Metastatic colonization is one of the critical steps in tumor metastasis. A pre-metastatic niche is required for metastatic colonization and is determined by tumor-stroma interactions, yet the ...mechanistic underpinnings remain incompletely understood.
PCR-based miRNome profiling, qPCR, immunofluorescent analyses evaluated the expression of exosomal miR-141 and cell-to-cell communication. LC-MS/MS proteomic profiling and Dual-Luciferase analyses identified YAP1 as the direct target of miR-141. Human cytokine profiling, ChIP, luciferase reporter assays, and subcellular fractionation analyses confirmed YAP1 in modulating GROα production. A series of in vitro tumorigenic assays, an ex vivo model and Yap1 stromal conditional knockout (cKO) mouse model demonstrated the roles of miR-141/YAP1/GROα/CXCR1/2 signaling cascade. RNAi, CRISPR/Cas9 and CRISPRi systems were used for gene silencing. Blood sera, OvCa tumor tissue samples, and tissue array were included for clinical correlations.
Hsa-miR-141-3p (miR-141), an exosomal miRNA, is highly secreted by ovarian cancer cells and reprograms stromal fibroblasts into proinflammatory cancer-associated fibroblasts (CAFs), facilitating metastatic colonization. A mechanistic study showed that miR-141 targeted YAP1, a critical effector of the Hippo pathway, reducing the nuclear YAP1/TAZ ratio and enhancing GROα production from stromal fibroblasts. Stromal-specific knockout (cKO) of Yap1 in murine models shaped the GROα-enriched microenvironment, facilitating in vivo tumor colonization, but this effect was reversed after Cxcr1/2 depletion in OvCa cells. The YAP1/GROα correlation was demonstrated in clinical samples, highlighting the clinical relevance of this research and providing a potential therapeutic intervention for impeding premetastatic niche formation and metastatic progression of ovarian cancers.
This study uncovers miR-141 as an OvCa-derived exosomal microRNA mediating the tumor-stroma interactions and the formation of tumor-promoting stromal niche through activating YAP1/GROα/CXCRs signaling cascade, providing new insight into therapy for OvCa patients with peritoneal metastases.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The merger of photoredox catalysis with transition metal catalysis, termed metallaphotoredox catalysis, has become a mainstay in synthetic methodology over the past decade. Metallaphotoredox ...catalysis has combined the unparalleled capacity of transition metal catalysis for bond formation with the broad utility of photoinduced electron- and energy-transfer processes. Photocatalytic substrate activation has allowed the engagement of simple starting materials in metal-mediated bond-forming processes. Moreover, electron or energy transfer directly with key organometallic intermediates has provided novel activation modes entirely complementary to traditional catalytic platforms. This Review details and contextualizes the advancements in molecule construction brought forth by metallaphotocatalysis.
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IJS, KILJ, NUK, PNG, UL, UM
Background & Aims Liver biopsy is the gold standard for diagnosing non-alcoholic fatty liver disease (NAFLD) but with practical constraints. Phosphorus magnetic resonance spectroscopy (31 P-MRS) ...allows in vivo assessment of hepatocellular metabolism and has shown potential for biochemical differentiation in diffuse liver disease. Our aims were to describe spectroscopic signatures in biopsy-proven NAFLD and to determine diagnostic performance of31 P-MRS for non-alcoholic steatohepatitis (NASH). Methods31 P-MRS was performed in 151 subjects, comprised of healthy controls (n = 19) and NAFLD patients with non-NASH (n = 37) and NASH (n = 95). Signal intensity ratios for phosphomonoesters (PME) including phosphoethanolamine (PE), phosphodiesters (PDE) including glycerophosphocholine (GPC), total nucleotide triphosphate (NTP) including α-NTP, and inorganic phosphate (Pi), expressed relative to total phosphate (TP) or PME+PDE and converted to percentage, were obtained. Results Compared to controls, both NAFLD groups had increased PDE/TP ( p <0.001) and decreased Pi/TP ( p = 0.011). Non-NASH patients showed decreased PE/PME+PDE ( p = 0.048), increased GPC/PME+PDE ( p <0.001), and normal NTP/TP and α-NTP/TP. Whereas, NASH patients had normal PE/PME+PDE and GPC/PME+PDE, but decreased NTP/TP ( p = 0.004) and α-NTP/TP ( p <0.001). The latter was significantly different between non-NASH and NASH ( p = 0.047) and selected as discriminating parameter, with area under the receiver-operating characteristics curve of 0.71 (95% confidence interval, 0.62–0.79). An α-NTP/TP cutoff of 16.36% gave 91% sensitivity and cutoff of 10.57% gave 91% specificity for NASH. Conclusions31 P-MRS shows distinct biochemical changes in different NAFLD states, and has fair diagnostic accuracy for NASH.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Malignant ascites in peritoneal metastases is a lipid-enriched microenvironment and is frequently involved in the poor prognosis of epithelial ovarian cancer (EOC). However, the detailed mechanisms ...underlying ovarian cancer (OvCa) cells dictating their lipid metabolic activities in promoting tumor progression remain elusive.
The omental conditioned medium (OCM) was established to imitate the omental or ascites microenvironment. Mass spectrometry, RT-qPCR, IHC, and western blot assays were applied to evaluate human fatty acid desaturases expressions and activities. Pharmaceutical inhibition and genetic ablation of SCD1/FADS2 were performed to observe the oncogenic capacities. RNA sequencing, lipid peroxidation, cellular iron, ROS, and Mito-Stress assays were applied to examine ferroptosis. OvCa patient-derived organoid and mouse model of peritoneal metastases were used to evaluate the combined effect of SCD1/FADS2 inhibitors with cisplatin.
We found that two critical fatty acid desaturases, stearoyl-CoA desaturase-1 (SCD1) and acyl-CoA 6-desaturase (FADS2), were aberrantly upregulated, accelerating lipid metabolic activities and tumor aggressiveness of ascites-derived OvCa cells. Lipidomic analysis revealed that the elevation of unsaturated fatty acids (UFAs) was positively associated with SCD1/FADS2 levels and the oncogenic capacities of OvCa cells. In contrast, pharmaceutical inhibition and genetic ablation of SCD1/FADS2 retarded tumor growth, cancer stem cell (CSC) formation and reduced platinum resistance. Inhibition of SCD1/FADS2 directly downregulated GPX4 and the GSH/GSSG ratio, causing disruption of the cellular/mitochondrial redox balance and subsequently, iron-mediated lipid peroxidation and mitochondrial dysfunction in ascites-derived OvCa cells.
Combinational treatment with SCD1/FADS2 inhibitors and cisplatin synergistically repressed tumor cell dissemination, providing a promising chemotherapeutic strategy against EOC peritoneal metastases.
The pathogenesis of primary mediastinal large B-cell lymphoma (PMBCL) is incompletely understood. Recently, specific genotypic and phenotypic features have been linked to tumor cell immune escape ...mechanisms in PMBCL. We studied 571 B-cell lymphomas with a focus on PMBCL. Using fluorescence in situ hybridization here, we report that the programmed death ligand (PDL) locus (9p24.1) is frequently and specifically rearranged in PMBCL (20%) as compared with diffuse large B-cell lymphoma, follicular lymphoma, and Hodgkin lymphoma. Rearrangement was significantly correlated with overexpression of PDL transcripts. Utilizing high-throughput sequencing techniques, we characterized novel translocations and chimeric fusion transcripts involving PDLs at base-pair resolution. Our data suggest that recurrent genomic rearrangement events underlie an immune privilege phenotype in a subset of B-cell lymphomas.
•Programmed death ligands 1 and 2 are rearranged at a frequency of 20% in PMBCL.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Extracellular RNAs (exRNAs) in human body fluids are emerging as effective biomarkers for detection of diseases. Saliva, as the most accessible and noninvasive body fluid, has been shown to harbor ...exRNA biomarkers for several human diseases. However, the entire spectrum of exRNA from saliva has not been fully characterized.
Using high-throughput RNA sequencing (RNA-Seq), we conducted an in-depth bioinformatic analysis of noncoding RNAs (ncRNAs) in human cell-free saliva (CFS) from healthy individuals, with a focus on microRNAs (miRNAs), piwi-interacting RNAs (piRNAs), and circular RNAs (circRNAs).
Our data demonstrated robust reproducibility of miRNA and piRNA profiles across individuals. Furthermore, individual variability of these salivary RNA species was highly similar to those in other body fluids or cellular samples, despite the direct exposure of saliva to environmental impacts. By comparative analysis of >90 RNA-Seq data sets of different origins, we observed that piRNAs were surprisingly abundant in CFS compared with other body fluid or intracellular samples, with expression levels in CFS comparable to those found in embryonic stem cells and skin cells. Conversely, miRNA expression profiles in CFS were highly similar to those in serum and cerebrospinal fluid. Using a customized bioinformatics method, we identified >400 circRNAs in CFS. These data represent the first global characterization and experimental validation of circRNAs in any type of extracellular body fluid.
Our study provides a comprehensive landscape of ncRNA species in human saliva that will facilitate further biomarker discoveries and lay a foundation for future studies related to ncRNAs in human saliva.
•Nonpharmaceutical interventions were effective in reducing COVID-19 transmission.•Social distancing is more effective than the other NPIs in containing COVID-19.•Two or more synchronous NPIs are ...more effective than a single type of NPI.
To evaluate and compare the effectiveness of four types of non-pharmaceutical interventions (NPIs) to contain the time-varying effective reproduction number (Rt) of coronavirus disease-2019 (COVID-19).
This study included 1,908,197 confirmed COVID-19 cases from 190 countries between 23 January and 13 April 2020. The implemented NPIs were categorised into four types: mandatory face mask in public, isolation or quarantine, social distancing and traffic restriction (referred to as mandatory mask, quarantine, distancing and traffic hereafter, respectively).
The implementations of mandatory mask, quarantine, distancing and traffic were associated with changes (95% confidence interval, CI) of −15.14% (from −21.79% to −7.93%), −11.40% (from −13.66% to −9.07%), −42.94% (from −44.24% to −41.60%) and −9.26% (from −11.46% to −7.01%) in the Rt of COVID-19 when compared with those without the implementation of the corresponding measures. Distancing and the simultaneous implementation of two or more types of NPIs seemed to be associated with a greater decrease in the Rt of COVID-19.
Our study indicates that NPIs can significantly contain the COVID-19 pandemic. Distancing and the simultaneous implementation of two or more NPIs should be the strategic priorities for containing COVID-19.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Novel corona virus disease 2019 (COVID-19), which first emerged in December 2019, has become a pandemic. This study aimed to investigate the associations between meteorological factors and COVID-19 ...incidence and mortality worldwide. This study included 1,908,197 confirmed cases of and 119,257 deaths from COVID-19 from 190 countries between 23 January and 13 April, 2020. We used a distributed lag non-linear model with city-/country-level random intercept to investigate the associations between COVID19 incidence and daily temperature, relative humidity, and wind speed. A series of confounders were considered in the analysis including demographics, socioeconomics, geographic locations, and political strategies. Sensitivity analyses were performed to examine the robustness of the associations. The COVID-19 incidence showed a stronger association with temperature than with relative humidity or wind speed. An inverse association was identified between the COVID-19 incidence and temperature. The corresponding 14-day cumulative relative risk was 1.28 95% confidence interval (CI), 1.20–1.36 at 5 °C, and 0.75 (95% CI, 0.65–0.86) at 22 °C with reference to the risk at 11 °C. An inverse J-shaped association was observed between relative humidity and the COVID-19 incidence, with the highest risk at 72%. A higher wind speed was associated with a generally lower incidence of COVID-19, although the associations were weak. Sensitivity analyses generally yielded similar results. The COVID-19 incidence decreased with the increase of temperature. Our study suggests that the spread of COVID-19 may slow during summer but may increase during winter.
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•A higher temperature was associated with a lower incidence of COVID-19.•The spread of COVID-19 may slow during summer but may increase during winter.•There was an inverse J-shaped association between relative humidity and the incidence of COVID-19.•The association between wind speed and the incidence of COVID-19 was nonlinear.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Techniques for analyzing circulating tumor DNA (ctDNA) to detect, characterize and monitor cancer have matured rapidly. An increasing body of clinical evidence is demonstrating the capabilities of ...this technology as a diagnostic test. The full potential of ctDNA liquid biopsy in the diagnosis, characterization and management of solid and hematological malignancies will be uncovered through interventional clinical trials evaluating clinical utility. In this Review, we discuss the current landscape of ctDNA liquid-biopsy applications across the cancer continuum and highlight opportunities for clinical investigation.
The novel coronavirus disease 2019 (COVID-19), which first emerged in Hubei province, China, has become a pandemic. However, data regarding the effects of meteorological factors on its transmission ...are limited and inconsistent. A mechanism-based parameterisation scheme was developed to investigate the association between the scaled transmission rate (STR) of COVID-19 and the meteorological parameters in 20 provinces/municipalities located on the plains in China. We obtained information on the scale of population migrated from Wuhan, the world epicentre of the COVID-19 outbreak, into the study provinces/municipalities using mobile-phone positioning system and big data techniques. The highest STRs were found in densely populated metropolitan areas and in cold provinces located in north-eastern China. Population density had a non-linear relationship with disease spread (linearity index, 0.9). Among various meteorological factors, only temperature was significantly associated with the STR after controlling for the effect of population density. A negative and exponential relationship was identified between the transmission rate and the temperature (correlation coefficient, −0.56; 99% confidence level). The STR increased substantially as the temperature in north-eastern China decreased below 0 °C (the STR ranged from 3.5 to 12.3 when the temperature was between −9.41 °C and −13.87 °C), whilst the STR showed less temperature dependence in the study areas with temperate weather conditions (the STR was 1.21 ± 0.57 when the temperature was above 0 °C). Therefore, a higher population density was linearly whereas a lower temperature (<0 °C) was exponentially associated with an increased transmission rate of COVID-19. These findings suggest that the mitigation of COVID-19 spread in densely populated and/or cold regions will be a great challenge.
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•A mechanism-based parameterisation scheme was developed for transmission rate.•Scale of population migration from Wuhan was incorporated.•Population density had a non-linear (linearity index, 0.9) impact on disease spread.•Transmission rate shows a negative and exponential temperature dependence.•COVID-19 mitigation in densely populated and cold regions will be a great challenge.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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