Transcriptomic and Metabolomic Profiling of Root Tissue in Drought-Tolerant and Drought-Susceptible Wheat Genotypes in Response to Water Stress.

Wheat is the most widely grown crop in the world; its production is severely disrupted by increasing water deficit. Plant roots play a crucial role in the uptake of water and perception and transduction of water deficit signals. In the past decade, the mechanisms of drought tolerance have been frequently reported; however, the transcriptome and metabolome regulatory network of root responses to water stress has not been fully understood in wheat. In this study, the global transcriptomic and metabolomics profiles were employed to investigate the mechanisms of roots responding to water stresses using the drought-tolerant (DT) and drought-susceptible (DS) wheat genotypes. The results showed that compared with the control group, wheat roots exposed to polyethylene glycol (PEG) had 25941 differentially expressed genes (DEGs) and more upregulated genes were found in DT (8610) than DS (7141). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the DEGs of the drought-tolerant genotype were preferably enriched in the flavonoid biosynthetic process, anthocyanin biosynthesis and suberin biosynthesis. The integrated analysis of the transcriptome and metabolome showed that in DT, the KEGG pathways, including flavonoid biosynthesis and arginine and proline metabolism, were shared by differentially accumulated metabolites (DAMs) and DEGs at 6 h after treatment (HAT) and pathways including alanine, aspartate, glutamate metabolism and carbon metabolism were shared at 48 HAT, while in DS, the KEGG pathways shared by DAMs and DEGs only included arginine and proline metabolism at 6 HAT and the biosynthesis of amino acids at 48 HAT. Our results suggest that the drought-tolerant genotype may relieve the drought stress by producing more ROS scavengers, osmoprotectants, energy and larger roots. Interestingly, hormone signaling plays an important role in promoting the development of larger roots and a higher capability to absorb and transport water in drought-tolerant genotypes.

Vitamin D deficiency and the risk of diabetic retinopathy in patients with type 2 diabetes in Tibet: a cross-sectional analysis.

BACKGROUND: Diabetic retinopathy (DR) is one of the most common complications of diabetes worldwide. The aim of this study was to assess the prevalence of DR in hospitalized patients with type 2 diabetes (T2DM) in Tibet and to identify risk factors that may influence the occurrence of DR. METHODS: This was a cross-sectional study conducted in a third-class hospital in the Tibet Autonomous Region. The prevalence of DR in hospitalized patients with T2DM was measured. Univariate and multivariate logistic regression, restricted cubic spline (RCS) analysis and receiver-operating characteristic curve analysis were used to investigate the risk factors for DR. RESULTS: The prevalence of DR was 29.3%. The duration of diabetes; concentrations of 25-OH-VitD3, hemoglobin, fasting insulin, alanine aminotransferase, total bilirubin, and creatinine; and HOMA-IR were significantly different between DR patients and non-DR patients (all P < 0.05). Univariate and multivariate logistic regression revealed that a longer duration of diabetes and lower 25-OH-VitD3 levels were associated with increased DR risk. RCS analysis suggested overall positive associations of the duration of diabetes and 25-OH-VitD3 concentrations with DR risk (P nonlinearity < 0.05). The turning points for the duration of diabetes and 25-OH-VitD3 concentrations were 5.1 years and 10.6 ng/mL, respectively. The sensitivity, specificity, and area under the receiver-operating characteristic curve for the combination of the duration of diabetes and 25-OH-VitD3 levels were 79.4%, 69.4% and 0.764, respectively. CONCLUSIONS: Given the high prevalence of DR in hospitalized patients with T2DM in Tibet, vitamin D supplementation seems to be important in the prevention of DR to some degree.

Pedogenesis of typical zonal soil drives belowground bacterial communities of arable land in the Northeast China Plain.

Belowground bacterial communities play essential roles in maintaining ecosystem multifunction, while our understanding of how and why their distribution patterns and community compositions may change with the distinct pedogenetic conditions of different soil types is still limited. Here, we evaluated the roles of soil physiochemical properties and biotic interactions in driving belowground bacterial community composition across three typical zonal soil types, including black calcium soil (QS), typical black soil (HL) and dark brown soil (BQL), with distinct pedogenesis on the Northeast China Plain. Changes in soil bacterial diversity and community composition in these three zonal soil types were strongly correlated with soil pedogenetic features. SOC concentrations in HL were higher than in QS and BQL, but bacterial diversity was low, and the network structure revealed greater stability and connectivity. The composition of the bacterial community correlated significantly with soil pH in QS but with soil texture in BQL. The bacterial co-occurrence network of HL had higher density and clustering coefficients but lower edges, and different keystone species of networks were also detected. This work provides a basic understanding of the driving mechanisms responsible for belowground bacterial biodiversity and distribution patterns over different pedogenetic conditions in agroecosystems.

A retrospective analysis of 25 cases of Addison's disease caused by adrenal tuberculosis in Tibet and review of related literature.

Background: To investigate the clinical characteristics of Addison's disease caused by adrenal tuberculosis in Tibet. After the anti-tuberculosis treatment, the clinical features between continuous glucocorticoid therapy and glucocorticoid withdrawal were analyzed. Methods: Clinical data of patients with Addison's disease caused by adrenal tuberculosis diagnosed in The People's Hospital of Tibet Autonomous Region from January 2015 to October 2021 were collected and analyzed. All patients were taking anti-tuberculosis and glucocorticoids replacement therapy, and the root cause of the disease was analyzed following prognosis observations. Results: There were 25 patients (24 Tibetan and 1 Han patient) with Addison's disease caused by adrenal tuberculosis, including 18 males and 7 females. A total of 21 cases were followed up successfully, of which 13 cases discontinued anti-tuberculosis drugs successfully, 6 cases discontinued glucocorticoid therapy among the rest, 6 cases continued anti-tuberculosis + glucocorticoid replacement therapy, and 2 cases died. Conclusion: Early diagnosis and proper anti-tuberculosis treatment can improve the prognosis of patients with adrenal tuberculosis. Moreover, screening and educating Tibetan people regarding the potential risk and adversities of adrenal tuberculosis is crucial for eradicating the disease.

Efficacy and safety of PARP inhibitors in the treatment of BRCA-mutated breast cancer: an updated systematic review and meta-analysis of randomized controlled trials.

INTRODUCTION: Poly-ADP-ribose polymerase inhibitors (PARPis) have emerged as a new class of therapeutic agents for breast cancer patients with breast cancer susceptibility gene (BRCA) mutations. However, the efficacy and toxicity of PARPis have not been clearly established. METHODS: This study comprehensively evaluated the efficacy and safety of PARPis in patients with BRCA-mutated breast cancer. Online databases were systematically searched, and six clinical trials were included. The primary endpoint of efficacy was progression-free survival (PFS), whereas the secondary endpoints were overall survival (OS) and objective response rate (ORR). Additionally, we assessed the safety of PARPis. RESULTS: The results of the meta-analysis showed that PARPis can effectively improve the PFS and OS in patients compared with the control group. The pooled HR (PARPi vs control groups) was 0.63 (95% CI, 0.55 - 0.73) and 0.83 (95% CI, 0.73 to -0.95) for PFS and OS, respectively. In safety, PARPis demonstrated controllable adverse reactions. There were no significant differences in overall AEs or grade ≥3 AEs between the PARP inhibitor and control arms. CONCLUSIONS: Our results confirm the efficacy and safety of PARPis in patients with BRCA-mutated breast cancer, and more specifically clarify the efficacy of PARPis alone or in combination with other chemotherapy drugs. [Figure: see text].

Corrigendum: SNORA72 activates the Notch1/c-Myc pathway to promote stemness transformation of ovarian cancer cells.

[This corrects the article DOI: 10.3389/fcell.2020.583087.].

A novel HIF-2α targeted inhibitor suppresses hypoxia-induced breast cancer stemness via SOD2-mtROS-PDI/GPR78-UPRER axis.

Hypoxic tumor microenvironment (TME) plays critical roles in induction of cancer stem cell-like phenotype in breast cancer and contribute to chemoresistance. However, the mechanism underlying stemness reprogramming of breast cancer cells (BCs) by hypoxic TME remains largely unknown. In the present study, we illustrated that HIF-2α, but not HIF-1α, induces stemness in BCs under hypoxia through SOD2-mtROS-PDI/GRP78-UPRER pathway, linking mitochondrial metabolic state to endoplasmic reticulum (ER) response via mitochondrial reactive oxygen species (mtROS) level. HIF-2α activates endoplasmic reticulum unfolded protein response (UPRER) in drug-sensitive MCF7 and T47D cells to induce drug-resistant stem-like phenotype. Genetic depletion or pharmacological inhibition (YQ-0629) of HIF-2α abolished hypoxia-induced stem-like phenotype in vitro and in vivo. Mechanistically, HIF-2α activates transcription of superoxide dismutase 2 (SOD2) under hypoxia and thereby decreases mtROS level. With less mtROS transported to endoplasmic reticulum, the expression and activity of protein disulfide isomerase (PDI) is suppressed, allowing glucose-regulated protein 78 (GRP78) to dissociate from receptor proteins of UPRER and bind misfolded protein to activate UPRER, which eventually confer chemoresistance and stem-like properties to BCs. Moreover, the increase in mtROS and PDI levels caused by HIF-2α knockdown and the subsequent UPRER inhibition could be substantially rescued by mitoTEMPOL (a mtROS scavenger), 16F16 (a PDI inhibitor), or GRP78 overexpression. Overall, we reported the critical roles of HIF-2α-SOD2-mtROS-PDI/GRP78-UPRER axis in mediating hypoxia-induced stemness in BCs, highlighting the interaction between organelles and providing evidence for further development of targeted HIF-2α inhibitor as a promising therapeutic strategy for chemoresistant breast cancer.

Immune-Related Long Non-coding RNA Constructs a Prognostic Signature of Ovarian Cancer.

BACKGROUND: Since ovarian cancer leads to the poor prognosis in women all over the world, we aim to construct an immune-related lncRNAs signature to improve the survival of ovarian cancer patients. METHODS: Normal and cancer patient samples and corresponding clinical data of ovarian were obtained from The Genotype-Tissue Expression (GTEx) portal and The Cancer Genome Atlas (TCGA) database. The predictive signature was constructed by the lasso penalty Cox proportional hazard regression model. The division of different risk groups was accounting for the optimal critical value of the time-dependent Receiver Operating Characteristic (ROC) curve. Finally, we validated and evaluated the application of this prognostic signature based on the clinical factors, chemo-sensitivity and immune status of different risk groups. RESULTS: The signature was established from 145 DEirlncRNAs and can be shown as an independent prognostic risk factor with accurate prediction on overall survival in ovarian cancer patients. Further analysis on the application of the prognostic signature showed that patients with low-risk had a better sensitivity to chemotherapy and a higher immunogenicity. CONCLUSION: We constructed and verified an effective signature based on DEirlncRNA pairs, which could predict the prognosis, drug sensitivity and immune status of ovarian cancer patients and promote the prognostic estimation and individualized treatment.

lncRNA-Xist/miR-101-3p/KLF6/C/EBPα axis promotes TAM polarization to regulate cancer cell proliferation and migration.

The phenotypic switch in tumor-associated macrophages (TAMs) mediates immunity escape of cancer. However, the underlying mechanisms in the TAM phenotypic switch have not been systematically elucidated. In this study, long noncoding RNA (lncRNA)-Xist, CCAAT/enhancer-binding protein (C/EBP)α, and Kruppel-like factor 6 (KLF6) were upregulated, whereas microRNA (miR)-101 was downregulated in M1 macrophages-type (M1). Knockdown of Xist or overexpression of miR-101 in M1 could induce M1-to-M2 macrophage-type (M2) conversion to promote cell proliferation and migration of breast and ovarian cancer by inhibiting C/EBPα and KLF6 expression. Furthermore, miR-101 could combine with both Xist and C/EBPα and KLF6 through the same microRNA response element (MRE) predicted by bioinformatics and verified by luciferase reporter assays. Moreover, we found that miR-101 knockdown restored the decreased M1 marker and the increased M2 marker expression and also reversed the promotion of proliferation and migration of human breast cancer cells (MCF-7) and human ovarian cancer (OV) cells caused by silencing Xist. Generally, the present study indicates that Xist could mediate macrophage polarization to affect cell proliferation and migration of breast and ovarian cancer by competing with miR-101 to regulate C/EBPα and KLF6 expression. The promotion of Xist expression in M1 macrophages and inhibition of miR-101 expression in M2 macrophages might play an important role in inhibiting breast and ovarian tumor proliferation and migration abilities.

SNORA72 Activates the Notch1/c-Myc Pathway to Promote Stemness Transformation of Ovarian Cancer Cells.

Cancer stem cells (CSCs) are responsible for the migration and recurrence of cancer progression. Small nucleolar RNAs (snoRNAs) play important roles in tumor development. However, how snoRNAs contribute to the regulation of the stemness of ovarian CSCs (OCSCs) remains unclear. In the present study, we found that SNORA72 was significantly upregulated in OVCAR-3 spheroids (OS) and CAOV-3 spheroids (CS) with the OCSC characteristics attained by serum-free culture in a suspension of OVCAR-3 (OV) and CAOV-3 (CA) cells. The overexpression of SNORA72 increased self-renewal abilities and migration abilities in OV and CA cells and upregulated the expressions of the stemness markers Nanog, Oct4, and CD133. In addition, the ectopic expression of SNORA72 can elevate the messenger RNA (mRNA) and protein expression levels of Notch1 and c-Myc in parental cells. The opposite results were observed in SNORA72-silenced OCSCs. Moreover, we found that Notch1 knockdown inversed the migration abilities and self-renewal abilities raised by overexpressing SNORA72. In summary, stemness transformation of ovarian cancer cells can be activated by SNORA72 through the Notch1/c-Myc pathway. This study introduces a novel therapeutic strategy for improving the treatment efficiency of ovarian cancer.

Hypoxia-mediated cancer stem cell resistance and targeted therapy.

Drug resistance is a major obstacle in the treatment of tumors, which easily lead to relapse or poor prognosis. Cancer stem cells (CSCs) are regarded as one of the important targets that mediate tumor resistance. Increasing evidence shows that the tumor hypoxia microenvironment is closely related to the resistance of CSCs to chemotherapy and radiotherapy. In this review, we intend to review the articles that have described how the hypoxic microenvironment affects CSC stemness and mediates tumor resistance and provide new directions and methods in the clinical treatment of tumors. Here, we also discuss the feasibility and development prospects of using hypoxia-inducible factors (HIFs) that regulate the hypoxic microenvironment of tumors as targeted agents to treat tumors, as well as to reduce or even reverse the resistance of tumors to chemotherapy and radiotherapy.

Source-sink modifications affect leaf senescence and grain mass in wheat as revealed by proteomic analysis.

BACKGROUND: The grain yield of cereals is determined by the synergistic interaction between source activity and sink capacity. However, source-sink interactions are far from being fully understood. Therefore, a field experiment was performed in wheat to investigate the responses of flag leaves and grains to sink/source manipulations. RESULTS: Half-degraining delayed but partial defoliation enhanced leaf senescence. Sink/source manipulations influenced the content of reactive oxygen species in the flag leaf and the concentration of phytohormones, including cytokinins, indoleacetic 3-acid and jasmonic acid, in the flag leaves (LDef) and grains (GDef) in defoliated plants and flag leaves (LDG) and grain (GDG) in de-grained plants. Isobaric tag for relative and absolute quantitation (iTRAQ)-based quantitative proteomic analysis indicated that at 16 days after manipulation, a total of 97 and 59 differentially expressed proteins (DEPs) from various functional categories were observed in the LDG and LDef groups, respectively, compared with the control, and 115 and 121 DEPs were observed in the GDG and GDef groups, respectively. The gene ontology annotation terms of the DEPs mainly included carbon fixation, hydrogen peroxide catabolic process, chloroplast and cytoplasm, oxidoreductase activity and glutamate synthase activity in the flag leaves of manipulated plants and organonitrogen compound metabolic process, cytoplasm, vacuolar membrane, CoA carboxylase activity, starch synthase activity and nutrient reservoir activity in the grains of manipulated plants. KEGG pathway enrichment analysis revealed that photosynthesis, carbon, nitrogen and pyruvate metabolism and glycolysis/gluconeogenesis were the processes most affected by sink/source manipulations. Sink/source manipulations affected the activities of amylase and proteinases and, ultimately, changed the mass per grain. CONCLUSIONS: Manipulations to change the sink/source ratio affect hormone levels; hydrolytic enzyme activities; metabolism of carbon, nitrogen and other main compounds; stress resistance; and leaf senescence and thus influence grain mass.

LncRNA HOTTIP facilitates the stemness of breast cancer via regulation of miR-148a-3p/WNT1 pathway.

Emerging evidence suggests that dysregulation of long non-coding RNA (lncRNA) plays a key role in tumorigenesis. The lncRNA, HOXA transcript at the distal tip (HOTTIP), has been reported to be up-regulated in multiple cancers, including breast cancer, and is involved in various biological processes, including the maintenance of stemness. However, the biological function and underlying modulatory mechanism of HOTTIP in breast cancer stem cells (BCSCs) remains unknown. In this study, we found that HOTTIP was markedly up-regulated in BCSCs and had a positive correlation with breast cancer progression. Functional studies revealed that overexpression of HOTTIP markedly promoted cell clonogenicity, increased the expression of the stem cell markers, OCT4 and SOX2, and decreased the expression of the differentiation markers, CK14 and CK18, in breast cancer cells. Knockdown of HOTTIP inhibited the CSC-like properties of BCSCs. Consistently, depletion of HOTTIP suppressed tumour growth in a humanized model of breast cancer. Mechanistic studies demonstrated that HOTTIP directly binds to miR-148a-3p and inhibits the mediation of WNT1, which leads to inactivation of the Wnt/ß-catenin signalling pathway. Our study is the first to report that HOTTIP regulates the CSC-like properties of BCSCs by as a molecular sponge for miR-148a-3p to increase WNT1 expression, offering a new target for breast cancer therapy.

A Combined four-mRNA Signature Associated with Lymphatic Metastasis for Prognosis of Colorectal Cancer.

Background: Colorectal cancer (CRC) is one of the most common malignant tumors in the world. Lymph node metastasis (LNM) is a common mode of metastasis of CRC. However, the combined mRNA biomarkers associated with LNM of CRC that can effectively predict CRC prognosis have not been reported yet. Methods: To identify biomarkers that are associated with LNM, we collected data from the The Cancer Genome Atlas (TCGA) database. The edgeR package was searched to seek LNM-related genes by comparisons between cancer samples and normal colorectal tissues and between LNM and non-LNM (NLNM) of CRC. Univariate and multivariate regression analysis of genes in the intersection to build gene signature associated with independent prognosis of CRC, and then verified by Kaplan-Meier curve and log-rank test, receiver operating characteristic (ROC) curve was used to determine the efficiency of survival prediction of our four-mRNA signature. Finally, the potential molecular mechanisms and properties of these gene signature were also explored with functional and pathway enrichment analysis. Results: 329 mRNAs were up-regulated in CRC tissues with LNM, and 8461 mRNAs were up-regulated in CRC tissues, the intersection is 100 mRNAs. After univariate and multivariate Cox regression analysis of 100 mRNAs, a novel four LNM related mRNAs (EPHA8, KRT85, GABRA3, and CLPSL1) were screened as independent prognostic indicators of CRC. Surprisingly, the four-mRNA signature can predict the prognosis of CRC patients independently of clinical factors andthe area under the curve (AUC) of the ROC is 0.730. The novel four-mRNA signature was used to identify high and low-risk groups. Stratified analysis indicated the risk score based on four-mRNA signature was an independent prognostic indicator for female, T3+T4, N1+N2 ,stage III+IV and patients with no new tumor event. Functional annotation of this risk model in high-risk patients revealed that pathways associated with neuroactive ligand-receptor interaction, estrogen signaling pathway, and steroid hormone biosynthesis. Conclusions: By conducting TCGA data mining, our study demonstrated that a four-mRNA signature associated with LNM can be used as a combined biomarker for independent prognosis of CRC.

Expression signature of six-snoRNA serves as novel non-invasive biomarker for diagnosis and prognosis prediction of renal clear cell carcinoma.

Increasing evidence has verified that small nucleolar RNAs (snoRNAs) play significant roles in tumorigenesis and exhibit prognostic value in clinical practice. In the study, we analysed the expression profile and clinical relevance of snoRNAs from TCGA database including 530 ccRCC (clear cell renal cell carcinoma) and 72 control cases. By using univariate and multivariate Cox analysis, we established a six-snoRNA signature and divided patients into high-risk or low-risk groups. We found patients in high-risk group had significantly shorter overall survival and recurrence-free survival than those in low-risk group in test series, validation series and entire series by Kaplan-Meier analysis. We also confirmed this signature had a great accuracy and specificity in 64 clinical tissue cases and 50 serum samples. Then, depending on receiver operating characteristic curve analysis we found the six-snoRNA signature was an superior indicator better than conventional clinical factors (AUC = 0.732). Furthermore, combining the signature with TNM stage or Fuhrman grade were the optimal indicators (AUC = 0.792; AUC = 0.800) and processed the clinical applied value for ccRCC. Finally, we found the SNORA70B and its hose gene USP34 might directly regulate Wnt signalling pathway to promote tumorigenesis in ccRCC. In general, our study established a six-snoRNA signature as an independent and superior diagnosis and prognosis indicator for ccRCC.

Current Iodine Nutrition Status and Prevalence of Thyroid Disorders in Tibetan Adults in an Oxygen-Deficient Plateau, Tibet, China: A Population-Based Study.

Background: Iodine deficiency (ID) is a global problem in individuals living in an iodine-deficient environment, specifically in mountainous regions. However, data regarding the iodine nutritional status of Tibetan people in the plateau are limited. Methods: A population-based survey was conducted from July 2016 to July 2017 in Lhasa, Tibet, including 12 communities in Lhasa city and 10 surrounding rural areas. The iodine nutritional status of Tibetan people was evaluated using the traditional iodine nutrition indexes: urinary iodine concentration (UIC), thyroid size, serum thyroxine, thyrotropin, thyroglobulin antibody and thyroid peroxidase antibody (TPOAb). Results: A total of 2295 healthy participants were screened, and 2160 participants who had completed all the required examinations were enrolled in this study (response rate, 94.1%). Urinary iodine showed a skewed distribution, with a median (upper and lower quartiles) of 154 (99-229) µg/L. The percentages of low iodine (UIC <100 µg/L), adequate iodine (UIC, 100-199 µg/L), and high iodine (UIC ≥200 µg/L) were 25.6%, 42.0%, and 32.4%, respectively. The urinary iodine level in the urban region was higher than that in the rural region (p < 0.05). Urinary iodine levels were lower with increasing age (p < 0.05). The prevalence of hyperthyroidism, hypothyroidism, goiter, TPOAb positivity, and thyroglobulin antibody positivity was 1.0%, 21.8%, 4.7%, 6.6%, and 10.4%, respectively. Logistic regression analysis found that urinary iodine was an independent risk factor for TPOAb positivity (odds ratio = 0.997 [95% confidence interval, 0.995-0.999]; p < 0.001). Conclusions: Compared with individuals living in the plains of China, Tibetan adults have a higher rate of ID. UIC was an independent risk factor for TPOAb positivity. This public health issue should be further investigated.

Erythrocytosis and Performance of HbA1c in Detecting Diabetes on an Oxygen-Deficient Plateau: A Population-based Study.

CONTEXT: The hemoglobin A1c (HbA1c) test is a standard test for diabetes screening and diagnosis. OBJECTIVE: To evaluate A1c performance for diabetes screening in high-altitude polycythemia compared to a population with a high proportion of people living in an oxygen-deficient environment. DESIGN: A population-based epidemiological survey was conducted. SETTING: The cities Lhasa and Shigatse were selected. Volunteers were recruited through educational advertisements about diabetes. PARTICIPANTS: A total of 1401 Tibetan adults without known diabetes. INTERVENTIONS: Oral glucose tolerance test (OGTT), HbA1c, and complete blood cell count were performed. Hemoglobin A1c was evaluated using high-performance liquid chromatography, and serum glucose level, using the hexokinase method. MAIN OUTCOME MEASURES: World Health Organization criteria were used to define diabetes and prediabetes. Hemoglobin A1c test performance was evaluated using receiver operating characteristic analysis. RESULTS: The participants' mean age was 44.3 ± 15.0 years; 33.3% of the participants were men and 38.6% lived in urban areas. The prediabetes and diabetes prevalence rates were 7.5% and 3.6%, respectively. The optimal HbA1c cutoff for detecting diabetes was 46 mmol/mol (6.4%), with a sensitivity and specificity of 60.8% and 93.6%, respectively. The cutoff for detecting diabetes was 6.7% (50 mmol/mol) in subjects with high-altitude polycythemia (HAPC). The relationship between red blood cell (RBC) counts and HbA1c was significant (P < 0.001), while there was no correlation between hemoglobin (Hb) and HbA1c (P = 0.085). Multiple linear regression analysis showed that after adjusting for age and fasting serum glucose or 2-hour OGTT (OGTT2h) serum glucose, RBC count and not Hb level was an independent risk factor for HbA1c (ß = 0.140, P < 0.001). CONCLUSIONS: The optimal HbA1c cutoff for detecting diabetes was 46 mmol/mol (6.4%) in Tibet. Red blood cell count was an independent risk factor for elevated HbA1c, and HAPC may affect the predictive ability of HbA1c.

Development of a novel gene signature in patients without Helicobacter pylori infection gastric cancer.

Gastric cancer (GC) is one of the most fatal common cancers in worldwide. Helicobacter pylori (H. pylori) infection is closely related to the development of GC, although the mechanism is still unclear. In our study, we aim to develop a robust messenger RNA (mRNA) signature associated with H. pylori (-) GC that can sensitively and efficiently predict the prognostic. The RNA-seq expression profile and corresponding clinical data of 598 gastric cancer samples and 63 normal samples obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus database. Using gene set enrichment analysis H. pylori (+) GC and H. pylori (-) GC patients and normal samples to select certain genes for further analysis. Using univariate and multivariate Cox regression model to establish a gene signature for predicting the overall survival (OS). Finally, we identified G2/M related seven-mRNA signature (TGFB1, EGF, MKI67, ILF3, INCENP, TNPO2, and CHAF1A) closely related to the prognosis of patients with H. pylori (-) GC. The seven-mRNA signature was identified to act as an independent prognostic biomarker by stratified analysis and multivariate Cox regression analysis. It was also validated on two test groups from TCGA and GSE15460 and shown that patients with high-risk scores based on the expression of the seven mRNAs had significantly shorter survival times compared to patients with low-risk scores (P < .0001). In this study, we developed a seven-mRNA signature related to G2/M checkpoint from H. pylori (-) GCs that as an independent biomarker potentially with a good performance in predicting OS and might be valuable for the clinical management for patients with GC.

Identification of a panel of mitotic spindle-related genes as a signature predicting survival in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is one of the most malignant tumor types worldwide. Our objective was to identify a genetic signature that could predict the prognosis of patients with LUAD. We extracted gene data sets from The Cancer Genome Atlas and obtained differentially expressed genes that were highly expressed at every stage. These genes were analyzed using gene set enrichment analysis to obtain four biological processes associated with LUAD. Subsequently, Cox univariate and multivariate analyses were performed to generate four optimized models (G2M checkpoint, E2F targets, mitotic spindle, and glycolysis). We identified a mitotic spindle-related signature (KIF15, BUB1, CCNB2, CDK1, KIF4A, DLGAP5, ECT2, and ANLN), which could be an independent prognostic indicator, to predict the prognosis of patients with LUAD. This new discovery should offer opportunities to explore the pathogenesis of LUAD and prove clinically useful in predicting LUAD patient prognosis.

SNORD89 promotes stemness phenotype of ovarian cancer cells by regulating Notch1-c-Myc pathway.

BACKGROUND: Ovarian cancer is the leading cause of death in gynecological cancer. Cancer stem cells (CSCs) contribute to the occurrence, progression and resistance. Small nucleolar RNAs (SnoRNAs), a class of small molecule non-coding RNA, involve in the cancer cell stemness and tumorigenesis. METHODS: In this study, we screened out SNORNAs related to ovarian patient's prognosis by analyzing the data of 379 cases of ovarian cancer patients in the TCGA database, and analyzed the difference of SNORNAs expression between OVCAR-3 (OV) sphere-forming (OS) cells and OV cells. After overexpression or knockdown SNORD89, the expression of Nanog, CD44, and CD133 was measured by qRT-PCR or flow cytometry analysis in OV, CAOV-3 (CA) and OS cells, respectively. CCK-8 assays, plate clone formation assay and soft agar colony formation assay were carried out to evaluate the changes of cell proliferation and self-renewal ability. Scratch migration assay and trans-well invasion analysis were used for assessing the changes of migration and invasion ability. RESULTS: High expression of SNORD89 indicates the poor prognosis of ovarian cancer patients and was associated with patients' age, therapy outcome. SNORD89 highly expressed in ovarian cancer stem cells. The overexpression of SNORD89 resulted in the increased stemness markers, S phase cell cycle, cell proliferation, invasion and migration ability in OV and CA cells. Conversely, these phenomena were reversed after SNORD89 silencing in OS cells. Further, we found that SNORD89 could upregulate c-Myc and Notch1 expression in mRNA and protein levels. SNORD89 deteriorates the prognosis of ovarian cancer patients by regulating Notch1-c-Myc pathway to promote cell stemness and acts as an oncogene in ovarian tumorigenesis. Consequently, SNORD89 can be a novel prognostic biomarker and therapeutic target for ovarian cancer.