Reactivating Hippo by drug compounds to suppress gastric cancer and enhance chemotherapy sensitivity.

The Hippo signaling pathway plays an essential role in organ size control and tumorigenesis. Loss of Hippo signal and hyper-activation of the downstream oncogenic YAP signaling are commonly observed in various types of cancers. We previously identified STRN3-containing PP2A phosphatase as a negative regulator of MST1/2 kinases (i.e., Hippo) in gastric cancer (GC), opening the possibility of selectively targeting the PP2Aa-STRN3-MST1/2 axis to recover Hippo signaling against cancer. Here, we further discovered 1) disulfiram (DSF), an FDA-approved drug, which can similarly block the binding of STRN3 to PP2A core enzyme and 2) CX-6258 (CX), a chemical inhibitor, that can disrupt the interaction between STRN3 and MST1/2, both allowing reactivation of Hippo activity to inhibit GC. More importantly, we found these two compounds, via an MST1/2 kinase-dependent manner, inhibit DNA repair to sensitize GC towards chemotherapy. In addition, we identified thiram, a structural analog of DSF, can function similarly to inhibit cancer cell proliferation or enhance chemotherapy sensitivity. Interestingly, inclusion of copper ion enhanced such effects of DSF and thiram on GC treatment. Overall, this work demonstrated that pharmacological targeting of the PP2Aa-STRN3-MST1/2 axis by drug compounds can potently recover Hippo signal for tumor treatment.

Betaine regulates adipogenic and osteogenic differentiation of hAD-MSCs.

BACKGROUND: With an ageing population, the incidence of bone loss and obesity are increasing. Numerous studies emphasized the multidirectional differentiation ability of mesenchymal stem cells (MSCs), and reported betaine modulated the osteogenic differentiation and adipogenic differentiation of MSCs in vitro. We wondered how betaine affected the differentiation of hAD-MSCs and hUC-MSCs. METHODS AND RESULTS: ALP staining and alizarin red S (ARS) staining were proved 10 mM betaine significantly increased the number of ALP-positive cells and plaque calcified extracellular matrices, accompanying by the up-regulation of OPN, Runx-2 and OCN. Oil red O staining demonstrated the number and size of lipid droplets were reduced, the expression of adipogenic master genes such as PPARγ, CEBPα and FASN were down-regulated simultaneously. For further investigating the mechanism of betaine on hAD-MSCs, RNA-seq was performed in none-differentiation medium. The Gene Ontology (GO) analysis showed fat cell differentiation and bone mineralization function terms were enriched, and KEGG showed PI3K-Akt signaling pathway, cytokine-cytokine receptor interaction and ECM-receptor interaction pathways were enriched in betaine treated hAD-MSCs, demonstrated betaine had a positive inducing effect on osteogenic of hAD-MSCs in the non-differentiation medium in vitro, which is opposite to the effect on adipogenic differentiation. CONCLUSIONS: Our study demonstrated that betaine promoted osteogenic and compromised adipogenic differentiation of hUC-MSCs and hAD-MSCs upon low concentration administration. PI3K-Akt signaling pathway, cytokine-cytokine receptor interaction and ECM-receptor interaction were significantly enriched under betaine-treated. We showed hAD-MSCs were more sensitive to betaine stimulation and have a better differentiation ability than hUC-MSCs. Our results contributed to the exploration of betaine as an aiding agent for MSCs therapy.

Long-term exposure to ambient ozone at workplace is positively and non-linearly associated with incident hypertension and blood pressure: longitudinal evidence from the Beijing-Tianjin-Hebei medical examination cohort.

BACKGROUND: There is limited longitudinal evidence on the hypertensive effects of long-term exposure to ambient O3. We investigated the association between long-term O3 exposure at workplace and incident hypertension, diastolic blood pressure (DBP), systolic blood pressure (SBP), pulse pressure (PP), and mean arterial pressure (MAP) in general working adults. METHODS: We conducted a cohort study by recruiting over 30,000 medical examination attendees through multistage stratified cluster sampling. Participants completed a standard questionnaire and comprehensive medical examination. Three-year ambient O3 concentrations at each employed participant's workplace were estimated using a two-stage machine learning model. Mixed-effects Cox proportional hazards models and linear mixed-effects models were used to examine the effect of O3 concentrations on incident hypertension and blood pressure parameters, respectively. Generalized additive mixed models were used to explore non-linear concentration-response relationships. RESULTS: A total of 16,630 hypertension-free working participants at baseline finished the follow-up. The mean (SD) O3 exposure was 45.26 (2.70) ppb. The cumulative incidence of hypertension was 7.11 (95% CI: 6.76, 7.47) per 100 person-years. Long-term O3 exposure was independently, positively and non-linearly associated with incident hypertension (Hazard ratios (95% CI) for Q2, Q3, and Q4 were 1.77 (1.34, 2.36), 2.06 (1.42, 3.00) and 3.43 (2.46, 4.79), respectively, as compared with the first quartile (Q1)), DBP (ß (95% CI) was 0.65 (0.01, 1.30) for Q2, as compared to Q1), SBP (ß (95% CI) was 2.88 (2.00, 3.77), 2.49 (1.36, 3.61) and 2.61 (1.64, 3.58) for Q2, Q3, and Q4, respectively), PP (ß (95% CI) was 2.12 (1.36, 2.87), 2.03 (1.18, 2.87) and 2.14 (1.38, 2.90) for Q2, Q3, and Q4, respectively), and MAP (ß (95% CI) was 1.39 (0.76, 2.02), 1.04 (0.24, 1.84) and 1.12 (0.43, 1.82) for Q2, Q3, and Q4, respectively). The associations were robust across sex, age, BMI, and when considering PM2.5 and NO2. CONCLUSIONS: To our knowledge, this is the first cohort study in the general population that demonstrates the non-linear hypertensive effects of long-term O3 exposure. The findings are particularly relevant for policymakers and researchers involved in ambient pollution and public health, supporting the integration of reduction of ambient O3 into public health interventions.

Revitalizing Iron Redox by Anion-Insertion-Assisted Ferro- and Ferri-Hydroxides Conversion at Low Alkalinity.

Iron hydroxides are desirable alkaline battery electrodes for low cost and environmental beneficence. However, hydrogen evolution on charging and Fe3O4 formation on discharging cause low storage capacity and poor cycling life. We report that green rust (GR) (Fe2+4Fe3+2 (HO-)12SO4), formed via sulfate insertion, promotes Fe(OH)2/FeOOH conversion and shows a discharge capacity of ∼211 mAh g-1 in half-cells and Coulombic efficiency of 93% after 300 cycles in full-cells. Theoretical calculations show that Fe(OH)2/FeOOH conversion is facilitated by intercalated sulfate anions. Classical molecular dynamics simulations reveal that electrolyte alkalinity strongly impacts the energetics of sulfate solvation, and low alkalinity ensures fast transport of sulfate ions. Anion-insertion-assisted Fe(OH)2/FeOOH conversion, also achieved with Cl- ion, paves a pathway toward efficient utilization of Fe-based electrodes for sustainable applications.

The effect of gradient nonlinearities on fiber orientation estimates from spherical deconvolution of diffusion magnetic resonance imaging data.

Gradient nonlinearities in magnetic resonance imaging (MRI) cause spatially varying mismatches between the imposed and the effective gradients and can cause significant biases in rotationally invariant diffusion MRI measures derived from, for example, diffusion tensor imaging. The estimation of the orientational organization of fibrous tissue, which is nowadays frequently performed with spherical deconvolution techniques ideally using higher diffusion weightings, can likewise be biased by gradient nonlinearities. We explore the sensitivity of two established spherical deconvolution approaches to gradient nonlinearities, namely constrained spherical deconvolution (CSD) and damped Richardson-Lucy (dRL). Additionally, we propose an extension of dRL to take into account gradient imperfections, without the need of data interpolation. Simulations show that using the effective b-matrix can improve dRL fiber orientation estimation and reduces angular deviations, while CSD can be more robust to gradient nonlinearity depending on the implementation. Angular errors depend on a complex interplay of many factors, including the direction and magnitude of gradient deviations, underlying microstructure, SNR, anisotropy of the effective response function, and diffusion weighting. Notably, angular deviations can also be observed at lower b-values in contrast to the perhaps common assumption that only high b-value data are affected. In in vivo Human Connectome Project data and acquisitions from an ultrastrong gradient (300 mT/m) scanner, angular differences are observed between applying and not applying the effective gradients in dRL estimation. As even small angular differences can lead to error propagation during tractography and as such impact connectivity analyses, incorporating gradient deviations into the estimation of fiber orientations should make such analyses more reliable.

Spherical deconvolution with tissue-specific response functions and multi-shell diffusion MRI to estimate multiple fiber orientation distributions (mFODs).

In diffusion MRI, spherical deconvolution approaches can estimate local white matter (WM) fiber orientation distributions (FOD) which can be used to produce fiber tractography reconstructions. The applicability of spherical deconvolution to gray matter (GM), however, is still limited, despite its critical role as start/endpoint of WM fiber pathways. The advent of multi-shell diffusion MRI data offers additional contrast to model the GM signal but, to date, only isotropic models have been applied to GM. Evidence from both histology and high-resolution diffusion MRI studies suggests a marked anisotropic character of the diffusion process in GM, which could be exploited to improve the description of the cortical organization. In this study, we investigated whether performing spherical deconvolution with tissue specific models of both WM and GM can improve the characterization of the latter while retaining state-of-the-art performances in WM. To this end, we developed a framework able to simultaneously accommodate multiple anisotropic response functions to estimate multiple, tissue-specific, fiber orientation distributions (mFODs). As proof of principle, we used the diffusion kurtosis imaging model to represent the WM signal, and the neurite orientation dispersion and density imaging (NODDI) model to represent the GM signal. The feasibility of the proposed approach is shown with numerical simulations and with data from the Human Connectome Project (HCP). The performance of our method is compared to the current state of the art, multi-shell constrained spherical deconvolution (MSCSD). The simulations show that with our new method we can accurately estimate a mixture of two FODs at SNR≥50. With HCP data, the proposed method was able to reconstruct both tangentially and radially oriented FODs in GM, and performed comparably well to MSCSD in computing FODs in WM. When performing fiber tractography, the trajectories reconstructed with mFODs reached the cortex with more spatial continuity and for a longer distance as compared to MSCSD and allowed to reconstruct short trajectories tangential to the cortical folding. In conclusion, we demonstrated that our proposed method allows to perform spherical deconvolution of multiple anisotropic response functions, specifically improving the performances of spherical deconvolution in GM tissue.

Generalized Richardson-Lucy (GRL) for analyzing multi-shell diffusion MRI data.

Spherical deconvolution is a widely used approach to quantify the fiber orientation distribution (FOD) from diffusion MRI data of the brain. The damped Richardson-Lucy (dRL) is an algorithm developed to perform robust spherical deconvolution on single-shell diffusion MRI data while suppressing spurious FOD peaks due to noise or partial volume effects. Due to recent progress in acquisition hardware and scanning protocols, it is becoming increasingly common to acquire multi-shell diffusion MRI data, which allows for the modelling of multiple tissue types beyond white matter. While the dRL algorithm could, in theory, be directly applied to multi-shell data, it is not optimised to exploit its information content to model the signal from multiple tissue types. In this work, we introduce a new framework based on dRL - dubbed generalized Richardson-Lucy (GRL) - that uses multi-shell data in combination with user-chosen tissue models to disentangle partial volume effects and increase the accuracy in FOD estimation. Further, GRL estimates signal fraction maps associated to each user-selected model, which can be used during fiber tractography to dissect and terminate the tracking without need for additional structural data. The optimal weighting of multi-shell data in the fit and the robustness to noise and to partial volume effects of GRL was studied with synthetic data. Subsequently, we investigated the performance of GRL in comparison to dRL and to multi-shell constrained spherical deconvolution (MSCSD) on a high-resolution diffusion MRI dataset from the Human Connectome Project and on an MRI dataset acquired at 3T on a clinical scanner. In line with previous studies, we described the signal of the cerebrospinal-fluid and of the grey matter with isotropic diffusion models, whereas four diffusion models were considered to describe the white matter. With a third dataset including small diffusion weightings, we studied the feasibility of including intra-voxel incoherent motion effects due to blood pseudo-diffusion in the modelling. Further, the reliability of GRL was demonstrated with a test-retest scan of a subject acquired at 3T. Results of simulations show that GRL can robustly disentangle different tissue types at SNR above 20 with respect to the non-weighted image, and that it improves the angular accuracy of the FOD estimation as compared to dRL. On real data, GRL provides signal fraction maps that are physiologically plausible and consistent with those obtained with MSCSD, with correlation coefficients between the two methods up to 0.96. When considering IVIM effects, a high blood pseudo-diffusion fraction is observed in the medial temporal lobe and in the sagittal sinus. In comparison to dRL and MSCSD, GRL provided sharper FODs and less spurious peaks in presence of partial volume effects, but the FOD reconstructions are also highly dependent on the chosen modelling of white matter. When performing fiber tractography, GRL allows to terminate fiber tractography using the signal fraction maps, which results in a better tract termination at the grey-white matter interface or at the outer cortical surface. In terms of inter-scan reliability, GRL performed similarly to or better than compared methods. In conclusion, GRL offers a new modular and flexible framework to perform spherical deconvolution of multi-shell data.

Hydroxysteroid sulfotransferase 2B1 affects gastric epithelial function and carcinogenesis induced by a carcinogenic agent.

BACKGROUND: A healthy gastric mucosal epithelium exhibits tumor-suppressive properties. Gastric epithelial cell dysfunction contributes to gastric cancer development. Oxysterols provided from food or cholesterol oxidation in the gastric epithelium may be further sulfated by hydroxysteroid sulfotransferase 2B1 (SULT2B1), which is highly abundant in the gastric epithelium. However, the effects of SULT2B1 on gastric epithelial function and gastric carcinogenesis are unclear. METHODS: A mouse gastric tumor model was established using carcinogenic agent 3-methylcholanthrene (3-MCA). A SULT2B1 deletion (SULT2B1-/-) human gastric epithelial line GES-1 was constructed by CRISPR/CAS9 genome editing system. RESULTS: The gastric tumor incidence was higher in the SULT2B1-/- mice than in the wild-type (WT) mice. In gastric epithelial cells, adenovirus-mediated SULT2B1b overexpression reduced the levels of oxysterols, such as 24(R/S),25-epoxycholesterol (24(R/S),25-EC) and 27-hydroxycholesterol (27HC). This condition also increased PI3K/AKT signaling to promote gastric epithelial cell proliferation, epithelization, and epithelial development. However, SULT2B1 deletion or SULT2B1 knockdown suppressed PI3K/AKT signaling, epithelial cell epithelization, and wound healing and induced gastric epithelial cell malignant transition upon 3-MCA induction. CONCLUSIONS: The abundant SULT2B1 expression in normal gastric epithelium might maintain epithelial function via the PI3K/AKT signaling pathway and suppress gastric carcinogenesis induced by a carcinogenic agent.

Upregulation of 24(R/S),25-epoxycholesterol and 27-hydroxycholesterol suppresses the proliferation and migration of gastric cancer cells.

Gastric cancer (GC) is one of the most common cancers and is the second-leading cause of cancer-associated morbidity worldwide. Oxysterols are oxidized derivatives of cholesterol that may be important in many biological processes, but the levels and roles of oxysterols in gastric tumours remain to be elucidated. The levels of cholesterol, oxysterols and sulfated oxysterols in human gastric tumour tissues, adjacent normal mucosal tissues, cancerous gastric juice and gastric juice obtained from healthy subjects were detected by LC-MS. It was found that the levels of 24(R/S),25-EC and 27HC in human gastric tumour tissues and cancerous gastric juice were significantly increased compared with those of adjacent normal mucosal tissues and gastric juice from healthy subjects. Compared with normal gastric mucosal tissue, the levels of sulfated 25-hydroxycholesterol (25HC3S) and the ratio of 25HC3S/25HC were decreased in human gastric tumour tissues, which might be related to the dramatically decreased SULT2A1 expression in gastric tumour tissue. Both 24(R/S),25-EC and 27HC suppressed gastric cancer proliferation, which was not altered by LXRα-siRNA treatment. The suppression of cell proliferation induced by 27HC was attenuated by LXRß-siRNA, but the suppression of cell proliferation induced by 24(R/S),25-EC was intensified by LXRß-siRNA. Both 24(R/S),25-EC and 27HC dramatically inhibited HGC-27 cell migration, which was attenuated by the co-transfection of cells with LXRα-siRNA and LXRß-siRNA, but not LXRα-siRNA or LXRß-siRNA alone. In conclusion, the accumulated 24(R/S),25-EC and 27HC in human gastric tumour tissues might play important roles in gastric cancer development.

Unlocking High Capacity and Reversible Alkaline Iron Redox using Silicate-Sodium Hydroxide Hybrid Electrolytes.

Alkaline iron (Fe) batteries are attractive due to the high abundance, low cost, and multiple valent states of Fe but show limited columbic efficiency and storage capacity when forming electrochemically inert Fe3O4 on discharging and parasitic H2 on charging. Herein, sodium silicate is found to promote Fe(OH)2/FeOOH against Fe(OH)2/Fe3O4 conversions. Electrochemical experiments, operando X-ray characterization, and atomistic simulations reveal that improved Fe(OH)2/FeOOH conversion originates from (i) strong interaction between sodium silicate and iron oxide and (ii) silicate-induced strengthening of hydrogen-bond networks in electrolytes that inhibits water transport. Furthermore, the silicate additive suppresses hydrogen evolution by impairing energetics of water dissociation and hydroxyl de-sorption on iron surfaces. This new silicate-assisted redox chemistry mitigates H2 and Fe3O4formation, improving storage capacity (199 mAh g-1 in half-cells) and coulombic efficiency (94% after 400 full-cell cycles), paving a path to realizing green battery systems built from earth-abundant materials.

Both miR-17-5p and miR-20a alleviate suppressive potential of myeloid-derived suppressor cells by modulating STAT3 expression.

Myeloid-derived suppressor cells (MDSCs) were one of the major components of the immune suppressive network. STAT3 has an important role in regulating the suppressive potential of MDSCs. In this study, we found that the expression of STAT3 could be modulated by both miR-17-5p and miR-20a. The transfection of miR-17-5p or miR-20a remarkably reduces the expression of reactive oxygen species and the production of H(2)O(2), which are regulated by STAT3. MDSCs transfected with miR-17-5p or miR-20a are less able to suppress Ag-specific CD4 and CD8 T cells. Importantly, both miR-17-5p and miR-20a alleviate the suppressive function of MDSCs in vivo. The expression of miR-17-5p and miR-20a in tumor-associated MDSCs was found to be lower than in Gr1(+)CD11b(+) cells isolated from the spleens of disease-free mice. Tumor-associated factor downregulates the expression of both miR-17-5p and miR-20a. The modulation of miR-17-5p and miR-20a expression may be important for the process by which patients with a tumor can overcome the immune tolerance mediated by MDSCs. Our results suggest that miR-17-5p and miR-20a could potentially be used for immunotherapy against diseases, especially cancer, by blocking STAT3 expression.

hTERT rs2736098 genetic variants and susceptibility of hepatocellular carcinoma in the Chinese population: a case-control study.

BACKGROUND: The human telomerase reverse transcriptase (hTERT) gene encodes the catalytic subunit of telomerase, which mediates pleiotropic effects, including the regulation of senescence and proliferation and plays an important role in carcinogenesis. This study attempts to clarify the genetic predisposition to hepatocellular carcinoma (HCC), focusing on the hTERT gene rs2736098 polymorphism. METHOD: Four hundred patients with HCC and 400 non-cancer controls were genotyped to elucidate the potential association between hTERT rs2736098 polymorphism and HCC risks. RESULTS: Compared with the controls, the patients with HCC had a lower frequency of G/G genotype (33.3% vs 44.3%, P=0.001) and a higher frequency of G/A (51.5% vs 39.5%, P=0.001). Allele genotypic frequencies in the patients differed from those of the controls (P=0.040). The data of this study rs2736098[A] allele contributed significantly to HCC risk in female patients (OR=1.78, 95% CI, 1.17-2.72, P=0.007), patients with HCV infection (OR=2.89, 95% CI, 1.08-7.70, P=0.031), non-drinker patients (OR=1.32, 95% CI, 1.06-1.65, P=0.015), and patients not affected by HBV (OR=1.77, 95% CI, 1.30-2.40, P<0.001). CONCLUSIONS: rs2736098[A] may be an independent hereditary parameter in HCC, but some risk factors would cover up the association by more powerful hepatocarcinogenesis. These results are important guidance for further studies in detecting HCC-associated single nucleotide polymorphisms.

Habitual night sleep duration is associated with general obesity and visceral obesity among Chinese women, independent of sleep quality.

Purpose: Research on the relationship between sleep duration and obesity defined using multiple anthropometric and bioelectrical indices in women remains scarce. We aimed to explore the association between sleep duration and body mass index (BMI), waist-hip ratio (WHR), body fat percentage (PBF) and visceral fat area (VFA) among females. Methods: We recruited women for medical examination using multistage cluster sampling. Sleep was assessed using Pittsburgh Sleep Quality Index (PSQI) and sleep duration was categorized into short (<7 h), optimal (7 <9 h) and long sleep (≥ 9 h). Weight and height were measured using a calibrated stadiometer. Waist circumference was manually measured. PBF, and VFA were estimated by bioelectrical impedance analysis. Data on sociodemographic characteristics and lifestyle factors were also collected and included in the logistic regression models to explore the independent association between sleep duration and obesity defined by different indices. Results: A total of 7,763 women with a mean age of 42.6 ± 13.5 years were included. The percentage of women reporting short and long sleep was 10.3 and 13.4% respectively. The mean BMI, WHR, PBF and VFA were 23.07 ± 3.30 kg/m2, 0.78 ± 0.06, 32.23 ± 6.08% and 91.64 ± 35.97cm2, respectively. Short sleep was independently associated with 35% (95% CI: 1.05-1.75) increased odds of general obesity (BMI ≥ 28 kg/cm2), and long sleep was associated with 18% (95% CI: 1.01-1.37) increased odds of visceral obesity (VFA > 100 cm2). No association was observed between sleep deprivation or excessive sleep and high WHR or high PBF. Conclusion: In women, short sleep was associated with an increased odds of general obesity, whereas long sleep was associated with an increased odds of visceral obesity. Longitudinal observations are needed to confirm this cross-sectional relationship.

SUN1/2 controls macrophage polarization via modulating nuclear size and stiffness.

Alteration of the size and stiffness of the nucleus triggered by environmental cues are thought to be important for eukaryotic cell fate and function. However, it remains unclear how context-dependent nuclear remodeling occurs and reprograms gene expression. Here we identify the nuclear envelope proteins SUN1/2 as mechano-regulators of the nucleus during M1 polarization of the macrophage. Specifically, we show that LPS treatment decreases the protein levels of SUN1/2 in a CK2-ßTrCP-dependent manner to shrink and soften the nucleus, therefore altering the chromatin accessibility for M1-associated gene expression. Notably, the transmembrane helix of SUN1/2 is solely required and sufficient for the nuclear mechano-remodeling. Consistently, SUN1/2 depletion in macrophages facilitates their phagocytosis, tissue infiltration, and proinflammatory cytokine production, thereby boosting the antitumor immunity in mice. Thus, our study demonstrates that, in response to inflammatory cues, SUN1/2 proteins act as mechano-regulators to remodel the nucleus and chromatin for M1 polarization of the macrophage.

A YAP/TAZ-CD54 axis is required for CXCR2-CD44- tumor-specific neutrophils to suppress gastric cancer.

As an important part of tumor microenvironment, neutrophils are poorly understood due to their spatiotemporal heterogeneity in tumorigenesis. Here we defined, at single-cell resolution, CD44-CXCR2- neutrophils as tumor-specific neutrophils (tsNeus) in both mouse and human gastric cancer (GC). We uncovered a Hippo regulon in neutrophils with unique YAP signature genes (e.g., ICAM1, CD14, EGR1) distinct from those identified in epithelial and/or cancer cells. Importantly, knockout of YAP/TAZ in neutrophils impaired their differentiation into CD54+ tsNeus and reduced their antitumor activity, leading to accelerated GC progression. Moreover, the relative amounts of CD54+ tsNeus were found to be negatively associated with GC progression and positively associated with patient survival. Interestingly, GC patients receiving neoadjuvant chemotherapy had increased numbers of CD54+ tsNeus. Furthermore, pharmacologically enhancing YAP activity selectively activated neutrophils to suppress refractory GC, with no significant inflammation-related side effects. Thus, our work characterized tumor-specific neutrophils in GC and revealed an essential role of YAP/TAZ-CD54 axis in tsNeus, opening a new possibility to develop neutrophil-based antitumor therapeutics.

Effect of estrogen sulfation by SULT1E1 and PAPSS on the development of estrogen-dependent cancers.

Estrogens are involved in the complex regulation of cell proliferation and apoptosis of hormone sensitive tumors including breast and endometrial cancers. Sulfation is the main pathway for estrogen metabolism, which is believed to be involved in the inactivation of estrogens in target tissues. SULT1E1 and PAPSS (PAPSS1 and PAPSS2) are responsible for the estrogen sulfation by providing catalyzing enzyme and universal sulfate donor. The present study showed the expression patterns of SULT1E1 and PAPSS in the breast and endometrial tissues by tissue array analysis and the assessment of clinical samples. The estrogen sulfation enzymes were comparatively higher in the tumorous tissues than their adjacent normal tissues. SULT1E1 overexpression inhibited the tumorigenesis in subcutaneous xenograft model. By CCK-8 assay and flow cytometry assay, overexpression of SULT1E1 and PAPSS1 by adenovirus blocked the estrogen pro-proliferating effect and promoted cell apoptosis induced by H(2)O(2) in MCF-7 cells. By real-time reverse transcription-polymerase chain reaction and western-blot assays, overexpression of SULT1E1 and PAPSS1 suppressed cell growth and triggered apoptosis by downregulating the levels of c-myc, cyclin D1 and bcl-2, meanwhile, upregulating bax expression. In conclusion, the discrepancies in expressions of SULT1E1 and PAPSS between breast and endometrial tumorous tissues and their adjacent normal tissues were prominent. Overexpression of SULT1E1 and PAPSS1 retarded MCF-7 cells growth in vivo and in vitro by arresting cell cycles and inducing apoptosis. Thus, targeting SULT1E1 and PAPSS expressions might be an important approach for estrogen-dependent cancers.

Prevalence of hyperuricemia and the population attributable fraction of modifiable risk factors: Evidence from a general population cohort in China.

Data on updated hyperuricemia prevalence in Beijing-Tianjin-Hebei (BTH) region in China, which is one of the world-class urban agglomerations, is sparse. Overweight/obesity, alcohol consumption, smoking and sedentary behavior are modifiable risk factors (MRFs) for elevated serum uric acid (SUA), but their population attributable fractions (PAFs) for hyperuricemia is still unclear. Using baseline data from the BTH Physical Examination General Population Cohort, we calculated the crude- and adjusted-prevalence of hyperuricemia based on the 30,158 participants aged 18-80 years. Hyperuricemia was defined as SUA >420 µmol/L in men and >360 µmol/L in women, or currently use of uric acid lowering drugs. Overweight/obesity, alcohol consumption, smoking and sedentary behavior were considered as MRFs and their adjusted PAFs were estimated. The prevalence of hyperuricemia was 19.37%, 27.72% in men and 10.69% in women. The PAFs and 95% confidence intervals for overweight, obesity were 16.25% (14.26-18.25%) and 12.08% (11.40-12.77%) in men, 13.95% (12.31-15.59%) and 6.35% (5.97-6.74%) in women, respectively. Alcohol consumption can explain 4.64% (2.72-6.56%) hyperuricemia cases in men, but with no statistical significance in women. Cigarette smoking contributed to 3.15% (1.09-5.21%) cases in men, but a much lower fraction in women (0.85%, 0.49-1.22%). Compared with sedentary time <2 h per day, the PAFs of 2-4 h, 4-6 h, and more than 6 h per day were 3.14% (1.34-4.93%), 6.72% (4.44-8.99%) and 8.04% (4.95-11.13%) in men, respectively. Sedentary time was not found to be associated with hyperuricemia in women. These findings concluded that hyperuricemia is prevalent in this representative Chinese adult general population with substantial sex difference. Four MRFs (overweight/obesity, alcohol consumption, cigarette smoking and sedentary behavior) accounted for a notable proportion of hyperuricemia cases. The PAF estimations enable the exploration of the expected proportion of hyperuricemia cases that could be prevented if the MRFs were removed, which warrants the public health significance of life-style intervention.

A Novel Method of Natural Orifice Specimen Extraction Surgery (NOSES) during Laparoscopic Anterior Resection for Rectal Cancer.

We propose a modification to the reconstruction method of natural orifice specimen extraction surgery (NOSES) during laparoscopic anterior resection (LAR) for rectal cancer (RC) and evaluated its feasibility and short-term safety by comparing surgical and postoperative outcomes with those of conventional LAR. Twenty patients with RC underwent "double-purse" NOSES-LAR from October 2017 to June 2018. Data of clinicopathological characteristics, surgical and postoperative outcomes, and follow-up findings in NOSES-LAR cases were collected and retrospectively compared with those of conventional LAR to clarify the clinical benefits. The median postoperative hospital stay was lower in the double-purse NOSES group than the conventional group (6.6 vs. 7.1 days, respectively). In the conventional group, anastomotic leakage and incision site infection occurred in one patient each. In contrast, there were no complications in the double-purse group. There were no significant differences in blood loss, surgical duration, and time of the first flatus between the two groups. Additionally, "double-purse" NOSES-LAR was more economical than the conventional LAR. "Double-purse" NOSES-LAR is a safe, feasible, and minimally invasive promising procedure for LAR of RC with faster recovery, while requiring less surgical skills and lower clinical costs.

Fiber orientation distribution from diffusion MRI: Effects of inaccurate response function calibration.

BACKGROUND AND PURPOSE: Diffusion MRI of the brain enables to quantify white matter fiber orientations noninvasively. Several approaches have been proposed to estimate such characteristics from diffusion MRI data with spherical deconvolution being one of the most widely used methods. Spherical deconvolution requires to define--or derive from the data--a response function, which is used to compute the fiber orientation distribution (FOD). Different characteristics of the response function are expected to affect the FOD computation and the subsequent fiber tracking. METHODS: In this work, we explored the effects of inaccuracies in the shape factors of the response function on the FOD characteristics. RESULTS: With simulations, we show that the apparent fiber density could be doubled in the presence of underestimated shape factors in the response functions, whereas the overestimation of the shape factor will cause more spurious peaks in the FOD, especially when the signal-to-noise ratio is below 15. Moreover, crossing fiber populations with a separation angle smaller than 60° were more sensitive to inaccuracies in the response function than fiber populations with more orthogonal separation angles. Results with in vivo data demonstrate angular deviations in the FODs and spurious peaks as a result of modified shape factors of the response function, while the reconstruction of the main parts of fiber bundles is well preserved. CONCLUSIONS: This work sheds light on how specific aspects of the response function shape can affect the estimated FODs, and highlights the importance of a proper calibration/definition of the response function.