Metabolic flux in macrophages in obesity and type-2 diabetes.

Recent literature extensively investigates the crucial role of energy metabolism in determining the inflammatory response and polarization status of macrophages. This rapidly expanding area of research highlights the importance of understanding the link between energy metabolism and macrophage function. The metabolic pathways in macrophages are intricate and interdependent, and they can affect the polarization of macrophages. Previous studies suggested that glucose flux through cytosolic glycolysis is necessary to trigger pro-inflammatory phenotypes of macrophages, and fatty acid oxidation is crucial to support anti-inflammatory responses. However, recent studies demonstrated that this understanding is oversimplified and that the metabolic control of macrophage polarization is highly complex and not fully understood yet. How the metabolic flux through different metabolic pathways (glycolysis, glucose oxidation, fatty acid oxidation, ketone oxidation, and amino acid oxidation) is altered by obesity- and type 2 diabetes (T2D)-associated insulin resistance is also not fully defined. This mini-review focuses on the impact of insulin resistance in obesity and T2D on the metabolic flux through the main metabolic pathways in macrophages, which might be linked to changes in their inflammatory responses. We closely evaluated the experimental studies and methodologies used in the published research and highlighted priority research areas for future investigations.

Molecular mechanism of miR-203a targeting Runx2 to regulate thiram induced-chondrocyte development.

Thiram is a kind of organic compound, which is commonly used for sterilization, insecticidal and deodorization in daily life. Its toxicology has been broadly studied. Recently, more and more microRNAs have been shown to participate in the regulation of cartilage development. However, the potential mechanism by which microRNA regulates chondrocyte growth is still unclear. Our experiments have demonstrated that thiram can hamper chondrocytes development and cause a significant increase in miR-203a content in vitro and in vivo trials. miR-203a mimic significantly decrease in mRNA and protein expression of Wnt4, Runx2, COL2A1, ß-catenin and ALP, and significantly enhance the mRNA and protein levels of GSK-3ß. It has been observed that overexpression of miR-203a hindered chondrocytes development. In addition, Runx2 was confirmed to be a direct target of miR-203a by dual luciferase report gene assay. Transfection of si-Runx2 into chondrocytes reveals that significant downregulation of genes is associated with cartilage development. Overall, these results suggest that overexpression of miR-203a inhibits the expression of Runx2. These findings are conducive to elucidate the mechanism of chondrocytes dysplasia induced by thiram and provide new research ideas for the toxicology of thiram.

Multi-scale adversarial learning with difficult region supervision learning models for primary tumor segmentation.

Objective.Recently, deep learning techniques have found extensive application in accurate and automated segmentation of tumor regions. However, owing to the variety of tumor shapes, complex types, and unpredictability of spatial distribution, tumor segmentation still faces major challenges. Taking cues from the deep supervision and adversarial learning, we have devised a cascade-based methodology incorporating multi-scale adversarial learning and difficult-region supervision learning in this study to tackle these challenges.Approach.Overall, the method adheres to a coarse-to-fine strategy, first roughly locating the target region, and then refining the target object with multi-stage cascaded binary segmentation which converts complex multi-class segmentation problems into multiple simpler binary segmentation problems. In addition, a multi-scale adversarial learning difficult supervised UNet (MSALDS-UNet) is proposed as our model for fine-segmentation, which applies multiple discriminators along the decoding path of the segmentation network to implement multi-scale adversarial learning, thereby enhancing the accuracy of network segmentation. Meanwhile, in MSALDS-UNet, we introduce a difficult region supervision loss to effectively utilize structural information for segmenting difficult-to-distinguish areas, such as blurry boundary areas.Main results.A thorough validation of three independent public databases (KiTS21, MSD's Brain and Pancreas datasets) shows that our model achieves satisfactory results for tumor segmentation in terms of key evaluation metrics including dice similarity coefficient, Jaccard similarity coefficient, and HD95.Significance.This paper introduces a cascade approach that combines multi-scale adversarial learning and difficult supervision to achieve precise tumor segmentation. It confirms that the combination can improve the segmentation performance, especially for small objects (our codes are publicly availabled onhttps://zhengshenhai.github.io/).

Ketones provide an extra source of fuel for the failing heart without impairing glucose oxidation.

BACKGROUND: Cardiac glucose oxidation is decreased in heart failure with reduced ejection fraction (HFrEF), contributing to a decrease in myocardial ATP production. In contrast, circulating ketones and cardiac ketone oxidation are increased in HFrEF. Since ketones compete with glucose as a fuel source, we aimed to determine whether increasing ketone concentration both chronically with the SGLT2 inhibitor, dapagliflozin, or acutely in the perfusate has detrimental effects on cardiac glucose oxidation in HFrEF, and what effect this has on cardiac ATP production. METHODS: 8-week-old male C57BL6/N mice underwent sham or transverse aortic constriction (TAC) surgery to induce HFrEF over 3 weeks, after which TAC mice were randomized to treatment with either vehicle or the SGLT2 inhibitor, dapagliflozin (DAPA), for 4 weeks (raises blood ketones). Cardiac function was assessed by echocardiography. Cardiac energy metabolism was measured in isolated working hearts perfused with 5 mM glucose, 0.8 mM palmitate, and either 0.2 mM or 0.6 mM ß-hydroxybutyrate (ßOHB). RESULTS: TAC hearts had significantly decreased %EF compared to sham hearts, with no effect of DAPA. Glucose oxidation was significantly decreased in TAC hearts compared to sham hearts and did not decrease further in TAC hearts treated with high ßOHB or in TAC DAPA hearts, despite ßOHB oxidation rates increasing in both TAC vehicle and TAC DAPA hearts at high ßOHB concentrations. Rather, increasing ßOHB supply to the heart selectively decreased fatty acid oxidation rates. DAPA significantly increased ATP production at both ßOHB concentrations by increasing the contribution of glucose oxidation to ATP production. CONCLUSION: Therefore, increasing ketone concentration increases energy supply and ATP production in HFrEF without further impairing glucose oxidation.

Mitochondrial fatty acid oxidation is the major source of cardiac adenosine triphosphate production in heart failure with preserved ejection fraction.

AIMS: Heart failure with preserved ejection fraction (HFpEF) is a prevalent disease worldwide. While it is well established that alterations of cardiac energy metabolism contribute to cardiovascular pathology, the precise source of fuel used by the heart in HFpEF remains unclear. The objective of this study was to define the energy metabolic profile of the heart in HFpEF. METHODS AND RESULTS: Eight-week-old C57BL/6 male mice were subjected to a '2-Hit' HFpEF protocol [60% high-fat diet (HFD) + 0.5 g/L of Nω-nitro-L-arginine methyl ester]. Echocardiography and pressure-volume loop analysis were used for assessing cardiac function and cardiac haemodynamics, respectively. Isolated working hearts were perfused with radiolabelled energy substrates to directly measure rates of fatty acid oxidation, glucose oxidation, ketone oxidation, and glycolysis. HFpEF mice exhibited increased body weight, glucose intolerance, elevated blood pressure, diastolic dysfunction, and cardiac hypertrophy. In HFpEF hearts, insulin stimulation of glucose oxidation was significantly suppressed. This was paralleled by an increase in fatty acid oxidation rates, while cardiac ketone oxidation and glycolysis rates were comparable with healthy control hearts. The balance between glucose and fatty acid oxidation contributing to overall adenosine triphosphate (ATP) production was disrupted, where HFpEF hearts were more reliant on fatty acid as the major source of fuel for ATP production, compensating for the decrease of ATP originating from glucose oxidation. Additionally, phosphorylated pyruvate dehydrogenase levels decreased in both HFpEF mice and human patient's heart samples. CONCLUSION: In HFpEF, fatty acid oxidation dominates as the major source of cardiac ATP production at the expense of insulin-stimulated glucose oxidation.

miR-181b-1-3p affects the proliferation and differentiation of chondrocytes in TD broilers through the WIF1/Wnt/ß-catenin pathway.

Thiram is a plant fungicide, its excessive use has exceeded the required environmental standards. It causes tibial dyschondroplasia (TD) in broilers which is a common metabolic disease that affects the growth plate of tibia bone. It has been studied that many microRNAs (miRNAs) are involved in the differentiation of chondrocytes however, their specific roles and mechanisms have not been fully investigated. The selected features of tibial chondrocytes of broilers were studied in this experiment which included the expression of miR-181b-1-3p and the genes related to WIF1/Wnt/ß-catenin pathway in chondrocytes through qRT-PCR, western blot and immunofluorescence. The correlation between miR-181b-1-3p and WIF1 was determined by dual luciferase reporter gene assay whereas, the role of miR-181b-1-3p and WIF1/Wnt/ß-catenin in chondrocyte differentiation was determined by mimics and inhibitor transfection experiments. Results revealed that thiram exposure resulted in decreased expression of miR-181b-1-3p and increased expression of WIF1 in chondrocytes. A negative correlation was also observed between miR-181b-1-3p and WIF1. After overexpression of miR-181b-1-3p, the expression of ACAN, ß-catenin and Col2a1 increased but the expression of GSK-3ß decreased. It was observed that inhibition of WIF1 increased the expression of ALP, ß-catenin, Col2a1 and ACAN but decreased the expression of GSK-3ß. It is concluded that miR-181b-1-3p can reverse the inhibitory effect of thiram on cartilage proliferation and differentiation by inhibiting WIF1 expression and activating Wnt/ß-catenin signaling pathway. This study provides a new molecular target for the early diagnosis and possible treatment of TD in broilers.

High level of winter warming aggravates soil carbon, nitrogen loss and changes greenhouse gas emission characteristics in seasonal freeze-thaw farmland soil.

Changes in the soil environment caused by winter warming is affecting the carbon and nitrogen cycles of seasonal freeze-thaw farmland soil. A field experiment was conducted in a seasonal freeze-thaw farmland soil of northeast China to investigate the effects caused from different levels of warming (W1 + 1.77 °C, W2 + 0.69 °C and C + 0 °C) on soil carbon and nitrogen dynamics, microbial biomass and greenhouse gases fluxes. During the early and middle winter, the contents of all kinds of soil carbon and nitrogen (Ammonium, nitrate, total nitrogen, dissolved organic carbon, readily oxidizable organic carbon and soil organic carbon) tended to increase with the increase of warming level, while during the late winter, their contents under different temperature treatments roughly present trend of W2 ≥C > W1. Except for the late thawing period, warming increased the contents of soil microbial biomass carbon and nitrogen, during the late thawing period, with the increase of warming level, MBC and MBN decreased significantly. Warming would stimulate the release of greenhouse gases from soil. But due to the differences of soil environmental conditions in each period and soil nutrient dynamics under different treatments, which made the effects of different levels of warming on soil GHGs fluxes in different periods are different. Our study suggested that low-level warming improved the availability of soil carbon and nitrogen, increased the contents of microbial biomass and greenhouse gas emissions. However, although high-level winter warming showed a similar phenomenon in the early and middle winter to the low-level warming, during the late winter, high-level warming increased soil nutrients loss and broke the seasonal coupling relationship between crop nutrient acquisition and soil microbial nutrient supply, and even led to the adaptation of soil CO2 release to it. This is of great significance for exploring the carbon and nitrogen cycle mechanisms of global terrestrial ecosystem.

A multicenter prospective study on quality of life and pain relief for cancer patient after 125I seed implantation.

Objective: To prospectively explore the efficacy of 125I seed implantation on quality of life and pain relief in cancer patient. Methods: Consecutive cancer patients who underwent 125I seed implantation in three centers in China between October 1, 2020 and March 31, 2021, were assessed. The Functional Assessment of Cancer Therapy and Brief Pain Inventory were used to evaluate patients' quality of life and pain relief on the day before, 1 week, 1 month, and 3 months after seed implantation. Results: A total of 104 cancer patients were enroled. Total score of quality of life was not statistically different 3 months after seed implantation compared with before implantation, while patients' quality of life was worse one week after seed implantation but then recovered. A total of 43 (41.3%) patients had pain before seed implantation, of which 16 (37.2%) patients had severe pain and 27 (62.8%) had mild-to-moderate pain. In patients with severe pain, the worst pain scores decreased significantly 3 months after implantation. In patients with mild-to-moderate pain, pain severity and pain interference score increased significantly after implantation compared with pre-implantation. Compared with pain before implantation, patients' quality of life of patients without pain was higher. Conclusions: 125I seed implantation maintains the quality of life of patients within 3 months. For patients with severe pain, seed implantation has obvious pain relief, which improves the quality of life of the patients. Nurses should provide personalized guidance for patients with different degrees of pain.

Vitamin C intake and multiple health outcomes: an umbrella review of systematic reviews and meta-analyses.

The purpose of this article was to assess the existing systematic reviews and meta-analyses for the association between vitamin C intake and multiple health outcomes. A total of 76 meta-analyses (51 papers) of randomised controlled trials and observational studies with 63 unique health outcomes were identified. Dose-response analysis showed that vitamin C intake was associated with reduced risk of all-cause mortality, cardiovascular disease (CVD), oesophageal cancer, gastric cancer, cervical cancer and lung cancer with an increment of 50-100 mg per day. Beneficial associations were also identified for respiratory, neurological, ophthalmologic, musculoskeletal, renal and dental outcomes. Harmful associations were found for breast cancer and kidney stones for vitamin C supplement intake. The benefits of vitamin C intake outweigh the disadvantages for a range of health outcomes. However, the recommendation of vitamin C supplements needs to be cautious. More prospective studies and well-designed randomised controlled trials (RCTs) are needed.

A Dose-Response Meta-Analysis of Dietary Fiber Intake and Breast Cancer Risk.

Whether dietary fiber intake could reduce the risk of breast cancer (BC) is still controversial. The articles related to breast cancer and dietary fiber were retrieved through PubMed and Web of Science database. Summary relative risk (RR) and attributable risk percentage (ARP) for dietary fiber intake on the development of breast cancer were calculated. Dose-response meta-analysis modeled the relationship between dietary fiber intake and breast cancer risk. A total of 10 studies were included in this study. Meta-analysis showed that dietary fiber intake was negatively associated with breast cancer (RR = 0.83). In dose-response analysis, the risk of breast cancer showed a statistically significant linear trend with increasing dietary fiber dose: when adding 10 g per day, the risk decreased by 4.7% (RR = 0.95). The ARP results demonstrated that the breast cancer dietary fiber-attributed percentage was 33.33% in Asia, which was higher than 16.28% in North America and 9.89% in Europe. In conclusion, dietary fiber intake may have a positive effect on reducing breast cancer risk, especially in high doses.

Association study of SNPs in LncRNA CDKN2B-AS1 with breast cancer susceptibility in Chinese Han population.

BACKGROUND: The study aimed to analysis the genetic variation of the lncRNA CDKN2B-AS1 SNPs, and explored the regulation of SNPs on the invasion and metastasis of Breast cancer (BC). METHODS: The SNPs (Single Nucleotide Polymorphisms) was screened for genotyping among 504 Chinese Han patients and 505 controls, which were frequency-matched for age ( ± 2 years). Logistic analysis was to explore the relationship between SNPs and the BC risk. Interactions between SNPs and reproductive factors was explored using the multifactor dimensionality reduction (MDR) method. qRT-PCR was conducted to detect the CDKN2B-AS1 expression in plasma of different rs10965215 and rs2518723 genotypes. The effect of rs10965215 A>G mutation on the binding ability of CDKN2B-AS1 and miR-4440 was verified by dual luciferase experiment. CCK-8, scratch and Transwell experiment were performed to explore the effect of miR-4440 over-expression on BC cell proliferation, migration and invasion. RESULTS: A total of 13 SNP was screened. The individuals with SNPs rs2518723C>T, rs10965215 A>G, rs77792598C>G, rs4977753 T > C, rs75917766C>T and rs78545330C>G mutations might increase the BC risk. MDR results revealed that individuals with rs10965215 G genotype who age at menarche≥ 13 and regardless of the number of abortion< 2 or ≥ 2 had a higher risk of BC. The relative expression of CDKN2B-AS1 in rs10965215 homozygous wild AA genotype (8.88 ± 3.43) was lower than heterozygous GA (11.08 ± 2.90) and homozygous mutant GG genotype (11.31 ± 2.90). When rs10965215 wild A genotype was carried, there was an interaction between CDKN2B-AS1 and miR-4440. The CCK-8, Transwell, and scratch experiment were all found that miR-4440 over-expression might enhance the proliferation, invasion and migration of BC cells. - CONCLUSION: CDKN2B-AS1 gene polymorphism might be related to the susceptibility of BC, CDKN2B-AS1 rs10965215 A/G genotype probably affect the proliferation, invasion and migration of BC cells by modulating the interactions with of miR-4440.

Polymorphisms in lncRNA MIR2052HG and susceptibility to breast cancer in Chinese population.

BACKGROUND: Published studies based on pharmacokinetics have explored the relationship between the lncRNA MIR2052HG and the prognosis of breast cancer (BC) resistance and recurrence. However, the underlying association of MIR2052HG SNPs with BC development remains unclear. METHODS: Combining bioinformatics and databases, SNPs (Single Nucleotide Polymorphisms) in the MIR2052HG gene were screened, and SNPs in the lncRNA MIR2052HG were selected for genotyping among 504 Chinese Han patients and 505 healthy controls, which were frequency-matched for age (±2 years). Logistic regression analysis was used to explore the association between MIR2052HG SNPs and the BC risk. Interactions between the MIR2052HG SNPs and reproductive factors were further evaluated using the multifactor dimensionality reduction (MDR) method. qRT-PCR was performed to detect MIR2052HG expression in individuals with different genotypes of rs34841297. The target miRNA, miR-4456 of MIR2052HG rs34841297 was predicted by websites and confirmed by performing dual luciferase gene reporter assays. CCK-8 and Transwell experiments were designed to explore the effects of miR-4456 on the proliferation, invasion and migration of BC cells. RESULTS: In this study, nine SNPs were screened. After adjusting for age, menarche age, menopausal status, number of pregnancies, history of abortions, breast feeding history and family history of BC, the results of the logistic regression analysis showed the rs34841297 A/- gene polymorphism was positively correlated with the incidence of BC. Compared with the AA genotype, patients with the A-+-- genotype of rs34841297 at age<50 years, and menarche age<14 years, Premenopausal status, history of abortion, no history of breastfeeding and no family history of tumors in first-degree relatives had an increased risk of BC. MDR results revealed that individuals with rs34841297 - (homozygous deletion) of the A allele who were not menopausal and had no history of breastfeeding had a higher risk of BC. qRT-PCR results revealed that homozygous deletion (1.68±1.37) of the rs34841297 A- genotype resulted in higher MIR2052HG expression than the heterozygous deletion genotype (0.95±0.94) and wild AA genotype (0.26±0.12). Binding between MIR2052HG and miR-4456 was occurred when rs34841297 carried the AA genotype. Moreover, preliminary functional studies indicated that the overexpression of miR-4456 increased the proliferation, invasion and migration of BC cells. CONCLUSION: Our study showed that the MIR2052HG gene polymorphism may be related to BC susceptibility, and the MIR2052HG rs34841297 A/- genotype may probably affect the proliferation, invasion and migration of BC cells by modulating the interactions with of miR-4456.

Risk Stratification of Cytogenetically Normal Acute Myeloid Leukemia With Biallelic CEBPA Mutations Based on a Multi-Gene Panel and Nomogram Model.

BACKGROUND: Approximately 30% of Chinese individuals with cytogenetically normal acute myeloid leukemia (CN-AML) have biallelic CEBPA (biCEBPA) mutations. The prognosis and optimal therapy for these patients are controversial in clinical practice. METHODS: In this study, we performed targeted region sequencing of 236 genes in 158 individuals with this genotype and constructed a nomogram model based on leukemia-free survival (LFS). Patients were randomly assigned to a training cohort (N =111) and a validation cohort (N =47) at a ratio of 7:3. Risk stratification was performed by the prognostic factors to investigate the risk-adapted post-remission therapy by Kaplan-Meier method. RESULTS: At least 1 mutated gene other than CEBPA was identified in patients and mutation number was associated with LFS (61.6% vs. 39.0%, P =0.033), survival (85.6% vs. 62.9%, P =0.030) and cumulative incidence of relapse (CIR) (38.4% vs. 59.5%, P =0.0496). White blood cell count, mutations in CFS3R, KMT2A and DNA methylation related genes were weighted to construct a nomogram model and differentiate two risk subgroups. Regarding LFS, low-risk patients were superior to the high-risk (89.3% vs. 33.8%, P <0.001 in training cohort; 87.5% vs. 18.2%, P =0.009 in validation cohort). Compared with chemotherapy, allogenic hematopoietic stem cell transplantation (allo-HSCT) improved 5-year LFS (89.6% vs. 32.6%, P <0.001), survival (96.9% vs. 63.6%, P =0.001) and CIR (7.2% vs. 65.8%, P <0.001) in high-risk patients but not low-risk patients (LFS, 77.4% vs. 88.9%, P =0.424; survival, 83.9% vs. 95.5%, P =0.173; CIR, 11.7% vs. 11.1%, P =0.901). CONCLUSIONS: Our study indicated that biCEBPA mutant-positive CN-AML patients could be further classified into two risk subgroups by four factors and allo-HSCT should be recommended for high-risk patients as post-remission therapy. These data will help physicians refine treatment decision-making in biCEBPA mutant-positive CN-AML patients.

Variant in BCAR4 gene correlated with the breast cancer susceptibility and mRNA expression of lncRNA BCAR4 in Chinese Han population.

BACKGROUND: Long non-coding RNA (LncRNA) Breast cancer anti-estrogen resistance 4 (BCAR4) has been shown to participate in the biological progress of various cancers including breast cancer. Genetic Polymorphisms in BCAR4 may have an influence on the progress of breast cancer, but it is rarely studied. METHODS: In our epidemiology study, three tagging SNPs (rs4561483, rs11649623 and rs13334967) in lncRNA BCAR4 were selected for genotyping among 487 breast cancer cases and 489 healthy controls. And quantitative real-time PCR (qRT-PCR) was performed to evaluate the relative mRNA expression of BCAR4 in different genotypes of the significant locus rs13334967. RESULTS: We found that BCAR4 rs13334967 is associated with lower breast cancer risk both in codominant model (AT vs AA, OR 0.632, 95% CI 0.429-0.931, TT vs AA, OR 0.731, 95% CI 0.511-0.990) and dominant model (AT + TT vs AA, OR 0.798, 95% CI 0.571-0.970). The further results of qRT-PCR displayed that carriers with rs13334967 AT, TT genotype have lower BCAR4 mRNA expression compared with AA genotype. CONCLUSION: The research study implied that BCAR4 rs13334967 was correlated with the susceptibility to breast cancer and may impact the mRNA expression of BCAR4. LncRNA BCAR4 may be a potential biomarker and therapeutic target for breast cancer.

Sedentary behavior and risk of breast cancer: a dose-response meta-analysis from prospective studies.

BACKGROUND: Emerging studies examined the association between sedentary behavior and risk of breast cancer, however, the dose-response relationship remained unclear. We aim to explore dose-response relationship of sedentary behavior and breast cancer risk based on relevant cohort studies. METHODS: Online database (PubMed, Web of Science, EMBASE and Cochrane Library) were searched up to March 29, 2019. Overall relative risk (RR) with 95% confidence interval (CI) were pooled, and generalized least squares (GLS) method and restricted cubic splines were applied to evaluate the linear or nonlinear relation. Attributable risk proportion (ARP) was used to assess the health hazards of sedentary behavior in different countries. RESULTS: Eight prospective studies were included in the meta-analysis, containing 17 048 breast cancer cases and 426 506 participants. The borderline statistical association was detected between prolonged sedentary behavior and risk of breast cancer (RR 1.08, 95% CI 0.99-1.19). Linear association between sedentary and breast cancer was observed (Pnonlinearity = 0.262), and for 1 h/d increment of sedentary behavior, there was 1% increase of breast cancer risk (RR 1.01, 95% CI1.00-1.02). Similar results were also found between TV viewing and risk of breast cancer (Pnonlinearity = 0.551), with 1 h/day increment of TV viewing daily attributing to 2% increase of breast cancer risk (RR 1.02, 95% CI 1.00-1.04). Moreover, sedentary behavior may statistically increase the risk of breast cancer by 21.6% for Asian countries, 8.26% for North America. CONCLUSIONS: Sedentary behavior was validated as a risk factor of breast cancer through dose-response analysis, especially TV viewing.

Osteoclast stimulatory transmembrane protein (OC-STAMP) is a promising molecular prognostic indicator for multiple myeloma.

BACKGROUND: Currently, the prognostic stratification and therapeutic evaluation systems for multiple myeloma (MM) lack specific molecular indicators. OC-STAMP is a new gene and is also highly expressed in MM. METHODS: A total of 160 MM patients have been investigated with both quantitative reverse transcription PCR (RT-qPCR), flow cytometry (FCM) and cytogenetic FISH on the same mononuclear cells isolated from bone marrow specimens. RESULTS: We found that OC-STAMP mRNA levels were significantly higher in newly diagnosed cases of MM than in healthy donors (median, 0.52% vs. 0.02%, P < .001). Moreover, the changes in the OC-STAMP mRNA levels paralleled the disease stages and minimal residual disease, as detected by FCM. Furthermore, we found that patients with high OC-STAMP mRNA levels were more likely to develop ≥3 bone lesions, be diagnosed with Durie-Salmon stages III, and have the P53 (17p13) deletion. In addition, advanced stage patients with high OC-STAMP mRNA levels had a lower 4-year progression-free survival (5.6% vs. 22.9%, P = .0055) and a worse 4-year overall survival (25.8% vs. 48.8%, P = .0137) compared to patients with low mRNA levels of this indicator. CONCLUSIONS: OC-STAMP may be a promising molecular indicator to monitor treatment effects and participate in the prognostic stratification of MM.

Alcohol Consumption by Beverage Type and Risk of Breast Cancer: A Dose-Response Meta-Analysis of Prospective Cohort Studies.

AIMS: Alcohol intake has been shown to increase the risk of breast cancer. However, the dose-response analysis of different alcoholic beverages (spirits, wine and beer) is not clear. Our meta-analysis aims to provide a dose-response estimation between different alcohols and breast cancer risk. METHODS: Search of PubMed and Web of Science and manual searches were conducted up to 1 December 2018, and summary relative risks (RRs) and attributable risk percentage (ARP) for alcohol intake on the development of breast cancer were calculated. Dose-response meta-analysis modeled relationships between drinking type and breast cancer risk. Sources of heterogeneity were explored, and sensitivity analyses were conducted to test the robustness of findings. RESULTS: In total, 22 cohort studies and 45,350 breast cancer cases were included. Current drinkers for ER+ had an increased risk compared with never drinkers. In dose-response analysis, there was a statistically significant linear trend with breast cancer risk increasing gradually by total alcohol and wine dose: when adding 10 g per day, the risk increased by 10.5% (RR = 1.10, 95%CI = 1.08-1.13) in total alcohol and 8.9% (RR = 1.08, 95%CI = 1.04-1.14) in wine. For postmenopausal women, the risk increases by 11.1% (RR = 1.11, 95%CI = 1.09-1.13) with every 10 g of total alcohol increase. Furthermore, the breast cancer alcohol-attributed percentage is higher in Europe than in North America and Asia. CONCLUSIONS: The effect of drinking on the incidence of breast cancer is mainly manifested in ER+ breast cancer. Quantitative analysis showed total drinking had a significant risk for breast cancer, especially for postmenopausal women. However, for different alcohols, just wine intake has the similar results.

A dose-response meta-analysis of green tea consumption and breast cancer risk.

Whether drinking green tea (GT) could reduce the risk of breast cancer (BC) is still controversial. The search was performed using PubMed, Embase and Web of Science databases. The generalised least square method and constrained cubic spline model were performed to assess the dose-response trends between GT consumption and BC risk. The attributable risk proportion (ARP) was also calculated. A total of 16 studies were included and the pooled relative risks was 0.86 (95%CI: 0.75-0.99) for BC risk at the highest vs. lowest levels of GT consumption. GT consumption (pnonlinearity = .110), drinking GT years (pnonlinearity = .393) and BC risk were both negatively linearly correlated. Moreover, The ARP results demonstrated in China, people who drink GT do not suffer from BC, 23.5% of which may be attributed to drinking GT. In conclusion, drinking GT may have a positive effect on reducing BC risk, especially in long-term, high doses.

MicroRNA-16 is involved in the pathogenesis of pre-eclampsia via regulation of Notch2.

In recent years, the role of microRNAs (miRNAs) in pre-eclampsia (PE) has been demonstrated, while the relevant mechanisms of miR-16 in PE await to be unearthed. Thus, the aim of this study is to explore whether miR-16 exerts its function in PE, and we assumed that miR-16 may be implicated in the occurrence of PE by adjusting the biological functions of trophoblast cells via modulating Notch2. Placental tissues of pregnant women with normal pregnancy and PE were collected to detect the expression of miR-16, Notch2, and Notch3. The effects of miR-16 and Notch2 on the biological functions of BeWo and JEG-3 cells were further determined. Expression of miR-16 and Notch2 in trophoblast cells was detected by reverse transcription quantitative polymerase chain reaction and western blot assay. Downregulated Notch2 and upregulated miR-16 and Notch3 were found in placental tissues of PE. There was a negative correlation between Notch2 and miR-16 expression (r = -0.769), and a positive correlation between Notch3 and miR-16 expression (r = 0.676; p < .05). Overexpression of miR-16 inhibited proliferation, migration, and invasion, and facilitated the apoptosis of BeWo and JEG-3 cells, but overexpression of Notch2 reversed this trend. Overexpression of miR-16 inhibited Notch2 expression in BeWo and JEG-3 cells, and Notch2 was the target gene of miR-16. Our study highlights that overexpression of miR-16 is involved in PE by regulating the biological functions of trophoblast cells via inhibition of Notch2. This paper provides a new idea for further study of the pathogenesis of PE.