Proteomic and metabolomic features in patients with HCC responding to lenvatinib and anti-PD1 therapy.

Combination therapy (lenvatinib/programmed death-1 inhibitor) is effective for treating unresectable hepatocellular carcinoma (uHCC). We reveal that responders have better overall and progression-free survival, as well as high tumor mutation burden and special somatic variants. We analyze the proteome and metabolome of 82 plasma samples from patients with hepatocellular carcinoma (HCC; n = 51) and normal controls (n = 15), revealing that individual differences outweigh treatment differences. Responders exhibit enhanced activity in the alternative/lectin complement pathway and higher levels of lysophosphatidylcholines (LysoPCs), predicting a favorable prognosis. Non-responders are enriched for immunoglobulins, predicting worse outcomes. Compared to normal controls, HCC plasma proteins show acute inflammatory response and platelet activation, while LysoPCs decrease. Combination therapy increases LysoPCs/phosphocholines in responders. Logistic regression/random forest models using metabolomic features achieve good performance in the prediction of responders. Proteomic analysis of cancer tissues unveils molecular features that are associated with side effects in responders receiving combination therapy. In conclusion, our analysis identifies plasma features associated with uHCC responders to combination therapy.

Spatiotemporal evolution and influencing factors of the allocation of social care resources for the older adults in China.

BACKGROUND: The reasonable allocation of social care resources for the older adults is a key measure to actively respond to population aging. This study aims to evaluate the evolutionary trend, spatial differences and influencing factors of the social elderly care resources (SECR) allocation in China. METHODS: This study constructed a comprehensive index system consisting of three dimensions: material resources, human resources and financial resources, to measure the level of SECR in mainland China. The Kernel density estimation was used to reveal the dynamic evolution trend, and Dagum Gini Coefficient and its decomposition method were used to investigate the equity of SECR allocation. Spatial panel regression models were used to analyze the influencing factors of the allocation of SECR. RESULTS: The level of SECR is rising from 0.197 in 2013 to 0.208 in 2019. The middle-high- and high-level areas of SECR were mainly distributed in the eastern and western China. The Gini coefficient of SECR decreased from 0.262 in 2013 to 0.249 in 2019. Per capita GDP, the proportion of social welfare expenditure in GDP and the proportion of the tertiary industry in GDP have significant positive effects on the allocation of SECR. Population aging and the development of service industry exhibit significant negative spatial spillover effects on the allocation of SECR. CONCLUSIONS: The fairness of the allocation of SECR in China has been improved, while the spatial distribution is imbalanced. Economic development, fiscal input and the development of service industry have significant positive effects while population aging has significant negative effects on the SECR allocation.

Constructing Solid Electrolyte Interphase for Aqueous Zinc Batteries.

Problems of zinc anode including dendrite and hydrogen evolution seriously degrade the performance of zinc batteries. Solid electrolyte interphase (SEI), which plays a key role in achieving high reversibility of lithium anode in aprotic organic solvent, is also beneficial to performance improvement of zinc anode in aqueous electrolyte. However, various studies about interphase for zinc electrode is quite fragmented, and lack of deep understanding on root causes or general design rules for SEI construction. And water molecules with high reactivity brings serious challenge to the effective SEI construction. Here, we reviewed the brief development history of zinc batteries firstly, then summarized the approaches to construct SEI in aqueous electrolyte. Furthermore, the formation mechanisms behind approaches are systematically analyzed, together with discussion on the SEI components and evaluation on electrochemical performance of zinc anode with various types of SEI. Meanwhile, the challenge between lab and industrialization are also discussed.

Propofol Regulates HIF-1 α Effect of Expression of Targeted SIRT1 Signal pathway on Kidney Renal Clear Cell Carcinoma.

The objective of this study was to investigate the effect of propofol on kidney renal clear cell carcinoma (KIRC) by regulating hypoxia-inducible factor-1α (HIF-1α) expression and silencing signal regulatory factor 1 (SIRT1) signal pathway. In this regard, human KIRC cell line RCC4 was added into 0, 5 and 10 µ G/ml propofol treatment and was divided into a control group (CG), low dose group (LG) and high dose group (HG). CCK8 was used to detect the proliferative ability of the three groups of cells, ELISA was used to detect the level of inflammatory factors in the cells, Western blot was used to detect the protein expression, qPCR was used to detect the related mRNA expression level, and Transwell method was used to detect the invasive ability of the cells in vitro. The experimental results showed that propofol decreased the proliferation and invasion ability of KIRC cells, up-regulated the expression of TGF- ß 1, IL-6, TNF- α, HIF-1 α, Fas, bax and FasL, and down-regulated the expression of SIRT1 in a dose-dependent manner. It was concluded that propofol can inhibit the SIRT1 signal pathway by up-regulating the level of HIF-1α in KIRC, which can significantly decrease the proliferation and invasion ability of KIRC cells, induce apoptosis and increase the release of intracellular inflammatory factors.

Spatial differentiation and driving factors of the high-quality development of undertakings for the aged of China.

BACKGROUND: Promoting the high-quality development (HQD) of undertakings for the aged is an important action to proactively respond to the rapid population aging in China. This study analyzes spatial differentiation and driving factors of the HQD of China's undertakings for the aged. METHODS: Based on a quantitative indicator system consisting of old-age social security, elder care services, health care service and older adults' social participation, the HQD levels of 31 Chinese provincial administrative regions during 2013-2019 are measured by using the entropy weight method. Spatial panel regression models are used to analyze the impact of population aging, economic development and digital technology on the HQD of undertakings for the aged. RESULTS: The comprehensive level of the HQD slightly increased from 0.212 to 2013 to 0.220 in 2019, and the overall level was low. The HQD of the eastern region was the highest (0.292), followed by the western region (0.215), and the central region was the lowest (0.151). The high-high cluster type was mainly distributed in the eastern region; the low-low cluster type was mainly distributed in the western and central regions. Economic development and digital technology have significant positive effects while population aging has significant negative effects on the HQD of undertakings for the aged. CONCLUSION: There is a significantly spatial differentiation in the HQD of China's undertakings for the aged. In order to promote the HQD of undertakings for the aged, it is necessary to identify development gaps through making HQD evaluation and to focus on the indicators that are critical in maintaining sustainable economic development and to develop digital technology in order to get rid of those gaps.

A self-charging salt water battery for antitumor therapy.

Implantable devices on the tumor tissue as a local treatment are able to work in situ, which minimizes systemic toxicities and adverse effects. Here, we demonstrated an implantable self-charging battery that can regulate tumor microenvironment persistently by the well-designed electrode redox reaction. The battery consists of biocompatible polyimide electrode and zinc electrode, which can consume oxygen sustainably during battery discharge/self-charge cycle, thus modulating hypoxia level in tumor microenvironment. The oxygen reduction in battery leads to the formation of reactive oxygen species, showing 100% prevention on tumor formation. Sustainable consumption of oxygen causes adequate intratumoral hypoxic conditions over the course of 14 days, which is helpful for the hypoxia-activated prodrugs (HAPs) to kill tumor cells. The synergistic effect of the battery/HAPs can deliver more than 90% antitumor rate. Using redox reactions in electrochemical battery provides a potential approach for the tumor inhibition and regulation of tumor microenvironment.

Intratumor microbiome features reveal antitumor potentials of intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is a rare malignancy with a high prevalence in China. This study aimed to characterize the ICC tissues' bacterial metagenomics signature and explore its antitumor potential for cancer. In this study, 16S rRNA sequencing was carried out on 99 tissues to characterize the features of intratumoral microbiota, followed by single-cell RNA sequencing (scRNA-seq) and multilevel validation. The presence of microbial DNA in tissues was determined using staining, fluorescence in situ hybridization (FISH), and transmission electron microscopy (TEM). A Gram-positive aerobic bacterium, identified as Staphylococcus capitis, was cultured from fresh tissues. Meanwhile, scRNA-seq showed that intratumoral bacteria could be present in multiple cell types. Using 16S rRNA sequencing, we identified a total of 2,320,287 high-quality reads corresponding to 4,594 OTU (operational taxonomic units) sequences. The most abundant bacterial orders include Burkholderiales, Pseudomonadales, Xanthomonadales, Bacillales and Clostridiales. Alpha and Beta diversity analysis revealed specific features in different tissues. In addition, the content of Paraburkholderia fungorum was significantly higher in the paracancerous tissues and negatively correlated with CA199 (Carbohydrate antigen199) levels. The results of in vitro and in vivo experiments suggest that P. fungorum possesses an antitumor activity against tumors. Metabolomics and transcriptomics showed that P. fungorum could inhibit tumor growth through alanine, aspartate and glutamate metabolism. We determined the characteristic profile of the intratumoral microbiota and the antitumor effect of P. fungorum in ICC.

Inhibition of miR-495-3p ameliorated sevoflurane induced damage through BDNF/ERK/CREB signaling pathways in HT22 cells.

OBJECTIVE: Sevoflurane is used in anesthesia for surgery including in organ transplantation. We investigated the role of a non-coding single-stranded microRNA, miR-495-3p, in the sevoflurane-induced neurotoxicity using a mouse hippocampal neuronal cell line (HT22). METHODS: The levels of miR-495-3p in sevoflurane-exposed mice and HT22 cells were determined via RT-qPCR. The role of miR-495-3p on cell viability and apoptosis were determined by CCK-8 and flow cytometric assay, respectively. Western blotting was explored to measure levels of Bax, Bcl-2, active caspase 3, BDNF, p-ERK/ERK and p-CREB/CREB in HT22 cells. ELISA assay was used to examine the levels of reactive oxygen species (ROS), superoxide dismutase (SOD) and glutathione peroxidase (GPX) in cells. Dual luciferase reporter assay was used to explore the interaction of miR-495-3p and BDNF. RESULTS: The level of miR-495-3p was increased sevoflurane-exposed mice and in sevoflurane-treated HT22 cells. Downregulation of miR-495-3p inhibited sevoflurane-induced apoptosis and promoted cell proliferation by upregulating the proteins of Bcl-2 and downregulating the expressions of Bax and active caspase-3 in HT22 cells. In addition, inhibition of miR-495-3p alleviated sevoflurane-induced oxidative injuries in HT22 cells via decline of ROS and upregulation of SOD and GPX. MiR-495-3p can inhibit the ERK/CREB pathway by targeting BDNF. CONCLUSION: Downregulation of miR-495-3p can decrease oxidative status in HT22 cells and alleviate sevoflurane-induced cytotoxicity through stimulating the BDNF/ERK/CREB pathway.

The Intratumoral Bacterial Metataxonomic Signature of Hepatocellular Carcinoma.

Microbiota is implicated in hepatocellular carcinoma (HCC). The spectrum of intratumoral microbiota associated with HCC progression remains elusive. Fluorescence in situ hybridization revealed that microbial DNAs were distributed in the cytosol of liver hepatocytes and erythrocytes. Viable anaerobic or aerobic bacteria were recovered in HCC tissues by fresh tissue culture. We performed a comprehensive DNA sequencing of bacterial 16S rRNA genes in 156 samples from 28 normal liver, 64 peritumoral, and 64 HCC tissues, and the DNA sequencing yielded 4.2 million high-quality reads. Both alpha and beta diversity in peritumor and HCC microbiota were increased compared to normal controls. The most predominant phyla in HCC were Patescibacteria, Proteobacteria, Bacteroidota, Firmicutes, and Actinobacteriota. phyla of Proteobacteria, Firmicutes, and Actinobacteriota, and classes of Bacilli and Actinobacteria, were consistently enriched in peritumor and HCC tissues, while Gammaproteobacteria was especially abundant in HCC tissues compared to normal controls. Streptococcaceae and Lactococcus were the marker taxa of HCC cirrhosis. The Staphylococcus branch and Caulobacter branch were selectively enriched in HBV-negative HCCs. The abundance of Proteobacteria, Gammaproteobacteria, Firmicutes, Actinobacteriota, and Saccharimonadia were associated with the clinicopathological features of HCC patients. The inferred functions of different taxa were changed between the microbiota of normal liver and peritumor/HCC. Random forest machine learning achieved great discriminative performance in HCC prediction (area under the curve [AUC] = 1.00 in the training cohort, AUC = 0.950 for top five class signature, and AUC = 0.943 for the top 50 operational taxonomy units [OTUs] in the validation cohort). Our analysis highlights the complexity and diversity of the liver and HCC microbiota and established a specific intratumoral microbial signature for the potential prediction of HCC. IMPORTANCE Gut microbiome is an important regulator of hepatic inflammation, detoxification, and immunity, and contributes to the carcinogenesis of liver cancer. Intratumoral bacteria are supposed to be closer to the tumor cells, forming a microenvironment that may be relevant to the pathological process of hepatocellular carcinoma (HCC). However, the presence of viable intratumoral bacteria remains unclear. It is worth exploring whether the metataxonomic characteristics of intratumoral bacteria can be used as a potential marker for HCC prediction. Here, we present the first evidence of the existence of viable intratumoral bacteria in HCC using the tissue culture method. We revealed that microbial DNAs were distributed in the cytosol of liver hepatocytes and erythrocytes. We analyzed the diversity, structure, and abundance of normal liver and HCC microbiota. We built a machine learning model for HCC prediction using intratumoral bacterial features. We show that specific taxa represent potential targets for both therapeutic and diagnostic interventions.

Discovery of 2H-benzo[b][1,4]oxazin-3(4H)-one derivatives as potent and selective CDK9 inhibitors that enable transient target engagement for the treatment of hematologic malignancies.

Cyclin-dependent kinase 9 (CDK9) is a transcriptional regulator and a potential therapeutic target in hematologic malignancies. Selective and transient CDK9 inhibition reduces Mcl-1 expression and induces apoptosis in Mcl-1-dependent tumor cells for survival. Here, we describe our efforts to discover a novel series of 2H-benzo[b][1,4]oxazin-3(4H)-one as CDK9 inhibitors. Compound 32k was identified as a selective CDK9 inhibitor with short pharmacokinetic and physicochemical properties suitable for intravenous administration. Short-term treatment with 32k resulted in a rapid dose-dependent decrease in cellular p-Ser2-RNAPII, Mcl-1 and c-Myc, leading to apoptosis in the MV4-11 cell line. Correspondingly, significant in vivo antitumor efficacy was observed in xenograft models derived from multiple hematological tumors with intermittent 32k dosing. These results provide evidence that selective transient CDK9 inhibitors could be used for the treatment of hematologic malignancies.

Effects of Drying Methods on the Physicochemical Aspects and Volatile Compounds of Lyophyllum decastes.

In this study, fresh Lyophyllum decastes was dried using hot air drying (HAD), hot air combined with vacuum drying (HAVD), and vacuum freeze drying (VFD). Additionally, the quality and volatile compounds were analyzed. VFD achieved the best color retention, the highest rehydration capacity, and the slightest damaged tissue structure; however, it recorded the longest drying time and the highest energy consumption. HAD was the most energy-efficient of the three methods. Furthermore, the products with more hardness and elasticity were obtained by HAD and HAVD-this finding was convenient for transportation. In addition, GC-IMS demonstrated that the flavor components had significantly changed after drying. A total of 57 volatile flavor compounds was identified, and the aldehyde, alcohol, and ketone compounds were the primary ingredient of the L. decastes flavor component, whereby the relative content of the HAD sample was apparently higher than HAVD and VFD. Taken together, VFD was better at preserving the color and shape of fresh L. decastes, but HAD was more appropriate for drying L. decastes because of the lower energy consumption, and was more economical. Meanwhile, HAD could be used to produce a more intense aroma.

Dual role of O2 concentration on the reducing gases produced and NO reduction during sewage sludge combustion in pilot scale cement precalciner.

The reducing gases produced and NO reduction by sewage sludge combustion were investigated in a self-made cement precalciner. The dual role of O2 concentration (0-5 vol%) in the production characteristics of reducing gases and the reduction efficiency of NO were evaluated experimentally. TG-FTIR analysis demonstrated that the key reducing gaseous species produced by sewage sludge combustion were HCN, NH3, CO, and CH4. And experiments demonstrated that O2 concentration had pronounced effects on NH3 distribution, the maximum production rate was obtained at an O2 concentration of 3 vol%. Meanwhile, the reducing gases NH3 and CO were the key species for NO reduction in the cement precalciner, and the reduction efficiency of NO, when reduced by NH3, increased with an increase in O2 concentration, while the reduction performance of NO by CO was limited by O2 concentration. Therefore, O2 concentration greatly influences NO reduction efficiency by sewage sludge combustion; the maximum NO reduction efficiency was 61.67% at an O2 concentration of 3 vol%. The difference in NO reduction by sewage sludge combustion under different O2 concentrations was primarily attributed to NH3 production rate and NO reduction by NH3 and CO, which is greatly affected by O2 concentration. Sewage sludge combustion can result in NO reduction in the cement kiln flue gas and resource utilisation of sewage sludge.

Towards High Performance Li-S Batteries via Sulfonate-Rich COF-Modified Separator.

Lithium-sulfur (Li-S) batteries are held great promise for next-generation high-energy-density devices; however, polysulfide shuttle and Li-dendrite growth severely hinders their commercial production. Herein, a sulfonate-rich COF (SCOF-2) is designed, synthesized, and used to modify the separator of Li-S batteries, providing a solution for the above challenges. It is found that the SCOF-2 features stronger electronegativity and larger interlayer spacing than that of none/monosulfonate COFs, which can facilitate the Li+ migration and alleviate the formation of Li-dendrites. Density functional theory (DFT) calculations and in situ Raman analysis demonstrate that the SCOF-2 possesses a narrow bandgap and strong interaction on sulfur species, thereby suppressing self-discharge behavior. As a result, the modified batteries deliver an ultralow attenuation rate of 0.047% per cycle over 800 cycles at 1 C, and excellent anti-self-discharge performance by a low-capacity attenuation of 6.0% over one week. Additionally, even with the high-sulfur-loading cathode (3.2-8.2 mgs cm-2 ) and lean electrolyte (5 µL mgs -1 ), the batteries still exhibit ≈80% capacity retention over 100 cycles, showing great potential for practical application.

Chemically Self-Charging Aqueous Zinc-Organic Battery.

Zn-organic batteries are attracting extensive attention, but their energy density is limited by the low capacity (<400 mAh g-1) and potential (<1 V vs Zn/Zn2+) of organic cathodes. Herein, we propose a long-life and high-rate Zn-organic battery that includes a poly(1,5-naphthalenediamine) cathode and a Zn anode in an alkaline electrolyte, where the cathode reaction is based on the coordination reaction between K+ and the C═N group (i.e., C═N/C-N-K conversion). Interestingly, we find that the discharged Zn-organic battery can recover to its initial state quickly with the presence of O2, and the theoretical calculation demonstrates that the K-N bond in the discharged cathode can be easily broken by O2 via redox reaction. Accordingly, we design a chemically self-charging aqueous Zn-organic battery. Benefiting from the excellent self-rechargeability, the organic cathode exhibits an accumulated capacity of 16264 mAh g-1, which enables the Zn-organic battery to show a record high energy density of 625.5 Wh kg-1.

Discovery of N-(4-(3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-yl)-4-(4-methylpiperazin-1-yl)quinazolin-7-amine as a Novel, Potent, and Oral Cyclin-Dependent Kinase Inhibitor against Haematological Malignancies.

Hematologic malignancies (HM) start in blood forming tissue or in the cells of the immune system. Cyclin-dependent kinases (CDKs) regulate cell cycle progression, and some of them control cellular transcription. CDK inhibition can trigger apoptosis and could be particularly useful in hematological malignancies. Herein, we describe our efforts toward the discovery of a novel series of quinazoline derivatives as CDK inhibitors. Intensive structural modifications lead to the identification of compound 37d as the most active inhibitors of CDKs 1, 2, 4, 8 and 9 with balancing potency and selectivity against CDKs. Further biological studies revealed that compound 37d can arrest the cell cycle and induce apoptosis via activating PARP and caspase 3. More importantly, compound 37d showed good antitumor efficacy in multiple HM mice xenograft models with no obvious toxicity. These results indicated that CDK 1, 2, 4, 8, and 9 inhibitors could be potentially used to treat certain hematologic malignancies.

Structure-based discovery of 1H-indole-2-carboxamide derivatives as potent ASK1 inhibitors for potential treatment of ulcerative colitis.

Apoptosis signal-regulating kinase 1 (ASK1), a member of the mitogen-activated protein kinase (MAPK) family, is implicated in many human diseases. Here, we describe the structural optimization of hit compound 7 and conduct further structure-activity relationship (SAR) studies that result in the development of compound 19 with a novel indole-2-carboxamide hinge scaffold. Compound 19 displays potent anti-ASK1 kinase activity and stronger inhibitory effect on ASK1 in AP1-HEK293 cells than previously described ASK1 inhibitor GS-4997. Besides improved in vitro activity, compound 19 also exhibits an appropriate in vivo PK profile. In a dextran sulfate sodium (DSS)-induced mouse model of ulcerative colitis (UC), compound 19 shows significant anti-UC efficacy and markedly attenuates DSS-induced body weight loss, colonic shortening, elevation in disease activity index (DAI) and inflammatory cell infiltration in colon tissues. Mechanistically, compound 19 represses the phosphorylation of ASK1-p38/JNK signaling pathways and suppresses the overexpression of inflammatory cytokines. Together, these findings suggest that ASK1 inhibitors can potentially be used as a therapeutic strategy for UC.

Effect of Ca(OH)2 on the Release Characteristics of HCl during Sludge Combustion.

With the addition of Ca(OH)2, the effects of combustion temperature, moisture, sludge particle size, and chlorine-containing additives on the removal of HCl during sludge combustion were studied. The experimental results showed that combustion temperature and moisture content promoted the formation of HCl and Ca(OH)2 played a key role in the formation of HCl during sludge combustion. Under the best conditions of a sludge particle size of 380-250 µm, moisture content of 5%, temperature of 850 °C, and Ca(OH)2/sludge weight ratio of 3/10, the HCl capture efficiency was 79.81%. In addition, the effect of PVC on the production of HCl was greater than that of NaCl, probably because the lattice energy of NaCl was much higher, indicating that inorganic chlorine was not the main source of HCl. Ca(OH)2 can effectively inhibit the formation of HCl, which had practical guiding significance for the formation of HCl during the sludge combustion, especially the sludge containing chlorine.

Study on the influencing factors of removal of NOX from cement kiln flue gas by sewage sludge as a denitration agent.

Experimental study on the influencing factors of using sewage sludge as a denitration agent for cement industry was carried out on a self-made laboratory-scale fluid-bed reactor. Results indicate that sludge combustion at 900 °C shows an ideal NOX (the sum of NO and NO2) removal activity under simulated working conditions of cement precalciner. The optimal removal efficiency of NOX can reach 70.36 ± 3.59% in the presence of cement raw meal (CRM) at a sludge particle size range of 0.18-0.25 mm and the sludge dosage of 0.75 g/min. Besides, the NOX removal efficiency increases to 76.94 ± 5.02% in the absence of CRM, indicating that cement raw meal inhibits the NOX removal. This phenomenon may be attributed to the fact that CRM has promotion effect on NH3 produced and obvious inhibitory effect on CO produced; while NH3 and CO play a leading role in NOX reduction, the combined effect leads to the decrease of NOX removal. Moreover, the relationship between the composition of CRM on the inhibition of NOX removal is MgO < CaCO3 < CRM < Al2O3

Discovery of coumarin derivatives as potent and selective cyclin-dependent kinase 9 (CDK9) inhibitors with high antitumour activity.

Specific inhibition of CDK9 is considered a promising strategy for developing effective anticancer therapeutics. However, most of the reported CDK9 inhibitors are still at an early stage of development and lack selectivity against other CDKs. Herein, we discovered coumarin derivative 30i as a potent CDK9 inhibitor with high selectivity (8300-fold over CDK7). Binding mode analysis illustrated that the substituent coumarin moiety is a critical group for CDK9 selectivity by occupying a flexible hinge/αD region, which is sterically hindered in other CDKs. Compound 30i showed excellent cellular antiproliferative activity, moderate pharmacokinetic property and low hERG inhibition. Moreover, 30i significantly induced tumour growth inhibition in a dose-dependent manner without causing an obvious loss of body weight in an MV4-11 xenograft mice model. Altogether, these results suggest that 30i may serve as a potential acute myeloid leukaemia (AML) therapeutics by selectively targeting CDK9.