lncRNA-encoded pep-AP attenuates the pentose phosphate pathway and sensitizes colorectal cancer cells to Oxaliplatin.

Oxaliplatin (L-OHP) is a standard treatment for colorectal cancer (CRC), but chemoresistance is a considerable challenge. L-OHP shows dose-dependent toxicity, and potential approaches that sensitize cancer cells to L-OHP could reduce the dosage. With the development of translatomics, it was found that some lncRNAs encode short peptides. Here, we use ribosome footprint profiling combined with lncRNA-Seq to screen 12 lncRNAs with coding potential, of which lnc-AP encodes the short peptide pep-AP, for their role in L-OHP resistance. Co-IP and LC-MS/MS data show that the TALDO1 protein interacts with pep-AP and that pep-AP suppresses the expression of TALDO1. The pep-AP/TALDO1 pathway attenuates the pentose phosphate pathway (PPP), reducing NADPH/NADP+ and glutathione (GSH) levels and causing ROS accumulation and apoptosis, which sensitizes CRC cells to L-OHP in vitro and in vivo. pep-AP thus might become a potential anticancer peptide for future treatments of L-OHP-resistant CRC.

Psychosocial risk factors for low back pain in US workers: Data from the 2002-2018 quality of work life survey.

BACKGROUND: Examining workplace psychosocial risk factors for back pain becomes increasingly important because of the changing nature of work and rising healthcare costs. Some psychosocial risk factors for back pain, such as work and family imbalance, exposure to a hostile work environment, and job insecurity, are understudied for the working population in the United States. METHODS: Data used in this study came from the Quality of Work Life Survey (QWL), a supplementary module of the General Social Survey conducted in the United States. Data from the 2002, 2006, 2010, 2014, and 2018 QWL surveys were used in these analyses, giving a total sample size of 6661. Five domains of workplace psychosocial risk factors for back pain were examined, including job strain, low social support, work-family imbalance, exposure to a hostile work environment (harassment and discrimination), and job insecurity. The adjusted odds ratio (aOR) of each psychosocial risk factor for back pain with 95% confidence intervals (CI) was estimated using a multivariable logistic regression model after controlling for job physical factors, occupation, and demographic and socioeconomic characteristics. RESULTS: Significant associations were found between back pain and several psychosocial factors including job strain (aOR 1.19; CI 1.00,1.41), work-family imbalance (aOR,1.42; CI 1.22,1.64), harassment (aOR 1.40; CI 1.15,1.71), and discrimination (aOR 1.20 CI 1.00,1.44). CONCLUSION: This study contributes to the understanding of the relationship between a variety of workplace psychosocial factors and back pain. Our findings suggest directions in future longitudinal research to examine emerging workplace psychosocial factors for back pain.

Correlation between vaginal microbiota and different progression stages of cervical cancer.

The process from high-risk human papillomavirus (HR-HPV) infection to cervical cancer is a continuous and long-term process, but the pathogenesis of the whole process is not completely clear. Here, 59 Chinese women were engaged in this study, and divided into five groups: normal healthy group, HR-HPV infections group, low-grade intraepithelial neoplasia (LSIL) group, high-SIL(HSIL) group, and cervical cancer group. With the occurrence of HR-HPV infection and the development of cervical lesions, the diversity of vaginal microbiota species was increased, and the relative abundance of Lactobacillus (L.), the dominant bacteria in maintaining vaginal microecological balance, was decreased gradually. In contrast, the abundance of Actinobacteria in the four disease groups was significantly higher than that in normal group. Furthermore L. iners may be related to the serious progression of cervical cancer. After analyzing the whole process, we found that Gardnerella(G.), Atopobium(A.) and Dialister(D.) have important effects on both persistent HR-HPV infection and the pathogenesis of cervical cancer. In addition, PICRUSt2 and KEGG results showed that the KEGG pathways enriched by the predicted genes of vaginal microbiota in cancer group included metabolic diseases, endocrine system and immune systems when compared with that in normal group. These findings may provide insights into the pathogenesis of cervical cancer, and help to improve the early detection and prevention of cervical precancerous lesions.

Gastric cancer derived exosomes mediate the delivery of circRNA to promote angiogenesis by targeting miR-29a/VEGF axis in endothelial cells.

Accumulating evidence has been found that circular RNA (circRNA) plays a critical role in the initiation and development of various diseases by modulating gene expression in the cytoplasm. However, the role of circ_0044366 (termed circ29) in gastric cancer (GC) has yet to be elusive. We detected that exosomal circ29 was confirmed to be highly expressed in GC and can significantly impair the proliferation, migration, tube formation of HUVEC by exosomal communication. Interestingly, this effect could be blocked by the effect of miR-29a. In brief, we confirmed that circ29, as a sponge of miR-29a, plays a responsible role in the occurrence and development of GC by regulating the VEGF pathway. Therefore, it may be used as a potential target for the treatment of GC.

CAF secreted miR-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancer.

BACKGROUND: Ferroptosis is a novel mode of non-apoptotic cell death induced by build-up of toxic lipid peroxides (lipid-ROS) in an iron dependent manner. Cancer-associated fibroblasts (CAFs) support tumor progression and drug resistance by secreting various bioactive substances, including exosomes. Yet, the role of CAFs in regulating lipid metabolism as well as ferroptosis of cancer cells is still unexplored and remains enigmatic. METHODS: Ferroptosis-related genes in gastric cancer (GC) were screened by using mass spectrum; exosomes were isolated by ultra-centrifugation and CAF secreted miRNAs were determined by RT-qPCR. Erastin was used to induce ferroptosis, and ferroptosis levels were evaluated by measuring lipid-ROS, cell viability and mitochondrial membrane potential. RESULTS: Here, we provide clinical evidence to show that arachidonate lipoxygenase 15 (ALOX15) is closely related with lipid-ROS production in gastric cancer, and that exosome-miR-522 serves as a potential inhibitor of ALOX15. By using primary stromal cells and cancer cells, we prove that exosome-miR-522 is mainly derived from CAFs in tumor microenvironment. Moreover, heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) was found to mediate miR-522 packing into exosomes, and ubiquitin-specific protease 7 (USP7) stabilizes hnRNPA1 through de-ubiquitination. Importantly, cisplatin and paclitaxel promote miR-522 secretion from CAFs by activating USP7/hnRNPA1 axis, leading to ALOX15 suppression and decreased lipid-ROS accumulation in cancer cells, and ultimately result in decreased chemo-sensitivity. CONCLUSIONS: The present study demonstrates that CAFs secrete exosomal miR-522 to inhibit ferroptosis in cancer cells by targeting ALOX15 and blocking lipid-ROS accumulation. The intercellular pathway, comprising USP7, hnRNPA1, exo-miR-522 and ALOX15, reveals new mechanism of acquired chemo-resistance in GC.

Clinical application of exosomes and circulating microRNAs in the diagnosis of pregnancy complications and foetal abnormalities.

During pregnancy in humans, the physiology of the mother and foetus are finely regulated by many factors. Inappropriate regulation can result in pregnancy disorders, such as complications and foetal abnormalities. The early prediction or accurate diagnosis of related diseases is a concern of researchers. Liquid biopsy can be analysed for circulating cells, cell-free nucleic acids, and exosomes. Because exosomes can be detected in the peripheral blood of women in early pregnancy, these vesicles and their contents have become the focus of early prediction or diagnostic biomarker research on pregnancy complications and foetal developmental disorders. In this review, we focus on recent studies addressing the roles of peripheral blood exosomes and circulating miRNAs in pregnancy complications and in pregnancies with abnormal foetal developmental disorders, with particular attention paid to the potential application value of exosomes and circulating miRNAs as disease-specific biomarkers.

Exosomal circRNA derived from gastric tumor promotes white adipose browning by targeting the miR-133/PRDM16 pathway.

Cancer-related cachexia is a metabolic syndrome characterized by a wasting disorder of adipose and skeletal muscle and is accompanied by body weight loss and systemic inflammation. The treatment options for cancer cachexia are limited, and the molecular mechanism remains poorly understood. Circular RNAs (circRNAs) are a novel family of endogenous noncoding RNAs that have been proposed to regulate gene expression in mammals. Exosomes are small vesicles derived from cells, and recent studies have shown that circRNAs are stable in exosomes. However, little is known about the biological role of circRNAs in exosomes. In our study, we showed that circRNAs in plasma exosomes have specific expression features in gastric cancer (GC), and ciRS-133 is linked with the browning of white adipose tissue (WAT) in GC patients. Exosomes derived from GC cells deliver ciRS-133 into preadipocytes, promoting the differentiation of preadipocytes into brown-like cells by activating PRDM16 and suppressing miR-133. Moreover, knockdown of ciRS-133 reduced cancer cachexia in tumor-implanted mice, decreasing oxygen consumption and heat production. Thus, exosome-delivered circRNAs are involved in WAT browning and play a key role in cancer-associated cachexia.

MiR-181a, a new regulator of TGF-ß signaling, can promote cell migration and proliferation in gastric cancer.

Transforming growth factor-beta (TGF-ß) signaling pathway plays pivotal roles in various types of cancer. TGF-ß receptor 2 (TGFßR2) contains a kinase domain that phosphorylates and activates the downstream of the TGF-ß signaling pathway. Our previous microarray analysis revealed marked changes in miR-181a expression in gastric cancers, and the bioinformatics analysis suggested that miR-181a negatively regulated TGFßR2. In order to verify the effect of miR-181a on TGFßR2 and clarify the influence of miR-181a on the migration and proliferation of gastric cancer, studies in gastric cancer cell lines and xenograft mouse models were carried out. We found that a reduced expression of TGFßR2 and an increased expression miR-181a in gastric cancer tissues compared to adjacent noncancerous tissues. A luciferase reporter assay confirmed that TGFßR2 was a target of miR-181a. In addition, we found that miR-181a mimics, which increased the level of miR-181a, downregulated the expression of TGFßR2 in the gastric cancer cell line SGC-7901. Moreover, both the overexpression of miR-181a and the downregulation of TGFßR2 promoted the migration and proliferation of SGC-7901 cells. Conversely, SGC-7901 cell migration and proliferation were inhibited by the downregulation of miR-181a and the overexpression of TGFßR2. Furthermore, the increased expression of miR-181a and the decreased expression of TGFßR2 also enhanced the tumor growth in mice bearing gastric cancer. Our results herein indicated that miR-181a promoted the migration and proliferation of gastric cancer cells by downregulating TGFßR2 at the posttranscriptional level. The present study suggests that miR-181a is a novel negative regulator of TGFßR2 in the TGF-ß signaling pathway and thus represents a potential new therapeutic target for gastric cancer.

Intracellular osteopontin negatively regulates toll-like receptor 4-mediated inflammatory response via regulating GSK3ß and 4EBP1 phosphorylation.

Toll-like receptors (TLRs) play an important role in host defense against invading pathogens. By initiating a signal transduction cascade, TLRs lead to the release of pro-inflammatory cytokines. However, the inappropriate activation of TLR signaling could result in inflammatory disorders or autoimmune diseases. Osteopontin (OPN) has been reported to be an inflammatory cytokine participating in cell-mediated immunity. However, the role of OPN in TLR-mediated immune responses is poorly understood. In the present study, OPN-deficient (OPN-/-) macrophages exhibited significantly higher levels of pro-inflammatory cytokines after stimulation with lipopolysaccharide (LPS). Our study also demonstrated that the intracellular OPN (iOPN) isoform acted as a negative regulator to inhibit LPS-induced inflammatory responses. Compared to WT macrophages, OPN-/- macrophages had lower Akt phosphorylation levels and higher GSK3ß phosphorylation levels, which were downregulated by p-Akt. Moreover, as a down-stream target of Akt, 4EBP1 was hypo-phosphorylated in OPN-/- macrophages compared to 4EBP1 in WT macrophages. These findings reveal that iOPN can regulate GSK3ß and 4EBP1 phosphorylation to inhibit TLR4-mediated inflammatory responses.

Iodine Promotes Tumorigenesis of Thyroid Cancer by Suppressing Mir-422a and Up-Regulating MAPK1.

BACKGROUND/AIMS: Iodine may trigger tumorigenesis and development of thyroid carcinoma, but the mechanisms involved remained elusive. MicroRNA (MiRNAs) are known to be involved in each stage of cancer development; however, the role of miRNAs in iodine-induced tumorigenesis of thyroid carcinoma remained unknown. In this study, we aimed at investigating miRNA related signaling pathway in thyroid cancer cells. METHODS: Levels of miRNAs and mRNAs were determined using RT-qPCR and proteins were quantified by western blotting. Cell migration and proliferation were checked using Transwell assay and CCK8 assay respectively. Tumor xenografts in nude mice were established by subcutaneous injection of cancer cells. RESULTS: Mitogen activated protein kinase 1 (MAPK1) was significantly up-regulated, while miR-422a was down-regulated in thyroid cancer cells cultured with high iodine; miR-422a directly bound to the 3'UTR of MAPK1 mRNA. Moreover, miR-422a negatively regulated MAPK1 expression, and down-regulated miR-422a promoted proliferation and migration of TPC-1 cells. In vivo studies also confirmed that iodine promoted tumor growth by suppressing miR-422a and up-regulating MAPK1. CONCLUSIONS: Our study illustrates a new pathway comprising iodine, miRNA and MAPK1, and defines a novel mechanism in thyroid cancer.

miR-26a/b Inhibit Tumor Growth and Angiogenesis by Targeting the HGF-VEGF Axis in Gastric Carcinoma.

BACKGROUND/AIMS: Abnormal expression of HGF is found in various cancers and correlates with tumor proliferation, metastasis and angiogenesis. However, the regulatory mechanism of the HGF-VEGF axis remains unclear. METHODS: The expression characteristic of HGF in human gastric cancer tissues was shown by an immunohistochemistry assay, and the expression levels of target protein were detected by Western blot. The relative levels of miR-26a/b and target mRNA were examined by qRT-PCR. We used bioinformatics tools to search for miRNAs that can potentially target HGF. A luciferase assay was used to confirm direct targeting. Furthermore, the functions of miR-26a/b and HGF were evaluated by cell proliferation and migration assays in vitro and by the mouse xenograft tumor model in vivo. RESULTS: We found that the HGF protein was clearly increased while miR-26a/b were dramatically down-regulated in gastric cancer. miR-26a/b directly bind to the 3'-UTR of HGF mRNA at specific targeting sites. We demonstrated that the repression of the HGF-VEGF pathway by miR-26a/b overexpression suppressed gastric cancer cell proliferation and migration. Furthermore, miR-26a/b also showed an anti-tumor effect in the xenograft mouse model by suppressing tumor growth and angiogenesis. CONCLUSIONS: miR-26a/b could suppress tumor tumorigenesis and angiogenesis by targeting the HGF-VEGF axis and could serve as a potential treatment modality for targeted therapy in the clinical treatment of gastric cancer.

The role of miR-485-5p/NUDT1 axis in gastric cancer.

BACKGROUND: Cancers can survive the oxidative conditions by upregulating nucleoside diphosphate linked moiety X-type motif 1 (NUDT1). However, the mechanisms underlying gastric carcinogenesis and the dys-regulation of NUDT1 in gastric cancer (GC) remain unknown. Our study aimed to explore the role of NUDT1 and its regulatory pathway by miR-485-5p in GC. METHODS: Gastric cancer tissues and paired noncancerous tissue samples were collected, and the expression level of NUDT1 and miR-485-5p were detected. Two cohorts from The Cancer Genome Atlas (TCGA) database and another cohort from the Tianjin Medical University Cancer Institute and Hospital were further analyzed. Luciferase assays were performed, and the effects of the miR-485-5p/NUDT1 axis on GC cells and normal gastric cells were determined by subsequent experiments. RESULTS: We found that the expression of miR-485-5p was clearly repressed in GC tissues, while NUDT1 expression level was dramatically increased. The overexpression of NUDT1 correlated closely with an increase in invasive depth and a decrease in survival in GC patients. MiR-485-5p could directly bind to the 3'UTR of NUDT1 mRNA and induce its degradation, thus down-regulate its expression. The miR-485-5p/NUDT1 axis could lead to the changes of 8-oxo-dG in GC cells. And the increased expression of NUDT1 resulting from the downregulation of miR-485-5p could accelerate cell proliferation and metastasis in GC. However, the growth and migration of normal gastric cells did not depend on the protection of NUDT1, while the overexpression of NUDT1 could promote malignant transition in normal gastric cells. CONCLUSIONS: MiR-485-5p acts as a tumor suppressor by targeting NUDT1 in GC. The miR-485-5p/NUDT1 axis is involved in the processes of cell growth and cell motility and plays a key role in the tumorigenesis of GC.

Three novel missense mutations in the filamin B gene are associated with isolated congenital talipes equinovarus.

Congenital talipes equinovarus (CTEV) is one of the most common musculoskeletal disorders. Genetic factors have been suggested to be an important contributor to its pathogenesis. Some genes, including PITX1, TBX4, and RBM10, have been associated with CTEV. We aimed to determine the disease-causing mutations in Chinese patients with isolated CTEV. Genomic DNA was extracted from peripheral blood samples of a three-generation pedigree and 53 sporadic patients with CTEV. Whole-exome sequencing and Sanger sequencing were used to identify and validate disease-causing mutations, respectively. A putative pathogenic mutation c.4717G>T (p.D1573Y) in the filamin B (FLNB) gene, which co-segregated with CETV, was identified in the pedigree. Two additional novel missense mutations in the same gene [c.1897A>G (p.M633V) and c.2195A>G (p.Y732C)] were identified from the 53 sporadic patients. Plasmids expressing wild-type or mutant constructs were transfected into HEK293T cells to determine whether these amino acid substitutions affect protein activity. All three (M633V, Y732C, and D1573Y) affected FLNB protein expression and led to cytoplasmic focal accumulation. Our results provide evidence for the involvement of FLNB in the pathogenesis of isolated CTEV and have expanded the clinical spectrum of FLNB mutations.

MiR-520b/e Regulates Proliferation and Migration by Simultaneously Targeting EGFR in Gastric Cancer.

BACKGROUND: MicroRNAs (miRNAs) have been demonstrated to play a crucial role in tumorigenesis. Previous studies have shown that miR-520b/e acts as a tumor suppressor in several tumors. Other studies indicated that epidermal growth factor receptor (EGFR) is highly expressed in many tumors, and involved in the development of tumors, such as cell proliferation, migration, angiogenesis and apoptosis. However, the correlation of miRNAs and EGFR in gastric cancer (GC) has not been adequately investigated. Our aim was to explore the relationship. METHODS: The expression levels of EGFR and miR-520b/e were examined by RT-PCR and Western blot. We also investigated the relationship between EGFR and miR-520b/e in GC cell lines by relevant experiments. RESULTS: In this study, we found that miR-520b/e inhibits the protein expression of EGFR by directly binding with the 3'-untranslated region (3'-UTR). And it was shown that the down-regulation of miR-520b/e promotes cell proliferation and migration by negative regulation of the EGFR pathway, while over-expression of miR-520b/e inhibits these properties. In addition, the biological function of EGFR in GC cell lines was validated by silencing and over-expression assays respectively. CONCLUSIONS: Taken together, our results demonstrate that miR-520b/e acts as a tumor suppressor by regulating EGFR in GC, and provide a novel marker and insight for the potential therapeutic target of GC.

A novel missense mutation of TNNI2 in a Chinese family cause distal arthrogryposis type 1.

The distal arthrogryposis (DA) syndromes are a group of disorders characterized by congenital contractures of limbs. According to phenotypical characteristics, DA syndromes have been clinically classified into 10 types. Currently, at least nine disease causing genes have been identified for different types of DA. Here, we report a 3-generation Chinese pedigree with three DA affected members. We performed whole exome sequencing on two affected and one unaffected individuals of this family and successfully identified a novel missense mutation in TNNI2 as the pathogenic mutation. The TNNI2 gene encodes a subunit of the troponin complex, a contractile machinery of the muscle. The mutation p.F178C that could change the H-bond formation of a neighboring residue occurs at a highly conserved position, suggesting that this variation probably affects the TNNI2 protein function. Our study also demonstrates the power of whole exome sequencing in causal mutation identification for phenotypically variable and genetically heterogeneous disorders.

Workplace psychosocial and organizational factors for neck pain in workers in the United States.

BACKGROUND: Neck pain is a prevalent musculoskeletal condition among workers in the United States. This study explores a set of workplace psychosocial and organization-related factors for neck pain. METHODS: Data used for this study come from the 2010 National Health Interview Survey which provides a representative sample of the US population. To account for the complex sampling design, the Taylor linearized variance estimation method was used. Logistic regression models were constructed to measure the associations. RESULTS: This study demonstrated significant associations between neck pain and a set of workplace risk factors, including work-family imbalance, exposure to a hostile work environment and job insecurity, non-standard work arrangements, multiple jobs, and long work hours. CONCLUSION: Workers with neck pain may benefit from intervention programs that address issues related to these workplace risk factors. Future studies exploring both psychosocial risk factors and physical risk factors with a longitudinal design will be important. Am. J. Ind. Med. 59:549-560, 2016. © 2016 Wiley Periodicals, Inc.

Low Back Pain Prevalence and Related Workplace Psychosocial Risk Factors: A Study Using Data From the 2010 National Health Interview Survey.

OBJECTIVES: The objectives of this study were to estimate prevalence of low back pain, to investigate associations between low back pain and a set of emerging workplace risk factors, and to identify worker groups with an increased vulnerability for low back pain in the United States. METHODS: The data used for this cross-sectional study came from the 2010 National Health Interview Survey, which was designed to collect data on health conditions and related risk factors from the US civilian population. The variance estimation method was used to compute weighted data for prevalence of low back pain. Multivariable logistic regression analyses stratified by sex and age were performed to determine the odds ratios (ORs) and the 95% confidence interval (CI) for low back pain. The examined work-related psychosocial risk factors included work-family imbalance, exposure to a hostile work environment, and job insecurity. Work hours, occupation, and other work organizational factors (nonstandard work arrangements and alternative shifts) were also examined. RESULTS: The prevalence of self-reported low back pain in the previous 3 months among workers in the United States was 25.7% in 2010. Female or older workers were at increased risk of experiencing low back pain. We found significant associations between low back pain and a set of psychosocial factors, including work-family imbalance (OR 1.27, CI 1.15-1.41), exposure to hostile work (OR 1.39, CI 1.25-1.55), and job insecurity (OR 1.44, CI 1.24-1.67), while controlling for demographic characteristics and other health-related factors. Older workers who had nonstandard work arrangements were more likely to report low back pain. Women who worked 41 to 45 hours per week and younger workers who worked >60 hours per week had an increased risk for low back pain. Workers from several occupation groups, including male health care practitioners, female and younger health care support workers, and female farming, fishing, and forestry workers, had an increased risk of low back pain. CONCLUSIONS: This study linked low back pain to work-family imbalance, exposure to a hostile work environment, job insecurity, long work hours, and certain occupation groups. These factors should be considered by employers, policymakers, and health care practitioners who are concerned about the impact of low back pain in workers.

[Application of X-Ray Fluorescence Spectrometry in Xujiahe Formation of Sichuan Basin for the Study of Sedimentary Facies].

Currently, X-ray fluorescence spectrometer (XRF) is not widely used in the determination of geological samples, and it's much less used in the study of sedimentary facies. XRF was firstly used to identify sedimentary environment of the T3x2 formation in central Sichuan region. In order to investigate the controversy of sedimentary facies and sedimentary environment of T3x2 formation of the Upper Triassic in the Central Part of Sichuan Basin, particularly whether the T3x2 formation is continental deposit or marine deposit, samples were collected in four representative zones from Xujiahe formation in Sichuan Basin. The method of X-ray fluorescence spectrometry were used to analyze the element contents and its' changing characteristics of the deposition from target formation. The sedimentary facies and sedimentary environment of target formation could be quantificationally analyzed by the symbol of corresponding element content. The results of the study show that the ratio of Sr/Ba, Mn/Fe and Sr/Ca of T3x2 formation belong to continental deposits, and it has no significant difference with characteristics of element contents from T3x3 or T3x4. The analysis results about the ratio of Sr/Cu show that the climatic environment of target formation was warm and humid, and T3x2 formation was belong to continental deposits in warm and humid environment, which is similar to the sedimentary environment of T3x3 or T3x4 formation. The relative errors between this method and conventional chemical analysis are less than 3%. The method of X ray fluorescence spectrometry is simple and feasible, which provides a quantitative analysis method for identification of sedimentary facies and sedimentary environment. The paper provides a new feasible method to solve the controversial sedimentary facies, which will promote the using of X-ray fluorescence spectrometric analysis method in geology.