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Significant anomalies in frequency of summer extreme hot days (SEHDs) are broadly observed in the Asian monsoon region (AMR) in the post-ENSO summers. The delayed ENSO impacts are mainly conveyed by provoking the Indo-western Pacific Ocean capacitor (IPOC) effect that maintains the anomalous anticyclone in the western North Pacific. The related diabatic heating anomaly can trigger the westward-propagating Rossby wave to the Indian subcontinent, which increases the geopotential heights, reduces the cloud cover, and thus increases the seasonal surface temperature and SEHD frequency in the southern AMR. Besides, the reduced atmospheric moisture in the western North Pacific hinders the northward propagation of intraseasonal oscillation (ISO) and modulates the occurrence frequency of individual ISO phases, contributing to the significantly increased/decreased SEHDs in eastern China/Hokkaido, Japan, in the post–El Niño summers. The 25-model-ensemble mean of CMIP6 historical runs can reproduce well the observed SEHD anomalies in the southern AMR in the post-ENSO summers mainly due to the realistic simulation of ENSO impacts on the seasonal surface temperature, although a large intermodel spread exists due to different strengths of IPOC effect in each model owing to model biases in the mean state of the eastern tropical Pacific, the ENSO variance, and teleconnection to the Indian Ocean. Furthermore, future projections under the SSP5-8.5 scenario show that the delayed ENSO impacts on the southern AMR remain stable under global warming via a similar mechanism as in the observations and historical runs.

Understanding and predicting extreme weather and climate are ultimately important for adaptation and resilience. Here, we assess the prediction skills of frequency of summer extreme hot days (SEHDs) in the Asian monsoon region (AMR) by using the 1981–2014 hindcasts of the Predictive Ocean Atmosphere Model for Australia version 2 (POAMA-2) subseasonal-to-seasonal prediction system. Generally, the good prediction skills of SEHD frequency appear in the southern AMR south of 30°N including the Indian subcontinent, Indo-China peninsula, and the Philippines; the anomaly correlation coefficients between the observed and predicted region-mean SEHD anomalies are 0.72, 0.72, 0.70, 0.60, 0.61, and 0.61 at 1–6 months lead, respectively, all statistically significant at the 99.9% confidence level. The high prediction skills in POAMA-2 are due to its capacity on reproducing the observed delayed ENSO impacts on the large-scale atmospheric circulation, the seasonal surface air temperature, and thus the SEHD frequency in the southern AMR via provoking the Indo–western Pacific Ocean capacitor effect. Since POAMA-2 only provides the prediction at most half a year in advance, we also conduct the hindcasts in the SINTEX-F that can reproduce well the robust ENSO–SEHD relationship and has high prediction skill of ENSO itself. Results show that skillful prediction of the region-mean SEHD frequency can be up to 14 months in advance. These results are complementary to Part I of this study that ENSO can impact the SEHDs in the AMR and provide the sources of predictability.

The Indian Ocean Dipole (IOD) is one of the leading modes of interannual climate variability in the tropical Indian Ocean (IO). Paleoclimate provides real climate scenarios to examine IOD behaviors and the linkage to basic states. Based on 18 models from the Coupled Model Intercomparison Project phase 5 and 6 (CMIP5/6), the IOD change from the preindustrial period to mid-Holocene is investigated. The multimodel mean reveals that the IOD variability weakens by 14% as measured by the standard deviation of the Dipole Mode Index, which is defined using the zonal sea surface temperature (SST) difference. Such attenuation is dominated by the spatially consistent suppression in the western-pole SST variability, while the eastern pole contributes little due to the opposite-signed changes in its northwestern and southeastern portions. The primary reason for the aforementioned changes comes from the altered climatic background, which displays a positive IOD-like pattern during IOD growing seasons, with intensified westward currents along the equator and northwestward currents in the southeastern equatorial IO. Such changes in the mean-state currents modulate the strength of the IOD-related anomalous advection and subsequently cause alterations in the IOD variability. Further analyses show that the IOD attenuation in the mid-Holocene is unlikely caused by the concurrently subdued El Niño–Southern Oscillation in the tropical Pacific partially because of the diminished connections between the two oscillations themselves. The above simulated changes in both the IO mean climatology and IOD variability agree well with the available paleo-records in literature.

Background: Tucidinostat (formerly known as chidamide) plus exemestane is approved for postmenopausal patients with advanced, hormone receptor-positive breast cancer. We evaluated the efficacy and safety of tucidinostat plus exemestane as the neoadjuvant strategy in hormone receptor-positive early breast cancer patients. Methods: NeoTEE is an open-label, single-center, phase II study. Patients with HR-positive, HER2-negative and stage II/III breast cancer were enrolled at the First Affiliated Hospital of Sun Yat-sen University. Eligible patients received 25 mg oral exemestane once daily for 2 weeks followed by 30 mg oral tucidinostat twice weekly in combination with 25mg oral exemestane once daily for 24 weeks. GnRHa was used for premenopausal patients. Endpoints assessed here included objective response rate (ORR), complete cell cycle arrest (CCCA, Ki-67≤2.7%) at surgery, disease control rate (DCR), pathological complete remission (pCR) and safety. Results: Between July 2020 and July 2022, 26 patients were enrolled, of whom 24 were evaluable for response per RECIST 1.1 criteria. Partial response (PR) was observed in 18 patients, with an ORR of 75% (18/24). The DCR was 100%. Of the 14 patients with surgery, one patient achieved pCR and 8 patients were exempt from postoperative adjuvant chemotherapy. CCCA at surgery was 64.3% (9/14). The follow-up remains ongoing and updated results will be presented thereafter. Most adverse events (AEs) were grade 1 or 2. Grade 3 AEs occurred in 8 of 26 patients, the most common were neutropenia 19.2%, leukopenia 7.7%, anemia 3.8%, ALT increased 3.8%, pneumonitis 3.8%. Only 1 patient experienced grade 4 neutropenia. Grade 3/4 neutropenia recovered after dose reduction or discontinuation of tucidinostat. No patient received G-CSF. Conclusions: Tucidinostat combined with exemestane was well tolerated and demonstrated meaningful responses in neoadjuvant setting for women with early HR+/HER2- breast cancer. Further investigation is warranted. Clinical trial information: NCT04465097. Citation Format: zhen shan, nan shao, xiaoling zhang, huijuan shi, yanling zheng, jia luo, tiantian zhen, ruping chen, Ying Lin. A phase II, single-arm study of histone deacetylases inhibitor Tucidinostat and Exemestane as neoadjuvant therapy in patients with hormone receptor positive HER2 negative breast cancer (NeoTEE trial) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-09-05.

Eastern China (EC) suffered an extreme drought with long-lasting duration and record-breaking intensity in late summer–autumn 2019. Our diagnosed results show that the central Pacific (CP) El Niño, in tandem with warm sea surface temperature anomalies (SSTAs) over the Kuroshio Extension (KE) region, induces the meridionally elongated cyclonic circulation anomalies stretching from the western North Pacific (WNP) to the Yellow Sea. Its western flank corresponds to overwhelming low-level northerly wind anomalies over EC, which result in deficient moisture and anomalous descent over EC and hence cause the extreme drought in 2019. To investigate the relative contributions of SSTAs over different regions, we performed sensitivity experiments, and analyzed the relationship between extreme drought like what occurred in 2019 (a 2019Drought-like event) and the SSTAs in CMIP6 historical simulations. Modeling evidences reveal that both warm SSTAs over the central equatorial Pacific and the KE region are indispensable for shaping the meridionally elongated cyclone anomaly. Specifically, the cyclone anomaly over the WNP induced by CP El Niño aligns with the cyclone anomaly over the Yellow Sea induced by the warm SSTAs over the KE region, merging into a meridionally stretched cyclone anomaly to the east of EC. Consequently, the northerly anomalies stretch across EC, leading to unfavorable atmospheric conditions and the rainfall deficit there. Projection results show that the occurrence probability of a 2019Drought-like event will increase by 20% (decrease by 40%–50%) under a high (medium-low) emission scenario compared to present-day climate, indicating the nonlinear response of extreme drought to different emission scenarios and the urgency of carbon emission reduction. Significance Statement An extreme drought hit the Eastern China (EC) region in 2019 and caused tremendous losses. This study proposed that both the 2019 CP El Niño and the warm SST anomalies over the Kuroshio Extension (KE) region induce the meridionally elongated circulation anomalies and the resultant extreme drought. We showed that the typical circulation anomalies induced by central Pacific (CP) El Niño cannot totally explain the meridionally elongated circulation anomalies in 2019. Our modeling evidences confirmed the indispensable role of warm SST anomalies over KE region in the 2019 extreme drought’s formation. The projection results show that extreme drought like that in 2019 will occur more (less) frequently under a high (medium-low) emission scenario compared to modern-day level, indicating the urgency of carbon emission reduction.

An environmentally benign electrochemical decyanative C(sp3)–H oxygenation of N-cyanomethylamines for the synthesis of structurally diverse formamides is described.

This work aimed to investigate the role of nuclear factor peroxisome proliferator-activated receptor α (PPARα) in modification of circadian clock and their relevance to development of nonalcoholic fatty liver disease (NAFLD). Both male wild-type (WT) and Pparα-null (KO) mice treated with high-fat diet (HFD) were used to explore the effect of PPARα and lipid diet on the circadian rhythm. WT, KO, and PPARα-humanized (hPPARα) mice were treated with PPARα agonist fenofibrate to reveal the hPPARα dependence of circadian locomotor output cycles kaput (CLOCK) down-regulation. The mouse model and hepatocyte experiments were designed to verify the action of PPARα in down-regulating CLOCK and lipid accumulation in vivo and in vitro. Strongest NAFLD developed in mice fed 45%HFD, and it was inhibited in WT mice. The activity rhythm of WT mice was found to be different from that of the KO mice on normal diet and HFD. The core circadian factor CLOCK was down-regulated by HFD in both WT and KO mice in the liver, not in the hypothalamus. More interestingly, hepatic CLOCK was down-regulated by basal PPARα and activated PPARα in dose dependence of fenofibrate. Accordingly, CLOCK down-regulation dependent of PPARα activity was involved in inhibition of lipid metabolism in hepatocytes. Down-regulation of hepatic CLOCK by basal PPARα contributes to tolerance against development of NAFLD. Inhibition of CLOCK by activated PPARα is involved in inhibition of NAFLD by PPARα agonists. KEY MESSAGES: • PPARα inhibited NAFLD development induced by HFD. • PPARα mediated modifications of circadian rhythm and the hepatic circadian factor CLOCK in NAFLD models. • Down-regulation of hepatic CLOCK by basal PPARα contributed to tolerance against development of NAFLD. • Inhibition of CLOCK by activated PPARα was involved in therapeutic actions against fatty liver diseases by PPARα agonists.

Alcohol exposure increases the risk of breast cancer. Alcohol consumption by adolescents is a serious social and public health issue. This study investigated the impact of adolescent alcohol consumption on mammary tumorigenesis and progression and compared it to that of adult alcohol exposure in animal models.Female adolescent (5 weeks) and adult (8 weeks) MMTV-Wnt1 mice were exposed to alcohol either chronically or acutely. For chronic alcohol exposure, animals were fed a liquid diet containing 6.7% ethanol for 23 weeks. For acute exposure, animals were treated with ethanol (2.5 g/kg, 25% w/v) via intraperitoneal (IP) injection for 15 days.In control animals, the tumor latency was 18.5 to 22 weeks. Both chronic and acute alcohol exposure in adolescent mice significantly shortened the tumor latency to 9.5 and 8.4 weeks, respectively. However, adult-initiated alcohol exposure had little effect on the tumor latency. Both adolescent- and adult-initiated alcohol exposure significantly increased lung metastasis. Adolescent-initiated alcohol exposure but not adult-initiated alcohol exposure increased the breast cancer stem cell population. Adolescent-initiated alcohol exposure significantly altered the proliferation of mammary epithelial cells, ductal growth, and the formation of terminal end buds in the mammary glands. Adolescent-initiated alcohol exposure but not adult-initiated alcohol exposure increased estradiol levels in the blood. Acute adolescent alcohol exposure also significantly increased blood progesterone levels. Furthermore, adolescent-initiated alcohol exposure activated PAK1 and p38γ MAPK, critical regulators of mammary tumorigenesis and aggressiveness, respectively, while adult-initiated alcohol exposure activated only p38γ MAPK. In addition, both adolescent and adult alcohol exposure significantly decreased the levels of a prognostic marker miR200b.Adolescent-initiated alcohol exposure enhanced both tumorigenesis and aggressiveness of mammary tumors, while adult-initiated alcohol exposure mainly promoted tumor metastasis. Thus, adolescent mice were more sensitive than adult mice in response to alcohol-induced tumor promotion.

The advent of the era of big data has caused great impact on enterprise financial management, but at the same time, enterprise financial management has also ushered in the opportunity of innovation and development. As a modern enterprise under the new economic situation, financial personnel should not only do a good job of self-positioning, but also conform to the development needs of the big data era, speed up the transformation and upgrading of enterprise financial accounting mode to management accounting mode, and formulate a transformation and upgrading scheme that is closely integrated with enterprise development, so as to ensure that enterprises are always in a favorable position in the fierce market competition on the premise of enhancing their comprehensive competitiveness. This paper mainly discusses and analyzes the strategy of financial accounting to management accounting in the era of big data.

A common opportunity to collect research samples is during image-guided percutaneous core needle biopsies (CNBs) performed when clinically indicated or for assessing clinical trial eligibility. The relative safety of extra CNBs collected for research is undefined.Patients who underwent CNB for research purposes only [RO], as clinically indicated [CI], or as part of a clinical trial [CT] were identified. 30-day post-procedure adverse events (AEs) among the cohorts were examined and compared to the 2020 Society of Interventional Radiology QI guidelines.236 patients with thoracic cancers (90 % NSCLC, 5 % SCLC, 4 % mesothelioma, and 1 % thymic) had 292 CNBs (63 RO, 229 CI + CT). AEs occurred in 13 % of both the RO and CI + CT groups. Compared to the CI + CT group, the RO group did not have a higher pneumothorax incidence (RO: 5/29 [17 %], CI + CT: 18/114 [16 %], p = 0.79); both were below the suggested QI threshold of 45 % for pneumothorax. There was a negative association between number of cores obtained and risk of AE (AE vs no AE mean cores = 3.5 vs 4.8). After adjusting for the number of cores and smoking history, RO vs CI + CT lung biopsies had a higher risk of AEs (adjusted relative risk [aRR] = 2.44, 1.08-5.55, p = 0.03 vs non-lung aRR = 0.86, 0.10-7.09, p = 0.89).CNBs performed for research purposes do not have a significantly increased risk of AEs when compared to those performed for clinical trials and/or when clinically indicated. However, AEs were most frequent in lung biopsies. When performing research biopsies, a target other than lung may be preferred when clinically appropriate.

From birth to adulthood, we often align our behaviors, attitudes, and opinions with a majority, a phenomenon known as social conformity. A seminal framework has proposed that conformity behaviors are mainly driven by three fundamental motives: a desire to gain more information to be accurate, to obtain social approval from others, and to maintain a favorable self-concept. Despite extensive interest in neuroimaging investigation of social conformity, the relationship between brain systems and these fundamental motivations has yet to be established. Here, we reviewed brain imaging findings of social conformity with a componential framework, aiming to reveal the neuropsychological substrates underlying different conformity motivations. First, information-seeking engages the evaluation of social information, information integration, and modification of task-related activity, corresponding to brain networks implicated in reward, cognitive control, and tasks at hand. Second, social acceptance involves the anticipation of social acceptance or rejection and mental state attribution, mediated by networks of reward, punishment, and mentalizing. Third, self-enhancement entails the excessive representation of positive self-related information and suppression of negative self-related information, ingroup favoritism and/or outgroup derogation, and elaborated mentalizing processes to the ingroup, supported by brain systems of reward, punishment, and mentalizing. Therefore, recent brain imaging studies have provided important insights into the fundamental motivations of social conformity in terms of component processes and brain mechanisms.

Dalbergia tonkinensis is very similar to Dalbergia odorifera in material, texture, and other macroscopic characteristics, and a comparison of the commonalities and differences in the chemical composition of the extractives may help to distinguish the two. However, the chemical composition of Dalbergia tonkinensis heartwood is unknown. The total flavonoid content of Dalbergia tonkinensis heartwood was determined to range between 49.67 to 101.95 mg, which indicated that Dalbergia tonkinensis is as equally rich in flavonoids as Dalbergia odorifera. Thirty-one flavonoids were identified via ultra-performance liquid chromatography-mass spectrometry in Dalbergia tonkinensis. Among them, the contents of 15 medicinal active flavonoids with were determined, and the liquiritigenin, naringenin, formononetin, pinocembrin, and biochanin A contents were found to be high. The 12 volatile compositions of Dalbergia tonkinensis heartwood identified via gas chromatography-mass spectrometry were very similar to those of Dalbergia odorifera and were dominated by trans-nerolidol, caryophyllene oxide, and eudesmol. The relationship between the chemical composition of Dalbergia tonkinensis and Dalbergia odorifera heartwood extracts was determined via a principal component analysis, and the results indicated that there was no significant difference in chemical composition between the two. This suggested that Dalbergia tonkinensis could be used as a potential substitute for Dalbergia odorifera.

The prognosis of thymic epithelial tumors (TETs) currently relies on the commonly adopted WHO classification and Masaoka staging system, which cannot reflect the undefined biological behaviors limiting them as prognostic factors.In this study, we first identified 40 genes and 179 genes, respectively that were epigenetically upregulated and silenced, corresponding to a total of 509 functionally methylated CpG sites between thymomas and thymic carcinomas by using the TCGA dataset.The methylation β-values of cg20068620 in MAPK4 and cg18770944 in USP51 were significantly associated with recurrence-free survival (RFS). In the independent validation cohort, only WHO classification and methylation β-values of cg20068620 in MAPK4 were independent prognostic factors for RFS in Chinese patients with TETs. A linear weighted model including these two factors was used to calculate the recurrence risk score (RRS). Time-dependent ROC curve analysis revealed that RRS was overwhelmingly superior to WHO classification for predicting 3-, 5-, and 10-year RFS and Masaoka stage for 3- and 5-year RFS.These results suggested that the methylation site cg20068620 in MAPK4 can improve the accuracy of the WHO classification alone regarding the prognostic value of TETs recurrence.

Immunotherapy is used to treat almost all patients with advanced non-small cell lung cancer (NSCLC); however, identifying robust predictive biomarkers remains challenging. Here we show the predictive capacity of integrating medical imaging, histopathologic and genomic features to predict immunotherapy response using a cohort of 247 patients with advanced NSCLC with multimodal baseline data obtained during diagnostic clinical workup, including computed tomography scan images, digitized programmed death ligand-1 immunohistochemistry slides and known outcomes to immunotherapy. Using domain expert annotations, we developed a computational workflow to extract patient-level features and used a machine-learning approach to integrate multimodal features into a risk prediction model. Our multimodal model (area under the curve (AUC) = 0.80, 95% confidence interval (CI) 0.74–0.86) outperformed unimodal measures, including tumor mutational burden (AUC = 0.61, 95% CI 0.52–0.70) and programmed death ligand-1 immunohistochemistry score (AUC = 0.73, 95% CI 0.65–0.81). Our study therefore provides a quantitative rationale for using multimodal features to improve prediction of immunotherapy response in patients with NSCLC using expert-guided machine learning.

Most basal-like breast cancers (BLBCs) are triple-negative breast cancers (TNBCs), which is associated with high malignancy, high rate of recurrence and distant metastasis, and poor prognosis among all types of breast cancer. However, there are currently no effective therapies for BLBC. Furthermore, chemoresistance limits the therapeutic options for BLBC treatment. In this study, we screen out protein activator of the interferon-induced protein kinase (PACT) as an essential gene in BLBC metastasis. We find that high PACT expression level was associated with poor prognosis among BLBC patients. In vivo and in vitro investigations indicated that PACT could regulate BLBC metastasis by interacting with SUMO-conjugating enzyme Ubc9 to stimulate the SUMOylation and thus consequently the activation of Rac1. BLBC patients receiving chemotherapy presents poorer prognosis with PACT high expression, and PACT disruption sensitizes experimental mammary tumor metastases to chemotherapy, thus providing insights to consider PACT as a potential therapeutic target to overcome acquired chemoresistance in BLBC.

Background Stress granules formation is closely associated with the progression of hepatocellular carcinoma (HCC). Factors determination this process remain to be elucidated. In this study, stress granule-related genes were validated as a predictor of HCC. Methods The stress granules-related associated genes were collected from the MSGP database and the MsigDB database. A novel prognostic risk scoring model were constructed by paired gene signature method. We identified eukaryotic translation initiation factor 4A3 (EIF4A3) and karyopherin subunit alpha 2 (KPNA2) as candidate prognostic biomarkers, and their correlation with both prognosis and immune infiltration in HCC were evaluated. The expression of EIF4A3 and KPNA2 in HCC tissues was detected through immunohistochemistry (IHC). Results Through pairing of all DESG gene, we obtained a total of 16251 significance pairs. Subsequently, 93 pairs of all pairs containing EIF4A3 were extracted in this research. As a stress granule formation regulator, KPNA2 displayed the greatest correlations with EIF4A3 in HCC. Hyperactivated EIF4A3 and KPNA2 is associated with the poor clinical outcome of HCCs after hepatic resection. Involvement of EIF4A3 and KPNA2 in immune infiltration have been showed. Conclusion Our study identified coexistence of EIF4A3 and KPNA2 dysregulation inform poor clinical outcomes in HCC.

The interactions between El Niño-Southern Oscillation (ENSO) and Indian Ocean Dipole (IOD) are known to have great implications for global climate variability and seasonal climate predictions. Observational analysis suggests that the ENSO–IOD inter-basin connection is time-varying and related to the Atlantic Multidecadal Oscillation (AMO) with weakened ENSO–IOD relationship corresponding to AMO warm phases. A suite of Atlantic pacemaker simulations successfully reproduces the decadal fluctuations in ENSO–IOD relationship and its link to the AMO. The warm sea surface temperature (SST) anomalies associated with the AMO drive a series of Indo-Pacific mean climate changes through tropical-wide teleconnections, including the La Niña-like mean SST cooling over the central Pacific and the deepening of mean thermocline depth in the eastern Indian Ocean. By modulating ocean–atmosphere feedback strength, those mean state changes decrease both ENSO amplitude and the Indian Ocean sensitivity to ENSO forcing, therefore decoupling the IOD from ENSO.

Background: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver diseases. In most cases, NAFLD progresses from benign steatosis to steatohepatitis (NASH), and then to cirrhosis. No treatment is currently approved for NAFLD/NASH in the clinic. Fenofibrate (FENO) has been clinically used to treat dyslipidemia for more than a half century, but its effects on NASH are not established. FENO’s half-life is quite different between rodent and human. The aim of this study was to investigate the potential of pharmacokinetic-based FENO regime for NASH treatment and the underlying mechanisms.Methods: Two typical mouse NASH models, methionine-choline deficient (MCD) diet-fed mice and choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD)-fed mice, were used. MCD model was designed as therapeutic evaluation in experiment 1 and CDAHFD model was designed as preventive in experiment 2. Three doses of FENO (5, 25, 125 mg/kg), two times a day (BID), were administered to the above models. Serum markers of liver injury, cholestasis, and the histology of liver tissues were investigated. Normal mice were used as a model in experiment 3 for toxicity evaluation, Quantitative-PCR and Western Blot assays were used to investigate the inflammatory responses, bile acid synthesis as well as lipid catabolism.Results: Mice on the MCD and CDAHFD diets developed steatohepatitis as expected. Treatment with FENO (25 mg/kg·BID) significantly decreased hepatic steatosis, inflammation and fibrosis in both therapeutic and preventive models. In the MCD model, the therapeutic action of FENO (25 mg/kg·BID) and 125 mg/kg·BID on histopathology and the expression of inflammatory cytokines were comparable. In reducing macrophage infiltration and bile acid load, FENO (25 mg/kg·BID) was superior to 125 mg/kg·BID. In all the aspects mentioned above, FENO (25 mg/kg·BID) was the best among the 3 doses in the CDAHFD model. In a third experiment, the effects of FENO (25 mg/kg·BID) and 125 mg/kg·BID on lipid catabolism were comparable, but 125 mg/kg·BID increased the expression of inflammatory factors and bile acid load. In both models, FENO (5 mg/kg·BID) showed little effect in hepatic steatosis and inflammation, neither the adverse effects. FENO (125 mg/kg·BID) aggravated liver inflammation, increased bile acid synthesis, and promoted the potential of liver proliferation. In toxicity risk assay, FENO (25 mg/kg·BID) treatment showed low potential to trigger bile acid synthesis, inflammation and hepatocyte proliferation.Conclusion: A new regime, FENO (25 mg/kg·BID) is potentially a therapeutic strategy for the NASH treatment. Translational medicine is warranted to prove its effectiveness in the clinic.

Background With the in-depth research on the tumor microenvironment, the tumor stroma is considered to play a leading role in malignant tumor behavior, and PD-L1 is also related to the tumor stroma. The tumor–stroma ratio (TSR) has been regarded as a novel prognostic factor in many cancers. Our study aims to assess the TSR and PD-L1 clinical value in hepatocellular carcinoma (HCC) patients. Methods Ninety-five patients who were diagnosed with HCC were included in our study. TSR was estimated on HCC specimen hematoxylin–eosin staining (HE) sections, and the optimal TSR cut-off value was determined by receiver operating characteristic (ROC) curves. The correlation between the TSR and clinicopathologic features was also calculated. Immunohistochemistry (IHC) staining was also carried out to analyze the PD-L1 expression level in HCCs. Results The optimal TSR cut-off value was 0.525. The median OS of the stroma-high and stroma-low groups was 27 and 36 months, respectively. The median RFS of the stroma-high and stroma-low groups was 14.5 and 27 months, respectively. In the Cox multivariate analysis, the TSR was an independent prognostic factor for HCC overall survival (OS) and recurrence-free survival (RFS) in patients who underwent liver resection. IHC staining revealed TSR-high HCC samples with high PD-L1-positive cell expression. Conclusions Our results suggest that the TSR can predict the prognosis of HCC patients who underwent liver resection. The TSR is related to PD-L1 expression and may be a therapeutic target that can dramatically improve HCC patients’ clinical outcomes.

Cognitive processing relies on the functional coupling between the cerebrum and cerebellum. However, it remains unclear how the 2 collaborate in amnestic mild cognitive impairment (aMCI) patients. With functional magnetic resonance imaging techniques, we compared cerebrocerebellar functional connectivity during the resting state (rsFC) between the aMCI and healthy control (HC) groups. Additionally, we distinguished coupling between functionally corresponding and noncorresponding areas across the cerebrum and cerebellum. The results demonstrated decreased rsFC between both functionally corresponding and noncorresponding areas, suggesting distributed deficits of cerebrocerebellar connections in aMCI patients. Increased rsFC was also observed, which were between functionally noncorresponding areas. Moreover, the increased rsFC was positively correlated with attentional scores in the aMCI group, and this effect was absent in the HC group, supporting that there exists a compensatory mechanism in patients. The current study contributes to illustrating how the cerebellum adjusts its coupling with the cerebrum in individuals with cognitive impairment.

Since the flight of Unmanned Aerial Vehicle (UAV) greatly consumes the limited on-board energy and affects the ability to afford computation services, it is urgent and challenging to minimize UAV’s endurance time while satisfying varieties of constraints from the UAVs and users, such as energy budgets, cache capacities, computation resources, and latency requirements. In this paper, the UAVs are endowed with the capability to temporarily buffer some offloaded tasks and process them later, then adopt cooperative computation and cache scheduling to minimize their total endurance time. Following this, the formulated problem is a mix-integer nonlinear programming problem, which can be further transformed into three more tractable subproblems: 1) PO, offloading decision and scheduling strategy for computing & caching; 2) PH, hovering trajectory design; 3) PC, computation resource allocation, and then iteratively tackled in a sequence. Due to the high complexity of solving PO, the low-complexity algorithm based on the K-means clustering and Penalty Method is proposed to reduce complexity and facilitate the processing procedure, which can save about 91.04%-189.36% running time and ONLY sacrifice 8.05%-22.08% of the total endurance time. Simulation results show that cooperative computation and cache scheduling has a great effect on saving endurance time.

Cutaneous metastases as an extrahepatic metastasis from hepatomas (HCC) is extremely rare and always carry a poor prognosis and less survival time. Previously, there has been a limited number of literature that reported skin metastasis in a large number of cases, which has rarely been discussed in the empirical treatment and therapy of cutaneous metastasis, especially for non-iatrogenic implantation. It is necessary to discuss this kind of metastasis.We summarize cases from our medical center from 2013 to 2021, there are 12 patients diagnosed with non-iatrogenic implantation of cutaneous metastasis after HCC. We conducted the investigation of the clinical prognosis, pathological characteristics, and treatment of those patients.All patients were male, the age ranged from 21 to 71 years old, the average size of primary HCC was over 5 cm, there was four patient's cutaneous metastasis from the skin of head (including scalp and occipital region), followed by right abdominal (2 patients), right chest wall (2 patients), back (2 patients), umbilical (1 patient), gluteal region (1 patient). The cutaneous metastases presented as solitary or multiple nodules, papules, and erythema without ulcers with sizes between 0.5 cm and 5 cm. 7 patients died after being diagnosed with cutaneous metastasis within 2-19 months.The rate of non-iatrogenic implantation cutaneous metastasis is low, but the prognosis is poor, combining with histopathological analysis and history of diseases can be helpful in diagnosis. For large HCC ( 5 cm), systematic treatment is recommended to prevent the occurrence of cutaneous metastasis and improve the prognosis after hepatectomy.

African swine fever virus (ASFV), a large and complex cytoplasmic double-stranded DNA virus, has developed multiple strategies to evade the antiviral innate immune responses. Cytosolic DNA arising from invading ASFV is mainly detected by the cyclic GMP-AMP synthase (cGAS) and then triggers a series of innate immune responses to prevent virus invasion. However, the immune escape mechanism of ASFV remains to be fully clarified. The pS273R of ASFV is a member of the SUMO-1-specific protease family and is crucial for valid virus replication. In this study, we identified pS273R as a suppressor of cGAS-STING pathway mediated type I interferon (IFN) production by ASFV genomic open reading frame screening. The pS273R was further confirmed as an inhibitor of IFN production as well as its downstream antiviral genes in cGAS-STING pathway. Mechanistically, pS273R greatly decreased the cGAS-STING signaling by targeting IKKε but not TBK1, and pS273R was found to disturb the interaction between IKKε and STING through its interaction with IKKε. Further, mutational analyses revealed that pS273R antagonized the cGAS-STING pathway by enzyme catalytic activity, which might affect the IKKε sumoylation state required for the interaction with STING. In summary, our results revealed for the first time that pS273R acts as an obvious negative regulator of cGAS-STING pathway by targeting IKKε via its enzymatic activity, which shows a new immune evasion mechanism of ASFV.