTS: Compared to sleeping for 7-8 h/day, the ORs for microalbuminuria for sleeping for >9 h/day, 8-9 h/day 6-7 h/day and <6 h/day were 1.343 (1.228-1.470, P<0.001), 1.223 (1.134-1.320, P<0.001), 1.130 (1.003-1.273, P = 0.045) and 1.140 (0.908-1.431, P = 0.259), respectively. The eGFR levels exhibited a U-shaped association with sleep duration among subjects with an eGFR ≥90 ml/min and an N-shaped association with sleep duration among subjects with an eGFR <90 ml/min. The OR for hyperfiltration for >9 h/day of sleep was 1.400 (1.123-1.745, P = 0.003) among participants with an eGFR ≥90 ml/min. Daytime napping had a negative effect on renal health. Compared to the absence of a napping habit, the ORs for microalbuminuria for 0-1 h/day, 1-1.5 h/day and >1.5 h/day of daytime napping were 1.552 (1.444-1.668, P<0.001), 1.301 (1.135-1.491, P<0.001) and 1.567 (1.353-1.814, P<0.001), respectively. CONCLUSION: The association of total sleep duration with renal health outcomes is U-shaped. Daytime napping has a negative effect on renal health.

LINE-1 Retrotransposition Promotes the Development and Progression of Lung Squamous Cell Carcinoma by Disrupting the Tumor-Suppressor Gene FGGY.

Somatic long interspersed element-1 (LINE-1) retrotransposition is a genomic process that relates to gene disruption and tumor occurrence. However, the expression and function of LINE-1 retrotransposition in lung squamous cell carcinoma (LUSC) remain unclear. We analyzed the transcriptomes of LUSC samples in The Cancer Genome Atlas and observed LINE-1 retrotransposition in 90% of tumor samples. Thirteen LINE-1 retrotranspositions of high occurrence were identified and further validated from an independent Chinese LUSC cohort. Among them, LINE-1-FGGY (L1-FGGY) was identified as the most frequent LINE-1 retrotransposition in the Chinese cohort and significantly correlated with poor clinical outcome. L1-FGGY occurred with smoke-induced hypomethylation of the LINE-1 promoter and contributed to the development of local immune evasion and dysfunctional metabolism. Overexpression of L1-FGGY or knockdown of FGGY promoted cell proliferation and invasion in vitro, facilitated tumorigenesis in vivo, and dysregulated cell energy metabolism and cytokine/chemotaxin transcription. Importantly, specific reverse transcription inhibitors, nevirapine and efavirenz, dramatically countered L1-FGGY abundance, inhibited tumor growth, recovered metabolism dysfunction, and improved the local immune evasion. In conclusion, hypomethylation-induced L1-FGGY expression is a frequent genomic event that promotes the development and progression of LUSC and represents a promising predictive biomarker and therapeutic target in LUSC. SIGNIFICANCE: LINE-1-FGGY is a prognosis predictive biomarker and potential therapeutic target to overcome local immune evasion in lung squamous cell carcinoma.

Elevated triglycerides rather than other lipid parameters are associated with increased urinary albumin to creatinine ratio in the general population of China: a report from the REACTION study.

BACKGROUND: Dyslipidaemia has always been regarded as the cornerstone of arteriosclerosis and is related to the pathogenesis of renal insufficiency. However, it is unclear which routinely available lipid parameter is related to urinary albumin to creatinine ratio (UACR). The purpose of this study was to examine the lipid abnormalities associated with UACR in the general population in China. METHODS: The present study was nested in an ongoing Risk Evaluation of cAncers in Chinese diabetic Individuals: A lONgitudinal (REACTION) study, which was designed to demonstrate the association of abnormal glucose metabolism with the risk of cancer in the Chinese population. This cross-sectional study included 34, 569 subjects (11, 390 males and 23, 179 females) from 8 different regional community cohorts, with an average age of 57.9 years. The UACR data were divided into the < 25% group, the 25-49% group, the 50-74% group, and the ≥ 75% group according to the quartile division of the centre where the subjects visited. The lipid classes were defined according to the guidelines for the prevention and treatment of dyslipidaemia in Chinese adults. Multiple logistic regression analysis was used to evaluate the association of the lipid parameters and UACR. RESULTS: Multivariable regression analysis revealed that compared with the other lipid parameters, triglycerides (TG) showed an adjusted odds ratio that was significant in model 1-4. This relationship was attenuated after adjusting for Haemoglobin A1c (HbA1c) and blood pressure (BP), but TG ≥ 2.3 mmol/L was still significantly associated with UACR in total subjects and in both men and women (OR: 1.131, 95% CI 1.065-1.203, P < 0.001 in total subjects; OR: 1.134, 95% CI 1.022-1.258, P = 0.017 in men; OR: 1.129, 95% CI 1.046-1.219, P = 0.002 in women). In the stratified analysis, elevated TG was significantly associated with increased urinary albumin in subjects with eGFR ≥ 90 mL/min per 1.73 m2, 5.6 ≤ FBG < 7.0 or 7.8 ≤ PBG < 11.1 mmol/L, 24 ≤ BMI < 28 kg/m2, 120 ≤ SBP < 140 and/or 80 ≤ DBP < 90 mmHg. CONCLUSIONS: We conclude that high TG levels rather than total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or non-high-density lipoprotein cholesterol levels are associated with UACR in the general population in China.

Association between the Number of Childbirths and the Progress of Atherosclerosis among Women with Diabetes: A Cohort Study Based on Chinese Population.

BACKGROUND: The aim of this study is to explore the association between the number of childbirths and the progress of atherosclerosis among Chinese women with hypertension or diabetes. METHODS: In total, 1159 Chinese parous women from a community longitudinal survey conducted in the communities of Shijingshan district, Beijing, China, were included in our study. They were divided into three groups according to the number of childbirths, and the change in pulse wave velocity (PWV) was as an indicator of the progression of atherosclerosis because the increased PWV reflected the more serious atherosclerosis. After 3 years, we conducted follow-up visits to the subjects. Logistical regression analyses were applied to investigate the relationship between the number of childbirths and the progression of atherosclerotic stiffness and a stratification analysis was performed for history of hypertension and diabetes. RESULTS: After 3-year follow-up, among women with diabetes, the OR of women with 2 childbirths was significant [3.5 (95% confidence interval 1.5, 7.9)] in model I, [3.1 (95% confidence interval 1.3, 7.2)] in model II, and the OR of women with ≥3 childbirths was significant [4.4 (95% confidence interval 1.3, 14.5)] in model I, [4.1 (95% confidence interval 1.2, 14.3)] in model II. Among women with hypertension, the risk of the progress of atherosclerosis was not significant. CONCLUSION: The increasing number of childbirths is associated with the progression of atherosclerotic stiffness among Chinese women with diabetes, independent of a variety of confounding factors.

Opposing roles and potential antagonistic mechanism between TGF-ß and BMP pathways: Implications for cancer progression.

The transforming growth factor ß (TGF-ß) superfamily participates in tumour proliferation, apoptosis, differentiation, migration, invasion, immune evasion and extracellular matrix remodelling. Genetic deficiency in distinct components of TGF-ß and BMP-induced signalling pathways or their excessive activation has been reported to regulate the development and progression of some cancers. As more in-depth studies about this superfamily have been conducted, more evidence suggests that the TGF-ß and BMP pathways play an opposing role. The cross-talk of these 2 pathways has been widely studied in kidney disease and bone formation, and the opposing effects have also been observed in some cancers. However, the antagonistic mechanisms are still insufficiently investigated in cancer. In this review, we aim to display more evidences and possible mechanisms accounting for the antagonism between these 2 pathways, which might provide some clues for further study in cancer.

Benefit of everolimus as a monotherapy for a refractory breast cancer patient bearing multiple genetic mutations in the PI3K/AKT/mTOR signaling pathway.

A postmenopausal patient with a diagnosis of estrogen receptor (ER) (+), progesterone receptor (PR) (+), and human epidermal growth factor receptor-2 (HER2) (-) breast cancer was reported. The patient refused surgery and was resistant to conventional chemotherapy regimens. Computed tomography and the circulating tumor cell test indicated that the patient's tumor burden increased rapidly even after several chemotherapy sessions. Multiple genetic aberrances in the phosphatidylinositol3-kinases (PI3K) signaling pathway were detected via next-generation sequencing (NGS)-based liquid biopsy, including a p. G1007R missense mutation in exon 21 of PIK3CA (33.61%), a p.L70fs frameshift mutation in exon 3 of phosphatase and tension homolog deleted on chromosome ten (PTEN) (49.14%), and a p. D1542Y missense mutation in exon 32 of mammalian target of rapamycin (mTOR) (1.66%). Therefore, only the mTOR inhibitor everolimus was administered to the patient. Partial remission (PR) was observed after 2 months, and sustained stable disease (SD) was observed after a year and a half. Subsequent sequencing showed that the mutation ratio of PIK3CA decreased to 4.17%, and that the PTEN and mTOR mutations disappeared, which revealed the significant curative effect of everolimus. We report the first case of successful monotherapy treatment using everolimus in a patient with advanced breast cancer bearing mutations in genes involved in the PI3K/ARK/mTOR signaling pathway. The success of this case highlights the invaluable clinical contribution of NGS-based liquid biopsy, as it successfully provided an optimal therapeutic target for the patient with advanced breast cancer.

SOCS3 Suppression Promoted the Recruitment of CD11b+Gr-1-F4/80-MHCII- Early-Stage Myeloid-Derived Suppressor Cells and Accelerated Interleukin-6-Related Tumor Invasion via Affecting Myeloid Differentiation in Breast Cancer.

Interleukin-6 (IL-6) is an important trigger for the expansion and recruitment of myeloid-derived suppressor cells (MDSCs), which are regarded to be major coordinators of the immunosuppressive tumor microenvironment. In this study, we constructed IL-6-knockdown breast cancer mice models to explore the molecular events involved in the IL-6-mediated effects on MDSC development. We defined a subset of early-stage MDSCs (e-MDSCs) with the phenotype of CD11b+Gr-1-F4/80-MHCII- in IL-6 high-expressing 4T1 mice mammary carcinoma models, which were the precursors of CD11b+Gr-1+ conventional MDSCs. Furthermore, sustained suppression of SOCS3 and aberrant hyperactivation of the JAK/STAT signaling pathway was exclusively detected in wide-type 4T1 tumor-bearing mice, which promoted the accumulation of e-MDSCs in situ and their immunosuppressive capability in vitro. After blocking the IL-6/STAT3 signaling pathway with the IL-6 receptor antibody or STAT3 antagonist JSI-124 in tumor-bearing mice, significant shrinkage of primary tumors and decrease in lung metastatic nodules were observed in vivo, accompanied by the dramatic decrease of e-MDSC recruitment and recovery of anti-tumor T cell immunity. Thus, SOCS3 suppression accelerated the IL-6-mediated growth and metastasis of mammary carcinoma via affecting myeloid differentiation in breast cancer. Moreover, the IL-6/STAT3 signaling pathway might be a promising candidate target in developing novel therapeutic strategies to eliminate e-MDSCs and improve breast cancer prognosis.