Association between coffee and tea consumption and ovarian cancer incidence: A prospective analysis in the PLCO dataset.

Epidemiological evidence regarding the relationship between coffee and tea consumption and the risk of ovarian cancer (OC) is inconsistent. Therefore, we aimed to quantitatively investigate this topic in a large prospective cohort study. This cohort study included 24,715 individuals recruited from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trials between 1993 and 2001. The data used for our analysis included the latest follow-up information collected up to 2015. Coffee intake of ≥4 cups/day (hazard ratio [HR], 0.586; 95% confidence interval [CI]: 0.356-0.966) or caffeine intake of 458.787 mg/day (HR, 0.607; 95% CI: 0.411-0.895) were associated with the lowest HR of incident OC in the fully adjusted model. Participants who consumed varying amounts of tea did not exhibit a statistically significant reduction in the risk of OC. Our findings suggest that a higher consumption of coffee or caffeine is associated with a reduced risk of OC. However, no statistically significant association was observed between tea consumption and the risk of OC.

Gut fungi of black-necked cranes (Grus nigricollis) respond to dietary changes during wintering.

BACKGROUND: Migratory birds exhibit heterogeneity in foraging strategies during wintering to cope with environmental and migratory pressures, and gut bacteria respond to changes in host diet. However, less is known about the dynamics of diet and gut fungi during the wintering period in black-necked cranes (Grus nigricollis). RESULTS: In this work, we performed amplicon sequencing of the trnL-P6 loop and ITS1 regions to characterize the dietary composition and gut fungal composition of black-necked cranes during wintering. Results indicated that during the wintering period, the plant-based diet of black-necked cranes mainly consisted of families Poaceae, Solanaceae, and Polygonaceae. Among them, the abundance of Solanaceae, Polygonaceae, Fabaceae, and Caryophyllaceae was significantly higher in the late wintering period, which also led to a more even consumption of various food types by black-necked cranes during this period. The diversity of gut fungal communities and the abundance of core fungi were more conserved during the wintering period, primarily dominated by Ascomycota and Basidiomycota. LEfSe analysis (P < 0.05, LDA > 2) found that Pyxidiophora, Pseudopeziza, Sporormiella, Geotrichum, and Papiliotrema were significantly enriched in early winter, Ramularia and Dendryphion were significantly enriched in mid-winter, Barnettozyma was significantly abundant in late winter, and Pleuroascus was significantly abundant in late winter. Finally, mantel test revealed a significant correlation between winter diet and gut fungal. CONCLUSIONS: This study revealed the dynamic changes in the food composition and gut fungal community of black-necked cranes during wintering in Dashanbao. In the late wintering period, their response to environmental and migratory pressures was to broaden their diet, increase the intake of non-preferred foods, and promote a more balanced consumption ratio of various foods. Balanced food composition played an important role in stabilizing the structure of the gut fungal community. While gut fungal effectively enhanced the host's food utilization rate, they may also faced potential risks of introducing pathogenic fungi. Additionally, we recongnized the limitations of fecal testing in studying the composition of animal gut fungal, as it cannot effectively distinguished between fungal taxa from food or soil inadvertently ingested and intestines. Future research on functions such as cultivation and metagenomics may further elucidate the role of fungi in the gut ecosystem.

Gut microbiota enhance energy accumulation of black-necked crane to cope with impending migration.

Less is known about the role of gut microbiota in overwintering environmental adaptation in migratory birds. Here, we performed metagenomic sequencing on fresh fecal samples (n = 24) collected during 4 periods of overwintering (Dec: early; Jan: middle I; Feb: middle II; Mar: late) to characterize gut microbial taxonomic and functional characteristics of black-necked crane (Grus nigricollis). The results demonstrated no significant change in microbial diversity among overwintering periods. Analysis of compositions of microbiomes with bias correction (ANCOM-BC) determined 15 Proteobacteria species enriched in late overwintering period. Based on previous reports, these species are associated with degradation of chitin, cellulose, and lipids. Meanwhile, fatty acid degradation and betalain biosynthesis pathways are enriched in late overwintering period. Furthermore, metagenomic binning obtained 91 high-quality bins (completeness >70% and contamination <10%), 5 of which enriched in late overwintering period. Carnobacterium maltaromaticum, unknown Enterobacteriaceae, and Yersinia frederiksenii have genes for chitin and cellulose degradation, acetate, and glutamate production. Unknown Enterobacteriaceae and Y. frederiksenii hold genes for synthesis of 10 essential amino acids required by birds, and the latter has genes for γ-aminobutyrate production. C. maltaromaticum has genes for pyridoxal synthesis. These results implied the gut microbiota is adapted to the host diet and may help black-necked cranes in pre-migratory energy accumulation by degrading the complex polysaccharide in their diet, supplying essential amino acids and vitamin pyridoxal, and producing acetate, glutamate, and γ-aminobutyrate that could stimulate host feeding. Additionally, enriched Proteobacteria also encoded more carbohydrate-active enzymes (CAZymes) and antibiotic resistance genes (ARGs) in late overwintering period. KEY POINTS: • Differences in gut microbiota function during overwintering period of black-necked cranes depend mainly on changes in core microbiota abundance • Gut microbiota of black-necked crane adapted to the diet during overwintering period • Gut microbiota could help black-necked cranes to accumulate more energy in the late overwintering period.

Universal relation with regime transition for sediment transport in fine-grained rivers.

Fine-grained sediment (grain size under 2,000 µm) builds floodplains and deltas, and shapes the coastlines where much of humanity lives. However, a universal, physically based predictor of sediment flux for fine-grained rivers remains to be developed. Herein, a comprehensive sediment load database for fine-grained channels, ranging from small experimental flumes to megarivers, is used to find a predictive algorithm. Two distinct transport regimes emerge, separated by a discontinuous transition for median bed grain size within the very fine sand range (81 to 154 µm), whereby sediment flux decreases by up to 100-fold for coarser sand-bedded rivers compared to river with silt and very fine sand beds. Evidence suggests that the discontinuous change in sediment load originates from a transition of transport mode between mixed suspended bed load transport and suspension-dominated transport. Events that alter bed sediment size near the transition may significantly affect fluviocoastal morphology by drastically changing sediment flux, as shown by data from the Yellow River, China, which, over time, transitioned back and forth 3 times between states of high and low transport efficiency in response to anthropic activities.

Human leukocyte antigen-G upregulates immunoglobulin-like transcripts and corrects dysfunction of immune cells in immune thrombocytopenia.

Human leukocyte antigen-G (HLA-G) is a non-classical major histocompatibility complex class I antigen with potent immune-inhibitory function. HLA-G benefit patients in allotransplantation and autoimmune diseases by interacting with its receptors, immunoglobulinlike transcripts. Here we observed significantly less HLA-G in plasma from immune thrombocytopenia (ITP) patients positive for anti-platelet autoantibodies compared with autoantibodies-negative patients or healthy controls, while we found that HLA-G is positively correlated with platelet counts in both patients and healthy controls. We also found less membranebound HLA-G and immunoglobulin-like transcripts on CD4+ and CD14+ cells in patients. Recombinant HLA-G upregulated immunoglobulin-like transcript 2 expression on CD4+ and immunoglobulin-like transcript 4 on CD14+ cells. HLA-G upregulated IL-4 and IL-10, and downregulated tumor necrosis factor-a, IL-12 and IL-17 secreted by patient peripheral blood mononuclear cells, suggesting a stimulation of Th2 differentiation and downregulation of Th1 and Th17 immune response. HLA-G-modulated dendritic cells from ITP patients showed decreased expression of CD80 and CD86, and suppressed CD4+ T-cell proliferation compared to unmodulated cells. Moreover, HLA-G-modulated cells from patients induced less platelet apoptosis. HLA-G administration also significantly alleviated thrombocytopenia in a murine model of ITP. In conclusion, our data demonstrated that impaired expression of HLA-G and immunoglobulin-like transcripts is involved in the pathogenesis of ITP; recombinant HLA-G can correct this abnormality via upregulation of immunoglobulin-like transcripts, indicating that HLA-G can be a diagnostic marker and a therapeutic option for ITP.

Structural changes in the gut microbiota community of the black-necked crane (Grus nigricollis) in the wintering period.

During overwintering of black-necked cranes (Grus nigricollis), the composition and function of the gut microbiota changes are of considerable interest for understanding its environmental adaption mechanism. In this study, we characterized the structure of the gut microbiota from the black-necked crane in the Dashanbao wintering area, and compared the early-winter (November) microbiota to the late-winter (March of the next year) microbiota. The results showed that the gut microbiota diversity of black-necked crane in the early-overwintering stage was higher than that in the late-overwintering stage, but it did not reach a significant level. Gut microbiota taxonomic composition analysis showed that relative abundance of Bacteroidota increased significantly, and showed decreased Firmicutes to Bacteroidota ratio at the phylum level, meanwhile, the abundance of Lactobacillus decreased significantly at the genus level. Explain gut microbiota between the early- and late-wintering showed some differences in microbiota richness but maintained a relatively conservative microbiota structure. PICRUSt2 method was used to predict and analyze the KEGG functional abundance of 16S rDNA sequences of bacteria, it was found that the changes in gut microbiota composition increased the abundance of bacteria associated with amino acid biosynthesis and acid metabolism in the late stage of overwintering. This work provides basic data for black-necked crane gut microbiota study, which might further contribute to their protection.

A CARD9 single-nucleotide polymorphism rs4077515 is associated with reduced susceptibility to and severity of primary immune thrombocytopenia.

Primary immune thrombocytopenia (ITP) is an acquired autoimmune disease characterized by a low platelet count and consequent increased risk of bleeding. The etiology underlying this condition remains poorly understood. The aim of this study is to evaluate the association of a single nucleotide polymorphism (SNP) rs4077515 in the caspase recruitment domain-containing protein 9 (CARD9) gene with the pathogenesis and therapy of ITP. Two hundred ninety-four patients with ITP and 324 age-matched healthy participants were recruited in this case-control study. Genotyping of CARD9 rs4077515 polymorphism was performed by Sanger sequencing. Our results revealed that a polymorphism rs4077515 in CARD9 gene is associated with decreased risk of susceptibility to and severity of ITP (susceptibility: codominant, AA vs. GG, OR = 0.175, 95% CI = 0.054-0.776, p = 0.001; recessive, GG + AG vs. AA, OR = 6.183, 95% CI = 2.287-16.715, p < 0.001; severity: allele, A vs. G, OR = 0.685, 95% CI = 0.476-0.985, p = 0.041; codominant, AG vs. GG, OR = 0.571, 95% CI = 0.350-0.931, p = 0.025; dominant, AA + AG vs. GG, OR = 0.558, 95% CI = 0.343-0.907, p = 0.019). The existence of the allele A, the mutant AA genotype and the heterozygous AG genotype of CARD9 rs4077515, plays a protective role in ITP. However, CARD9 rs4077515 polymorphism had no effect on corticosteroid sensitivity or refractoriness of ITP.

MLH1 enhances the sensitivity of human endometrial carcinoma cells to cisplatin by activating the MLH1/c-Abl apoptosis signaling pathway.

BACKGROUND: MLH1 plays a critical role in maintaining the fidelity of DNA replication, and defects in human MLH1 have been reported. However, the role of MLH1 in endometrial carcinoma has not been fully investigated. Therefore, we aimed to study the role of MLH1 in the sensitivity of human endometrial carcinoma cells to cisplatin. METHODS: In this study, we detected the expression of MLH1 in Ishikawa and RL95-2 cells. MLH1-siRNA and ADV-MLH1 were adopted for the silencing and overexpression of MLH1, respectively. Real-time polymerase chain reaction, Western blotting, cell proliferation assays, and cell cycle and apoptotic analyses by flow cytometry were employed to explore the underlying mechanism. A mouse xenograft model was used to investigate the effect of MLH1 on tumor growth after treatment with cisplatin. RESULTS: Over-expression of MLH1 in Ishikawa cells dramatically increased the sensitivity of cells to cisplatin and enhanced cell apoptosis. By contrast, knockdown of MLH1 yielded the opposite effects in vitro. Mechanistically, cisplatin induced the MLH1/c-Abl apoptosis signaling pathway in ADV-MLH1-infected endometrial carcinoma cells, and these effects involved c-Abl, caspase-9, caspase-3 and PARP. Altogether, our results indicate that ADV-MLH1 might attenuate Ishikawa cell growth in vivo, resulting in increased cisplatin sensitivity. CONCLUSIONS: MLH1 may render endometrial carcinoma cells more sensitive to cisplatin by activating the MLH1/c-Abl apoptosis signaling pathway. In addition, an applicable adenovirus vector (ADV-MLH1) for MLH1 overexpression in endometrial carcinoma was generated. Thus, ADV-MLH1 might be a novel potential therapeutic target for endometrial carcinoma.

A Rapid, Sensitive, and High-throughput Method for the Simultaneous Determination of Antihypertensive Drug Combinations in Dog Plasma by UHPLC-MS/MS: The Assessment of Predicable Bioequivalence of In-vitro Dissolution Condition.

BACKGROUND: Essential hypertension is a common clinical disease and a risk factor for cardiovascular and cerebrovascular diseases. Olmesartan medoxomil, amlodipine, and hydrochlorothiazide are commonly used antihypertensive drugs. The aim of this study was to establish a robust UPLC-MS/MS method for the simultaneous determination of olmesartan medoxomil, amlodipine, and hydrochlorothiazide in dog plasma. At the same time, the release in vivo and in vitro studies were conducted, and a preliminary in vitro-in vivo correlation (IVIVC) evaluation was performed. METHODS: The bioequivalence experiment was conducted with a double-crossed design. Three major components were extracted and analyzed by UHPLC-MS/MS. With the MRM scan, olmesartan and amlodipine were quantified by fragment conversion (m/z 447.10→190.10) and (m/z 408.95→294.00) under positive ESI mode, while hydrochlorothiazide was quantified with fragment conversion (m/z 295.90→268.90) under negative ESI mode. The in vitro release studies were performed using a USP paddle, and the dissolution medium was chosen from pH 6.0 to pH 6.8 according to the BCS classification of compounds. The IVIVC was calculated using the Wagner-Nelson equation. RESULTS: The linear ranges of olmesartan, amlodipine, and hydrochlorothiazide in the plasma were 5.0-2500, 0.1-50, and 3.0-1500 ng/mL, respectively. All accuracies were within 3.8% of the target values, and the findings revealed that intra-day and inter-day accuracy was less than 12.1%. Moreover, the recoveries exceeded 88.3%, the matrix effect tests were positive, and the stability tests were positive. With the establishment of correlation, the distinguishable dissolution condition (pH 6.8) was selected as the predictable condition. CONCLUSION: The established method was suitable for the preclinical pharmacokinetic study of tripartite drugs with strong specificity and high sensitivity. Through the evaluation of IVIVC, the connection between in vivo and in vitro drug testing was initially established.

The impact of lymphadenectomy on the survival outcomes of ovarian clear cell carcinoma: A retrospective study of the SEER database and Chinese registry.

BACKGROUND: Ovarian clear cell carcinoma (OCCC) is a rare pathological type of ovarian cancer with a poor prognosis, and lymphadenectomy is controversial in patients with OCCC. The objective of this study was to evaluate the impact of lymphadenectomy on the prognosis of patients with OCCC. METHODS: In this retrospective study, we collected data from the Surveillance, Epidemiology and End Results (SEER) database and institutional registries in China. The SEER cohort included 1777 women diagnosed with OCCC between 2010 and 2019, while the Chinese cohort included 199 women diagnosed between April 2004 and April 2021. Recurrence-free survival (RFS) and overall survival (OS) were studied using Kaplan-Meier curve and Cox regression analysis. We also employed propensity score matching (PSM) to adjust for baseline imbalances between the lymphadenectomy group and the no-lymphadenectomy group. RESULTS: Multivariate cox regression analysis showed that lymphadenectomy was not associated with better overall survival (OS) in either early (hazard ratio [HR] 0.84[0.50-1.43], p = 0.528) or advanced (HR 0.78[0.50-1.21], p = 0.270) patients in the SEER cohort after PSM. Additionally, in the Kaplan-Meier curve analysis, lymphadenectomy did not significantly improve OS in both early (p = 0.28) and advanced (p = 0.49) patients in the SEER cohort after PSM. Similarly, in the Chinese cohort, lymphadenectomy had no significant effect on OS (early p = 0.22; advanced p = 0.61) or RFS (early p = 0.18; advanced p = 0.83) in both early and advanced patients. CONCLUSION: In completely homogeneous groups, lymphadenectomy in women diagnosed with OCCC had no effect on either recurrence-free survival or overall survival compared to patients without lymphadenectomy.

Metabarcoding of protozoa and helminth in black-necked cranes: a high prevalence of parasites and free-living amoebae.

Parasites and free-living amoebae (FLA) are common pathogens that pose threats to wildlife and humans. The black-necked crane (Grus nigricollis) is a near-threatened species and there is a shortage of research on its parasite diversity. Our study aimed to use noninvasive methods to detect intestinal parasites and pathogenic FLA in G. nigricollis using high-throughput sequencing (HTS) based on the 18S rDNA V9 region. A total of 38 fresh fecal samples were collected in Dashanbao, China, during the overwintering period (early-, middle I-, middle II-, and late-winter). Based on the 18S data, eight genera of parasites were identified, including three protozoan parasites: Eimeria sp. (92.1%) was the dominant parasite, followed by Tetratrichomonas sp. (36.8%) and Theileria sp. (2.6%). Five genera of helminths were found: Echinostoma sp. (100%), Posthodiplostomum sp. (50.0%), Euryhelmis sp. (26.3%), Eucoleus sp. (50.0%), and Halomonhystera sp. (2.6%). Additionally, eight genera of FLA were detected, including the known pathogens Acanthamoeba spp. (n = 13) and Allovahlkampfia spp. (n = 3). Specific PCRs were used to further identify the species of some parasites and FLA. Furthermore, the 18S data indicated significant changes in the relative abundance and genus diversity of the protozoan parasites and FLA among the four periods. These results underscore the importance of long-term monitoring of pathogens in black-necked cranes to protect this near-endangered species.

Title: Métabarcoding des protozoaires et des helminthes chez les grues à cou noir : forte prévalence de parasites et d'amibes libres. Abstract: Les parasites et les amibes libres sont des agents pathogènes courants qui constituent une menace pour la faune et les humains. La grue à cou noir (Grus nigricollis) est une espèce quasi menacée et les recherches sur sa diversité parasitaire sont insuffisantes. Notre étude visait à utiliser des méthodes non invasives pour détecter les parasites intestinaux et les amibes libres pathogènes chez G. nigricollis en utilisant le séquençage à haut débit basé sur la région V9 de l'ADNr 18S. Au total, 38 échantillons de matières fécales fraîches ont été collectés à Dashanbao, en Chine, au cours de la période d'hivernage (début, milieu I, milieu II et fin de l'hiver). Sur la base des données 18S, huit genres de parasites ont été identifiés, dont trois parasites protozoaires : Eimeria sp. (92,1 %) était le parasite dominant, suivi de Tetratrichomonas sp. (36,8 %) et Theileria sp. (2,6 %). Cinq genres d'helminthes ont été trouvés : Echinostoma sp. (100 %), Posthodiplostomum sp. (50,0 %), Euryhelmis sp. (26,3 %), Eucoleus sp. (50,0 %) et Halomonhystera sp. (2,6 %). De plus, huit genres d'amibes libres ont été détectés, y compris les agents pathogènes connus Acanthamoeba spp. (n = 13) et Allovahlkampfia spp. (n = 3). Des PCR spécifiques ont été utilisées pour identifier davantage les espèces de certains parasites et amibes libres. En outre, les données 18S ont indiqué des changements significatifs dans l'abondance relative et la diversité des genres des parasites protozoaires et des amibes au cours des quatre périodes. Ces résultats soulignent l'importance de la surveillance à long terme des agents pathogènes chez les grues à cou noir pour protéger cette espèce quasi menacée.

Radiomics-based fertility-sparing treatment in endometrial carcinoma: a review.

In recent years, with the increasing incidence of endometrial carcinoma in women of child-bearing age, to decision of whether to preserve patients' fertility during treatment has become increasingly complex, presenting a formidable challenge for both physicians and patients. Non-fertility-sparing treatment can remove lesions more thoroughly than fertility-sparing treatment. However, patients will permanently lose their fertility. In contrast, fertility-sparing treatment can treat tumors without impairing fertility, but the risk of disease progression is high as compared with non-fertility-sparing treatment. Therefore, it is extremely important to accurately identify patients who are suitable for fertility-sparing treatments. The evaluation of prognostic factors, including myometrial invasion, the presence of lymph node metastases, and histopathological type, is vital for determining whether a patient can receive fertility-sparing treatment. As a non-invasive and quantitative approach, radiomics has the potential to assist radiologists and other clinicians in determining more precise judgments with regard to the above factors by extracting imaging features and establishing predictive models. In this review, we summarized currently available fertility-sparing strategies and reviewed the performance of radiomics in predicting risk factors associated with fertility-sparing treatment. This review aims to assist clinicians in identifying patients suitable for fertility-sparing treatment more accurately and comprehensively and informs more appropriate and rigorous treatment decisions for endometrial cancer patients of child-bearing age.Critical relevance statement: Radiomics is a promising tool that may assist clinicians identify risk factors about fertility-sparing more accurately and comprehensively.

Scenario-based multi-objective optimization of reservoirs in silt-laden rivers: A case study in the Lower Yellow River.

Severe sedimentation often takes place in the river channel of silt-laden rivers, which is often mitigated through water-sediment regulation of the reservoirs. However, watersediment regulation is often competitive with other objectives of reservoirs, like water supply and hydropower generation; on the other hand, the reduction of channel sedimentation is often achieved at the expense of reservoir sedimentation, which reduces the service life of reservoirs. The Yellow River used to be the river with largest sediment transport over the world, but has experienced significant declination of runoff and sediment in recent years. This study presents a scenario-based multi-objective optimization operation model for the Xiaolangdi reservoir considering hydropower generation, reservoir sedimentation and channel sedimentation, with a generalized linear model coupled to calculate channel sedimentation based on runoff and sediment time series. A stochastic model that can reproduce both spatial correlations and low frequency attributes of the data series is adopted to generate two different scenarios based on different periods of observation and the performance of the multi-objective operation model under different scenarios is tested. The results indicate that: (1) the proposed optimization model can generate different schemes of reservoir operation and enhance operation performance; (2) the generalized linear model can well fit the relationship between daily channel sedimentation and runoff-sediment factors, but tends to overestimate the erosion efficiency after 2005; (3) the reservoir sedimentation and channel sedimentation show linear competitive relation, i.e., an average increase of 1 ton in reservoir sedimentation would result in declination of channel sedimentation from 0.455 to 0.488 tons, while the competitive relationship between hydropower generation and reservoir sedimentation is non-linear and weak; (4) the increase in the proportion of non-flood sediment load to the total sediment load makes it more difficult to prevent the reservoir from silting up.

Simultaneous and trace level quantification of two potential genotoxic impurities in valsartan drug substance using UPLC-MS/MS.

A sensitive and selective Ultra-performance liquid chromatography-mass spectrometry (UPLC-MS/MS) method was developed for the identification and quantification of two potential genotoxic impurities (PGIs) - viz. methyl N-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-N-nitroso-L-valinate (PGI-1) and N-nitroso Valsartan (PGI-2) - in the angiotensin II receptor blocker valsartan. Among these impurities, PGI-1 is a distinctive compound which has never been reported. For this, chromatographic separation was performed using a Waters XBridge BEH C18 column (150 mm × 4.6 mm, 2.5 µm), with ammonium acetate aqueous solution (0.01 mol/L) as mobile phase A and acetonitrile as mobile phase B, in a gradient elution mode at a 0.5 mL/min flow rate. Mass spectrometric conditions were optimized using electrospray ionization (ESI) in positive mode. Following the International Conference of Harmonization (ICH) guidelines, this methodology is capable of quantifying 2 PGIs at 0.016 ppm in samples at 50 mg/mL concentration. This validated approach presented good linearity over the concentration range of 0.016-0.06 ppm for 2 PGIs. The correlation coefficient of each impurity was observed greater than 0.999. The accuracy of this method was in the range of 83-113% for the aforementioned PGIs. In addition, expert knowledge rules (Derek-based) and statistical (Q) SAR evaluation system (Sarah-based) were used to evaluate and classify the genotoxicity of both valsartan-related PGIs as well as to define their standard limits. The predicted results were positive and classified into the third category, and the total nitrosamine limit was set to 0.03 ppm. As such, this approach represents a good quality control system for the simultaneous and precise quantitation of PGIs in valsartan.

Amplification of downstream flood stage due to damming of fine-grained rivers.

River dams provide many benefits, including flood control. However, due to constantly evolving channel morphology, downstream conveyance of floodwaters following dam closure is difficult to predict. Here, we test the hypothesis that the incised, enlarged channel downstream of dams provides enhanced water conveyance, using a case study from the lower Yellow River, China. We find that, although flood stage is lowered for small floods, counterintuitively, flood stage downstream of a dam can be amplified for moderate and large floods. This arises because bed incision is accompanied by sediment coarsening, which facilitates development of large dunes that increase flow resistance and reduce velocity relative to pre-dam conditions. Our findings indicate the underlying mechanism for such flood amplification may occur in >80% of fine-grained rivers, and suggest the need to reconsider flood control strategies in such rivers worldwide.

Probing cell metabolism on insulin like growth factor(IGF)-1/tumor necrosis factor(TNF)-α and chargeable polymers co-immobilized conjugates.

Cell culturing on different synthetic biomaterials would reprogram cell metabolism for adaption to their living conditions because such alterations in cell metabolism were necessary for cellular functions on them. Here we used metabolomics to uncover metabolic changes when liver cells were cultured on insulin-like growth factor (IGF)/tumor necrosis factor-α (TNF-α) and chargeable polymers co-modified biomaterials with the aim to explain their modulating effects on cell metabolism. The results showed that cell metabolism on IGF-1/TNF-α co-immobilized conjugates was significantly regulated according to their scatterings on the score plot of principal component analysis. Specifically, cell metabolisms were reprogrammed to the higher level of pyrimidine metabolism, ß-alanine metabolism, and pantothenate and CoA biosynthesis, and the lower level of methionine salvage pathway in order to promote cell growth on IGF/TNF-α co-modified surface. Furthermore, cell senescence on PSt-PAAm-IGF/TNF-α surface was delayed through the regulation of branch amino acid metabolism and AMPK signal pathway. The research showed that metabolomics had great potential to uncover the molecular interaction between biomaterials and seeded cells, and provide the insights about cell metabolic reprogramming on IGF/TNF-α co-modified conjugates for cell growth.

EIF5A2 enhances stemness of epithelial ovarian cancer cells via a E2F1/KLF4 axis.

BACKGROUND: Ovarian cancer stem cells (OCSC), endowed with tumor-initiating and self-renewal capacity, would account not only for the tumor growth, the peritoneal metastasis, and the relapse, but also for the acquisition of chemotherapy resistance. Nevertheless, figuring out their phenotypical and functional traits has proven quite challenging, mainly because of the heterogeneity of ovarian cancer. A deeper understanding of OCSC mechanisms will shed light on the development of the disease. Therefore, we aim to explore it for the design of innovative treatment regimens which aim at the eradication of ovarian cancer through the elimination of the CSC component. METHODS: In this study, immunohistochemistry assay and western blot assay were used to detect protein expression in the primary tumor and peritoneal multi-cellular aggregates/spheroids (MCAs/MCSs). OCSCs induced from cell line SKOV3 and HO-8910 were enriched in a serum-free medium (SFM). The effect of EIF5A2 on CSC-like properties was detected by sphere-forming assays, re-differentiation assays, quantitative real-time polymerase chain reaction, western blotting, flow cytometry, cell viability assays, immunofluorescence staining, and in vivo xenograft experiments. RNA-sequencing (RNA-seq) was used to reveal the mechanism by which EIF5A2 positively modulates the stem-like properties of ovarian cancer cells. RESULTS: Expression of EIF5A2 was significantly higher in peritoneal MCAs/MCSs compared to matched primary tumors, and EIF5A2 was also unregulated in ovarian cancer cell line-derived spheroids. Knockdown of EIF5A2 reduced the expression of the stem-related markers (ALDH1A1 and OCT-4), inhibited self-renewal ability, improved the sensitivity to chemotherapeutic drugs, and inhibited tumorigenesis in vivo. Mechanistic studies revealed that EIF5A2 knockdown reduced the expression of KLF4, which could partially rescue stem-like properties abolished by EIF5A2 knockdown or strengthened by EIF5A2 overexpression, through the transcription factor E2F1, which directly bind to KLF4 promoter. CONCLUSION: Our results imply that EIF5A2 positively regulates stemness in ovarian cancer cells via E2F1/KLF4 pathway and may serve as a potential target in CSCs-targeted therapy for ovarian cancer.

HDAC6, modulated by miR-206, promotes endometrial cancer progression through the PTEN/AKT/mTOR pathway.

Endometrial cancer (EC) is the sixth most common cancer in women. Since early EC has a good prognosis, identifying methods for early diagnosis is valuable. Here, we aimed to study the role of HDAC6, which has been indicated important in many kinds of cancers, in EC diagnosis and therapy. First, the expression levels of HDAC6 in EC tissues and cells were measured by qRT-PCR and Western blotting, and through bioinformatics and dual luciferase assays, HDAC6 was found to be a direct target of miR-206. Then, CCK-8, colony formation, wound healing, and Transwell assays were performed; these results indicated that HDAC6 promoted EC cell proliferation, metastasis and invasion, while miR-206 produced the opposite effects. In addition, rescue assays verified that the effect of miR-206 could be reversed by HDAC6, and global gene expression analysis confirmed the relationship between miR-206 and HDAC6. Finally, we measured the levels of PTEN, p-AKT and p-mTOR and other key molecules and speculated that miR-206 might target HDAC6 to suppress EC progression via the PTEN/AKT/mTOR pathway. In conclusion, downregulation of miR-206 and upregulation of HDAC6 in EC may predict poor prognosis, and as the target gene of miR-206, HDAC achieves its carcinogenic effect through the PTEN/AKT/mTOR pathway.

Adjuvant chemoradiotherapy versus radiotherapy in cervical cancer patients with intermediate-risk factors: A systematic review and meta-analysis.

BACKGROUND: At present, extensive hysterectomy and pelvic lymph node dissection are preferred for early-stage cervical cancer. However, additional adjuvant therapy could be considered if there is a risk for recurrence. Postoperative pelvic radiotherapy plus concurrent platinum-based chemotherapy are recommended for patients with high risk factors. The treatment regimen for patients with intermediate-risk factors, however, remains unclear. We, thus, performed a systematic review and meta-analysis to assess the recurrence-free survival (RFS), overall survival (OS), grade III/IV hematologic toxicity and grade III/IV non-hematologic toxicity in chemoradiotherapy (CRT) versus radiotherapy (RT) groups. METHODS: We systematically searched PubMed, Cochrane, and Embase to identify relevant studies published before November 30, 2018 to compare CRT with RT as a postoperative adjuvant therapy in early-stage cervical cancer patients with intermediate-risk factors. We used Stata (version 14.0) to calculate odds risks (ORs) and 95% confidence intervals (CIs) and pooled data was assessed by the fixed-effects model. RESULTS: Of the 428 identified studies, only 9 were eligible and included in our analysis (CRT: n = 870; RT: n = 932). CRT significantly prolonged RFS (OR = 3.43, 95% CI 2.08-5.67, P = 0.000) and OS (OR = 1.80, 95% CI 1.30-2.50, P = 0.000). The occurrence rate of grade III/IV hematologic toxicity (OR = 16.07, 95% CI 6.47-39.93, P = 0.000) was significantly higher in CRT, while grade III/IV non-hematologic toxicity was ambiguous for CRT and RT with an OR of 1.91 (95% CI 0.95-3.83, P = 0.069). CONCLUSIONS: For early-stage cervical cancer patients with intermediate-risk factors, CRT can dramatically improve RFS and OS compared with RT. Apart from the increase in grade III/IV hematologic toxicity, CRT was well tolerated and accepted treatment for early-stage cervical cancer.

Adenovirus-mediated down-regulation of miR-21-5p alleviates experimental autoimmune uveoretinitis in mice.

MiR-21-5p has been found to be up-regulated in the retina of experimental autoimmune uveoretinitis (EAU) mice and correlated with the pathogenesis of EAU. The objective of the present study is to explore the role of miR-21-5p in EAU. C57 mice were immunized with residue1-20 (IRBP1-20) in complete Freund's adjuvant supplemented with Mycobacterium tuberculosis H37Ra to induce EAU, and miR-21-5p was knocked down via subretinal injection of anti-miR-21-5p adenovirus. The pathological score, TUNEL positive cells and the expression of pro-inflammatory factors in the retina were reduced, and the expression of IL-10 was increased by down-regulation of miR-21-5p. Up-regulation of miR-21-5p significantly decreased the mRNA and protein levels of IL-10 in ARPE-19 cells. The binding activity of miR-21-5p on the 3'UTR of IL-10 mRNA was confirmed by luciferase reporter assay. Moreover, the miR-21-5p level in splenic lymphocytes of EAU mice was increased at the 7th day after immunization and reached its peak at the 14th day, that was in accordance with the changing trend with the Th17 cell frequency in the spleen. Besides, lentivirus-mediated down-regulation of miR-21-5p reduced the Th17 cell frequency and increased the Treg cell fraction of IRBP1-20-stimulated lymphocytes in vitro. Taken together, in situ down-regulation of miR-21-5p attenuates EAU by inhibiting inflammatory responses and reducing retinal cell apoptosis. miR-21-5p may also participate in the progress of EAU by affecting Th17/Treg balance via the regulation of IL-10. Therefore, we demonstrate that miR-21-5p can serve as a therapeutic target in the management of uveitis and other autoimmune diseases.