Scaling of the strange-metal scattering in unconventional superconductors.

Marked evolution of properties with minute changes in the doping level is a hallmark of the complex chemistry that governs copper oxide superconductivity as manifested in the celebrated superconducting domes and quantum criticality taking place at precise compositions1-4. The strange-metal state, in which the resistivity varies linearly with temperature, has emerged as a central feature in the normal state of copper oxide superconductors5-9. The ubiquity of this behaviour signals an intimate link between the scattering mechanism and superconductivity10-12. However, a clear quantitative picture of the correlation has been lacking. Here we report the observation of precise quantitative scaling laws among the superconducting transition temperature (Tc), the linear-in-T scattering coefficient (A1) and the doping level (x) in electron-doped copper oxide La2-xCexCuO4 (LCCO). High-resolution characterization of epitaxial composition-spread films, which encompass the entire overdoped range of LCCO, has enabled us to systematically map its structural and transport properties with unprecedented accuracy and with increments of Δx = 0.0015. We have uncovered the relations Tc ~ (xc - x)0.5 ~ (A1□)0.5, where xc is the critical doping in which superconductivity disappears and A1□ is the coefficient of the linear resistivity per CuO2 plane. The striking similarity of the Tc versus A1□ relation among copper oxides, iron-based and organic superconductors may be an indication of a common mechanism of the strange-metal behaviour and unconventional superconductivity in these systems.

Exosomal long non-coding RNA TRPM2-AS promotes angiogenesis in gallbladder cancer through interacting with PABPC1 to activate NOTCH1 signaling pathway.

BACKGROUND: Abnormal angiogenesis is crucial for gallbladder cancer (GBC) tumor growth and invasion, highlighting the importance of elucidating the mechanisms underlying this process. LncRNA (long non-coding RNA) is widely involved in the malignancy of GBC. However, conclusive evidence confirming the correlation between lncRNAs and angiogenesis in GBC is lacking. METHODS: LncRNA sequencing was performed to identify the differentially expressed lncRNAs. RT-qPCR, western blot, FISH, and immunofluorescence were used to measure TRPM2-AS and NOTCH1 signaling pathway expression in vitro. Mouse xenograft and lung metastasis models were used to evaluate the biological function of TRPM2-AS during angiogenesis in vivo. EDU, transwell, and tube formation assays were used to detect the angiogenic ability of HUVECs. RIP, RAP, RNA pull-down, dual-luciferase reporter system, and mass spectrometry were used to confirm the interaction between TRPM2-AS, IGF2BP2, NUMB, and PABPC1. RESULTS: TRPM2-AS was upregulated in GBC tissues and was closely related to angiogenesis and poor prognosis in patients with GBC. The high expression level and stability of TRPM2-AS benefited from m6A modification, which is recognized by IGF2BP2. In terms of exerting pro-angiogenic effects, TRPM2-AS loaded with exosomes transported from GBC cells to HUVECs enhanced PABPC1-mediated NUMB expression inhibition, ultimately promoting the activation of the NOTCH1 signaling pathway. PABPC1 inhibited NUMB mRNA expression through interacting with AGO2 and promoted miR-31-5p and miR-146a-5p-mediated the degradation of NUMB mRNA. The NOTCH signaling pathway inhibitor DAPT inhibited GBC tumor angiogenesis, and TRPM2-AS knockdown enhanced this effect. CONCLUSIONS: TRPM2-AS is a novel and promising biomarker for GBC angiogenesis that promotes angiogenesis by facilitating the activation of the NOTCH1 signaling pathway. Targeting TRPM2-AS opens further opportunities for future GBC treatments.

Structure/Composition/Phase Regulations of Dealloying-Derived Nanoporous Metals and Their Solar Steam Generation Performances.

Structural regulation is of primary importance in structure-property/application studies of dealloyed nanoporous metals. Three aspects are mainly considered to affect the microstructure of nanoporous metals: design of precursor alloy, choosing of dealloying parameter, and annealing treatment. Herein, through the combination of the above three strategies, the regulation of structure, composition and phase in nanoporous metals are simultaneously achieved. With a dilute Cu99Ag0.75Au0.25 as the precursor, three kinds of nanoporous films are fabricated, including bi-phase nanoporous Cu-Ag-Au (B-NP-CuAgAu), hierarchically nanoporous Au (H-NPG) and single-phase homogeneously nanoporous Au (S-NPG). In situ X-ray diffraction and ex situ characterizations are utilized to reveal the structure/composition/phase evolutions during dealloying of Cu99Ag0.75Au0.25, as well as the macroscopic changes of the dealloyed samples. Notably, the ultrafine ligaments/channels of B-NP-CuAgAu and the two-level nanoporous structure of H-NPG endow them with good broadband light absorption and excellent hydrophilicity, which contribute to their outstanding solar steam generation (SSG) performances. Specially, the B-NP-CuAgAu film shows a more efficient SSG performance with water evaporation rate of 1.49 kg m-2 h-1 and photothermal efficiency of 93.6% at 1 kW m-2, and good seawater desalination ability.

HDAC3 Controls Liver Homeostasis More by Facilitating Deoxyribonucleic Acid Damage Repair than by Regulating Transcription in Hepatocytes.

By controlling DNA damage repair and regulating gene transcription, the critical epigenetic regulator histone deacetylase 3 (HDAC3) plays pivotal roles in liver cancer and liver regeneration; however, the role of HDAC3 in liver homeostasis has not been fully elucidated. In this study, we found that HDAC3-deficient livers developed a defective morphology and metabolism with an increasing degree of DNA damage in the hepatocytes along the portal-central axis of the lobule. Most strikingly, in the Alb-CreERT:Hdac3-/- mice, it was demonstrated that HDAC3 ablation did not impair liver homeostasis in terms of histologic characteristics, function, proliferation, or gene profiles prior to the profound accumulation of DNA damage. Next, we identified that the hepatocytes in the portal area, which carried less DNA damage than those in the central area, repopulated the hepatic lobule by active regeneration and movement toward the center. As a result, the liver became more viable after each surgery. Furthermore, in vivo tracing of keratin-19-expressing hepatic progenitor cells, which lacked HDAC3, showed that the hepatic progenitor cells gave rise to newly generated periportal hepatocytes. In hepatocellular carcinoma, HDAC3 deficiency impaired DNA damage response and enhanced radiotherapy sensitivity in vitro and in vivo. Taken together, we demonstrated that HDAC3 deficiency interferes with liver homeostasis, which is more dependent on the accumulation of DNA damage in hepatocytes than on transcriptional dysregulation. Our findings support the hypothesis that selective HDAC3 inhibition has the potential to augment the effect of chemoradiotherapy aimed at inducing DNA damage in cancer therapy.

Increased Small Ubiquitin-like Modifier-Activating Enzyme SAE1 Promotes Hepatocellular Carcinoma by Enhancing mTOR SUMOylation.

SUMOylation, one of the most important posttranslational modifications of proteins, plays an essential role in various biological processes; however, enzymes that control SUMOylation in hepatocellular carcinoma (HCC) are still unclear. Comprehensive exploration of the expression and clinical significance of SUMO enzymes in HCC would be of great value. Here, we obtained the gene expression profile of each small ubiquitin-like modifier (SUMO) protein and the corresponding clinical information from The Cancer Genome Atlas. We found that all SUMO enzymes were significantly increased in HCC tissues compared with that in adjacent nontumorous tissues. We identified a 6-gene prognostic signature, including SAE1, PIAS2, PIAS3, SENP3, SENP5, and UBC9, that could effectively predict the overall survival in patients with HCC. Specifically, SAE1 was the most valuable prognostic indicator. In 282 clinical samples, we found that SAE1 was closely related to the clinicopathologic parameters and prognosis of patients with HCC. In vitro and in vivo studies showed that SAE1 knockdown inhibits the proliferation, migration, and invasion of HCC cells. Mechanistically, we confirmed that SAE1 plays a role in driving HCC progression, which is largely dependent on the SUMOylation of mTOR signaling. In conclusion, our study revealed that the expression of SUMO enzymes, especially SAE1, is highly associated with HCC development and acts as a promising prognostic predictor.

VICT2 Trait: Prognostic Alternative to Peritumoral Hepatobiliary Phase Hypointensity in HCC.

Background Peritumoral hepatobiliary phase (HBP) hypointensity is an established prognostic imaging feature in hepatocellular carcinoma (HCC), often associated with microvascular invasion (MVI). Similar prognostic features are needed for non-HBP MRI. Purpose To propose a non-hepatobiliary-specific MRI tool with similar prognostic value to peritumoral HBP hypointensity. Materials and Methods From December 2011 to November 2021, consecutive patients with HCC who underwent preoperative contrast-enhanced MRI were retrospectively enrolled and followed up until recurrence. All MRI scans were reviewed by two blinded radiologists with 7 and 10 years of experiences with liver MRI. A scoring system based on non-hepatobiliary-specific features that highly correlated with peritumoral HBP hypointensity was identified in a stratified sampling-derived training set of the gadoxetate disodium (EOB) group by means of multivariable logistic regression, and its values to predict MVI and recurrence-free survival (RFS) were assessed. Results There were 660 patients (551 men; median age, 53 years; IQR, 45-61 years) enrolled. Peritumoral portal venous phase hypoenhancement (odds ratio [OR] = 8.8), incomplete "capsule" (OR = 3.3), corona enhancement (OR, 2.6), and peritumoral mild-moderate T2 hyperintensity (OR, 2.2) (all P < .001) were associated with peritumoral HBP hypointensity and constituted the "VICT2 trait" (test set area under the receiver operating characteristic curve = 0.84; 95% CI: 0.78, 0.90). For the EOB group, both peritumoral HBP hypointensity (OR for MVI = 2.5, P = .02; hazard ratio for RFS = 2.5, P < .001) and the VICT2 trait (OR for MVI = 5.1, P < .001; hazard ratio for RFS = 2.3, P < .001) were associated with MVI and RFS, despite a higher specificity of the VICT2 trait for MVI (89% vs 80%, P = .01). These values of the VICT2 trait were confirmed in the extracellular contrast agent group (OR for MVI = 4.0; hazard ratio for RFS = 1.7; both P < .001). Conclusion Based on four non-hepatobiliary-specific MRI features, the VICT2 trait was comparable to peritumoral hepatobiliary phase hypointensity in predicting microvascular invasion and postoperative recurrence of hepatocellular carcinoma. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Harmath in this issue.

Hepatocyte-specific HDAC3 ablation promotes hepatocellular carcinoma in females by suppressing Foxa1/2.

BACKGROUND: Hepatocellular carcinoma (HCC), the most common primary liver cancer, prevails mainly in males and has long been attributed to androgens and higher circumstantial levels of interleukin-6 (IL-6) produced by resident hepatic macrophages. METHODS: Constitutively hepatocyte-specific histone deacetylase 3 (HDAC3)-deficient (HDAC3LCKO) mice and constitutively hepatocyte-specific HDAC3 knockout and systemic IL-6 simultaneously ablated (HDAC3LCKO& IL-6-/-) mice were used in our study to explore the causes of sex differences in HCC. Additionally, we performed human HCC tissues with an IHC score. Correlation analysis and linear regression plots were constructed to reveal the association between HDAC3 and its candidate genes. To further elucidate that HDAC3 controls the expression of Foxa1/2, we knocked down HDAC3 in HUH7 liver cancer cells. RESULTS: We observed a contrary sex disparity, with an earlier onset and higher incidence of HCC in female mice when HDAC3 was selectively ablated in the liver. Loss of HDAC3 led to constant liver injury and the spontaneous development of HCC. Unlike the significant elevation of IL-6 in male mice at a very early age, female mice exhibit stable IL-6 levels, and IL-6 ablation did not eliminate the sex disparity in hepatocarcinogenesis in HDAC3-deficient mice. Oestrogen often protects the liver when combined with oestrogen receptor alpha (ERα); however, ovariectomy in HDAC3-ablated female mice significantly delayed tumourigenesis. The oestrogen-ERα axis can also play a role in tumour promotion in the absence of Foxa1 and Foxa2 in the receptor complex. Loss of HDAC3 profoundly reduced the expression of both Foxa1 and Foxa2 and impaired the binding between Foxa1/2 and ERα. Furthermore, a more frequent HDAC3 decrease accompanied by the simultaneous Foxa1/2 decline was found in female HCC compared to that in male HCC. CONCLUSION: In summary, we reported that loss of HDAC3 reduces Foxa1/2 and thus promotes HCC development in females in an oestrogen-dependent manner.

Understanding the Reaction Chemistry of 1,1,3,3-Tetramethyldisilazane as a Precursor Gas in a Catalytic Chemical Vapor Deposition Process.

The reaction chemistry of 1,1,3,3-tetramethyldisilazane (TMDSZ) in catalytic chemical vapor deposition (Cat-CVD), including its primary decomposition on a heated W filament and secondary gas-phase reactions in a Cat-CVD reactor, was studied using 10.5 eV vacuum ultraviolet single-photon ionization and/or laser-induced electron ionization in tandem with time-of-flight mass spectrometry. It has been demonstrated that TMDSZ initially breaks down to form various species, including methyl radical (•CH3), ammonia (NH3), and 1,1-dimethylsilanimine (DMSA). The activation energies (Ea) for the formation of •CH3 and NH3 were determined to be 61.2 ± 1.0 and 42.1 ± 0.9 kJ mol-1, respectively, in the temperature range of 1400-2000 and 900-2400 °C. It was found that the formation of DMSA may have two different contributing routes, i.e., a concerted one (Ea = 33.6 ± 2.3 kJ mol-1) at lower temperatures of 900-1500 °C and a stepwise one (Ea = 155.0 ± 7.8 kJ mol-1) at higher temperatures of 2100-2400 °C. The secondary gas-phase reactions occurring in the Cat-CVD reactor environment were found to stem from two competing processes. The first one, free-radical short-chain reactions initiated by •CH3 formation and propagated by H abstraction reactions, is the dominating chemical process, producing many high-mass stable alkyl-substituted or silyl-substituted disilazane or trisilazane products via radical recombination reactions. Head-to-tail cycloaddition of unstable DMSA is the second contributing chemical process, which forms cyclodisilazane species. In addition, evidence was found for the conversion of NH3 into H2 and N2 in the Cat-CVD reactor.

Genetic Association of Circulating Adipokines with Risk of Idiopathic Pulmonary Fibrosis: A Two-Sample Mendelian Randomization Study.

PURPOSE: The causal relationships between circulating adipokines and idiopathic pulmonary fibrosis (IPF) are yet to be established. We performed a two-sample Mendelian randomization (MR) study to investigate the causal roles of adipokines on IPF risk. METHODS: We analyzed the summary data from genome-wide association studies (GWAS), including adiponectin, leptin, resistin and monocyte chemoattractant protein-1 (MCP-1) and IPF. The inverse-variance weighted (IVW) method was considered as the major method and the MR-Egger, weighted median, simple mode and weighted mode were utilized as complementary methods. We also performed the sensitivity analyses, including heterogeneity test, horizontal pleiotropy test and leave-one-out analysis. RESULTS: The selected number of single nucleotide polymorphisms (SNPs) was 13 for adiponectin, 6 for leptin,12 for resistin, and 6 for MCP-1, respectively. The results showed a causal effect of the circulating adiponectin levels on the risk of IPF (OR 0.645, 95% CI 0.457-0.911, P = 0.013). However, we did not observe significant associations of genetic changes in serum leptin (OR 1.018, 95% CI 0.442-2.346, P = 0.967), resistin (OR 1.002, 95% CI 0.712-1.408, P = 0.993), and MCP-1 (OR 1.358, 95% CI 0.891-2.068, P = 0.155) with risk of developing IPF. There was no evidence of heterogeneity or horizontal pleiotropy. The sensitivity analyses confirmed that our results were stable and reliable. CONCLUSIONS: The increase in serum adiponectin was associated causally with a decreased risk of developing IPF. There is no evidence to support a causal association between leptin, resistin or MCP-1 with risk of IPF. Further studies are needed to confirm our findings.

Association of admission lactate with mortality in adult patients with severe community-acquired pneumonia.

PURPOSE: The present study was conducted to investigate the association of admission lactate with mortality in severe community-acquired pneumonia (SCAP). METHODS: We performed a retrospective, observational, cohort study on adult SCAP patients admitted to intensive care unit (ICU) in West China Hospital of Sichuan University between December 2011 and December 2018. The primary outcome was hospital mortality. Univariate and then multivariate analysis were performed to identify independent risk factors for hospital mortality. The association of admission lactate categories with hospital mortality was examined in three logistic regression models and Kaplan-Meier plots. We also applied restricted cubic splines to estimate the potential non-linear associations. RESULTS: In total, 2275 SCAP patients were included. Admission lactate remained a significant factor for mortality after multivariate regression (OR: 1.085; 95% CI: 1.033,1.141; by continuous variable). After lactate was categorized into quartiles and the confounders were fully adjusted, compared with the quartile 1, ORs (95% CIs) of hospital mortality for quartile 2, quartile 3 and quartile 4 were 1.001 (0.759-1.321), 1.153 (0.877-1.516) and 1.593 (1.202-2.109), respectively (P for trend =0.001). Survival curves indicated that elevated lactate was associated with poor prognosis (P < 0.001). Moreover, this association was non-linear, indicating that increased lactate has the most notable impact on mortality within the range of 1.5 to 4 mmol/L (P non-linear: 0.029 for hospital mortality; 0.004 for ICU mortality). CONCLUSION: Elevated admission lactate has a significant, independent, and potentially non-linear association with increased mortality in SCAP patients.

Design, Synthesis, and Biological Activities of Novel 2-Cyanoacrylate Compounds Containing Substituted Pyrazolyl or 1,2,3-Triazolyl Moiety.

To develop novel 2-cyanoacrylate derivatives with potential bioactivity, a number of 2-cyanoacrylate compounds, including substituted pyrazole or 1,2,3-triazole ring, were designed, prepared, and structurally detected by 1H NMR, 13C NMR, and elemental analysis. The biological assessment displayed that some designed compounds had significant herbicidal activities against Brassica juncea, Chenopodium serotinum, Rumex acetosa, Alopecurus aequalis, Polypogon fugax, and Poa annua at a dosage of 1500 g/ha. Furthermore, some derivatives still expressed satisfactory herbicidal activities against Brassica juncea, Chenopodium serotinum, and Rumex acetosa when the dosage was lowered to 150 g/ha, especially the inhibitory effects of compounds 9a, 9d, 9f, 9i, 10a, 10b, 10e, and 10n against Brassica juncea were all over 80%, compounds 9d, 9f, 9g, 9h, 9i, 10h, 10i, 10m, 10n, and 10o possessed more than 70% inhibition rates against Chenopodium serotinum, and compound 9d indicated 70% herbicidal activity against Rumex acetosa. These results provided an important basis for further design and discovery of biologically active 2-cyanoacrylate compounds.

Brahma-Related Gene 1 Inhibition Prevents Liver Fibrosis and Cholangiocarcinoma by Attenuating Progenitor Expansion.

BACKGROUND AND AIMS: Intrahepatic cholangiocarcinoma (iCCA) is closely correlated with hepatic progenitor cell (HPC) expansion and liver fibrosis. Brahma-related gene 1 (Brg1), an enzymatic subunit of the switch/sucrose nonfermentable complex that is critical in stem cell maintenance and tumor promotion, is prominently up-regulated in both HPCs and iCCA; however, its role in this correlation remains undefined. APPROACH AND RESULTS: A retrospective cohort study indicated that high Brg1 expression suggests poor prognosis in patients with iCCA. In chronically injured livers induced by a 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet or bile duct ligation surgery, HPCs were dramatically activated, as indicated by their enhanced expression of Brg1 and a subset of stem cell markers; however, Brg1 ablation in HPCs strongly suppressed HPC expansion and liver fibrosis. Furthermore, in a chemically induced iCCA model, inhibition of Brg1 by a specific inhibitor or inducible gene ablation markedly improved histology and suppressed iCCA growth. Mechanistically, in addition to transcriptionally promoting both Wnt receptor genes and target genes, Brg1 was found to bind to the ß-catenin/transcription factor 4 transcription complex, suggesting a possible approach for regulation of Wnt/ß-catenin signaling. CONCLUSIONS: We have demonstrated the function of Brg1 in promoting HPC expansion, liver cirrhosis, and, ultimately, iCCA development in chronically injured livers, which is largely dependent on Wnt/ß-catenin signaling. Our data suggest that therapies targeting Brg1-expressing HPCs are promising for the treatment of liver cirrhosis and iCCA.

A prediction model for hospital mortality in patients with severe community-acquired pneumonia and chronic obstructive pulmonary disease.

BACKGROUND: No personalized prediction model or standardized algorithm exists to identify those at high risk of death among severe community-acquired pneumonia (SCAP) patients with chronic obstructive pulmonary disease (COPD). The aim of this study was to investigate the risk factors and to develop a useful nomogram for prediction of mortality in those patients. METHODS: We performed a retrospective, observational, cohort study in the intensive care unit (ICU) of West China Hospital, Sichuan University with all consecutive SCAP patients with COPD between December 2011 and December 2018. The clinical data within 24 h of admission to ICU were collected. The primary outcome was hospital mortality. We divided the patients into training and testing cohorts (70% versus 30%) randomly. In the training cohort, univariate and multivariate logistic regression analysis were used to identify independent risk factors applied to develop a nomogram. The prediction model was assessed in both training and testing cohorts. RESULTS: Finally, 873 SCAP patients with COPD were included, among which the hospital mortality was 41.4%. In training cohort, the independent risk factors for hospital mortality were increased age, diabetes, chronic renal diseases, decreased systolic blood pressure (SBP), and elevated fibrinogen, interleukin 6 (IL-6) and blood urea nitrogen (BUN). The C index was 0.840 (95% CI 0.809-0.872) in training cohort and 0.830 (95% CI 0.781-0.878) in testing cohort. Furthermore, the time-dependent AUC, calibration plots, DCA and clinical impact curves indicated the model had good predictive performance. Significant association of risk stratification based on nomogram with mortality was also found (P for trend < 0.001). The restricted cubic splines suggested that estimated associations between these predictors and hospital mortality were all linear relationships. CONCLUSION: We developed a prediction model including seven risk factors for hospital mortality in patients with SCAP and COPD. It can be used for early risk stratification in clinical practice after more external validation.

Formation of Au, Pt, and bimetallic Au-Pt nanostructures from thermal dewetting of single-layer or bilayer thin films.

Formation of Au, Pt, and bimetallic Au-Pt nanostructures by thermal dewetting of single-layer Au, Pt and bilayer Au-Pt thin films on Si substrates was systematically studied. The solid-state dewetting of both single-layer and bilayer metallic films was shown to go through heterogeneous void initiation followed by void growth via capillary agglomeration. For the single-layer of Au and Pt films, the void growth started at a temperature right above the Hüttig temperature, at which the atoms at the surface or at defects become mobile. Uniformly distributed Au (7 ± 1 nm to 33 ± 8 nm) and Pt (7 ± 1 nm) NPs with monodispersed size distributions were produced from complete dewetting achieved for thinner 1.7-5.5 nm thick Au and 1.4 nm thick Pt films, respectively. The NP size is strongly dependent on the initial thin film thickness, but less so on temperature and time. Thermal dewetting of Au-Pt bilayer films resulted in partial dewetting only, forming isolated nano-islands or large particles, regardless of sputtering order and total thin film thickness. The increased resistance to thermal dewetting shown in the Au-Pt bilayer films as compared to the individual Au or Pt layer is a reflection of the stabilizing effect that occurs upon adding Pt to Au in the bimetallic system. Energy dispersive x-ray spectroscopic analysis showed that the two metals in the bilayer films broke up together instead of dewetting individually. According to the x-ray diffraction analysis, the produced Au-Pt nanostructures are phase-segregated, consisting of an Au-rich phase and a Pt-rich phase.

Theoretical Study on the Decomposition Kinetics and Thermochemistry of Tetramethyldisilazane and Hexamethyldisilazane─Formation of Silanimine and Silene Species.

The gas-phase decomposition kinetics and thermochemistry of 1,1,1,3,3,3-hexamethyldisilazane (HMDSZ) and 1,1,3,3-tetramethyldisilazane (TMDSZ), two potential single-source precursors for the chemical vapor deposition of silicon carbonitride thin films, were systematically investigated using ab initio calculations at the B3LYP/6-311++G(d,p)//CCSD(T)/6-311++G(d,p) level of theory. Both concerted and stepwise decomposition routes for each molecule were examined, allowing for a comparison of the reactions involving the cleavages of common bonds of Si-C, Si-N, and N-H for the two molecules. A new set of reaction pathways open to TMDSZ due to the presence of a Si-H bond was also explored. It was found that all three bonds of Si-N, Si-C, and N-H could be broken more easily in TMDSZ than HMDSZ. Both HMDSZ and TMDSZ are capable of producing silene and silanimine species upon decomposition. In fact, the most kinetically and thermodynamically favorable pathways fall in the formation of these species. The concerted formation of 1-dimethylsilylaminosilene via the elimination of methane from TMDSZ is the most kinetically and thermodynamically favorable route between the two molecules with an activation barrier (ΔH0⧧) of 48.5 kcal mol-1 and reaction enthalpy (ΔH0) of 11.6 kcal mol-1, respectively. These values are lower than the corresponding lowest values in HMDSZ of ΔH0⧧ = 66.4 kcal mol-1 for the concerted production of 1,1-dimethylsilene and trimethylsilylamine and ΔH0 = 41.7 kcal mol-1 for the formation of CH4 and N-trimethylsilyl-1,1-dimethylsilanimine. Overall, this work has provided insights into the reactivity of the two molecules. It has been shown that TMDSZ is more reactive than its analog HMDSZ due to the presence of the Si-H bonds and reduced steric hindrance.

Pathophysiological Changes in Rhesus Monkeys with Paraquat-Induced Pulmonary Fibrosis.

PURPOSE: Pulmonary fibrosis is a life-threatening lung disorder. A comprehensive understanding of the pathophysiological changes in the development of pulmonary fibrosis will lead to new insights into its treatment. METHODS: We used a paraquat (PQ)-induced rhesus monkey model of pulmonary fibrosis to comprehensively investigate the process of pulmonary fibrosis development. Rhesus monkeys were orally administered PQ at concentrations of 25 mg/kg, 40 mg/kg, and 80 mg/kg. The dose was given once. Behavior and clinical data, such as PQ concentration, arterial oxygen saturation, biochemical evaluation, lung histopathology, and medical imaging, were continuously observed. RESULTS: Paraquat-exposed monkeys developed pulmonary fibrosis following an expected time course, especially at 25 mg/kg. CT images showed ground-glass lesions in the lung after 4 weeks, and pulmonary fibrosis persisted until the end of follow-up. Using pathological examination, the lung sustained collagen deposition and slight inflammatory cell infiltration. All rhesus monkeys had obvious inflammatory infiltration within 1 week according to the immunohistochemical results and the number of leukocytes in the blood. The CT results showed that pulmonary fibrosis had not formed, indicating that drugs with powerful anti-inflammatory ability are potential candidates for early pulmonary fibrosis treatment. CONCLUSION: Our study describes the dynamic process of paraquat-induced pulmonary fibrosis in rhesus monkeys and provided a pathophysiological basis for the treatment of pulmonary fibrosis.

Clinical profile analysis and nomogram for predicting in-hospital mortality among elderly severe community-acquired pneumonia patients with comorbid cardiovascular disease: a retrospective cohort study.

BACKGROUND: Researchers have linked cardiovascular disease (CVD) with advancing age; however, how it drives disease progression in elderly severe community acquired pneumonia (SCAP) patients is still unclear. This study aims to identify leading risk predictors of in-hospital mortality in elderly SCAP patients with CVD, and construct a comprehensive nomogram for providing personalized prediction. PATIENTS AND METHODS: The study retrospectively enrolled 2365 elderly patients identified SCAP. Among them, 413 patients were found to have CVD. The LASSO regression and multivariate logistic regression analysis were utilized to select potential predictors of in-hospital mortality in elderly SCAP patients with CVD. By incorporating these features, a nomogram was then developed and subjected to internal validations. Discrimination, calibration, and clinical use of the nomogram were assessed via C-index, calibration curve analysis, and decision plot. RESULTS: Compared with patients without CVD, elderly SCAP patients with CVD had a significant poor outcome. Further analysis of the CVD population identified 7 independent risk factors for in-hospital mortality in elderly SCAP patients, including age, the use of vasopressor, numbers of primary symptoms, body temperature, monocyte, CRP and NLR. The nomogram model incorporated these 7 predictors showed sufficient predictive accuracy, with the C-index of 0.800 (95% CI 0.758-0.842). High C-index value of 0.781 was obtained in the internal validation via bootstrapping validation. Moreover, the calibration curve indicative a good consistency of risk prediction, and the decision curve manifested that the nomogram had good overall net benefits. CONCLUSION: An integrated nomogram was developed to facilitate the personalized prediction of in-hospital mortality in elderly SCAP patients with CVD.

Development of New Thiophene-Containing Triaryl Pyrazoline Derivatives as PI3Kγ Inhibitors.

A series of new thiophene-containing triaryl pyrazoline derivatives, 3a-3t, were synthesized and evaluated regarding PI3K inhibition activity and anti-tumor potency based on a trial of introducing significant moieties, including pyrazoline and thiophene, and simplifying the parallel ring structures. Most of the tested compounds indicated potent PI3K inhibitory potency, with this series of compounds showing more potency for PI3Kγ than PI3Kα. The top hit 3s seemed more potent than the positive control LY294002 on inhibiting PI3Kγ (IC50 values: 0.066 µM versus 0.777 µM) and more selective from PI3Kα (Index values: 645 versus 1.74). It could be inferred that the combination of para- and meta-, as well as the modification of the electron-donating moieties, led to the improvement in potency. The anti-proliferation inhibitory activity and the enzymatic inhibition potency indicated consistent tendencies. The top hit 3s could inhibit the phosphorylation of Akt by inhibiting PI3K through the PI3K-Akt-mTOR pathway. The molecular docking simulation indicated that the binding pattern of 3s into PI3Kγ was preferable than that of PI3Kα, with more hydrogen bond, more π-involved interactions, and fewer π-sulfur interactions. The information in this work is referable for the further development of selective inhibitors for specific isoforms of PI3K.

Intrahepatic cholangiocarcinoma: MRI texture signature as predictive biomarkers of immunophenotyping and survival.

OBJECTIVE: Clinical evidence suggests that the response to immune checkpoint blockade depends on the immune status in the tumor microenvironment. This study aims to predict the immunophenotyping (IP) and overall survival (OS) of intrahepatic cholangiocarcinoma (ICC) patients using preoperative magnetic resonance imaging (MRI) texture analysis. METHODS: A total of 78 ICC patients were included and divided into inflamed (n = 26) or non-inflamed (n = 52) immunophenotyping based on the density of CD8+ T cells. The enhanced T1-weighted MRI in the arterial phase was employed with texture analysis. The logistic regression analysis was applied to select the significant features related to IP. The OS-related feature was determined by Cox proportional-hazards model and Kaplan-Meier analysis. IP and OS predictive models were developed using the selected features, respectively. RESULTS: Three wavelets and one 3D feature have favorable ability to discriminate IP, a combination of which performed best with an AUC of 0.919. The inflamed immunophenotyping had a better prognosis than the non-inflamed one. The 5-year survival rates of the two groups were 48.5% and 25.3%, respectively (p < 0.05). The only wavelet-HLH_firstorder_Median feature was associated with OS and used to build the OS predictive model with a C-index of 0.70 (95% CI, 0.57, 0.82), which could well stratify ICC patients into high- and low-risk groups. The 1-, 3-, and 5-year survival probabilities of the stratified groups were 62.5%, 30.0%, and 24.2%, and 89.5%, 62.2%, and 42.1%, respectively (p < 0.05). CONCLUSION: The MRI texture signature could serve as a potential predictive biomarker for the IP and OS of ICC patients. KEY POINTS: • The MRI texture signature, including three wavelets and one 3D feature, showed significant associations with immunophenotyping of ICC, and all have favorable ability to discriminate immunophenotyping; a combination of the above features performed best with an AUC of 0.919. • The only wavelet-HLH_firstorder_Median feature was associated with the OS of ICC and used to build the OS predictive model, which could well stratify ICC patients into high- and low-risk groups.

Combined hepatocellular-cholangiocarcinoma: can we use contrast-enhanced ultrasound Liver Imaging Reporting and Data System (LI-RADS) to predict the patient's survival?

OBJECTIVES: To evaluate the relationship between contrast-enhanced (CE) ultrasound Liver Reporting and Data System (LI-RADS) classification of combined hepatocellular-cholangiocarcinoma (cHCC-CCA) and their histopathological component predominance, and to determine if the CEUS LI-RADS category can be used to predict the patient's survival after surgical resection. METHODS: Between January 2011 and December 2018, medical records and CEUS of patients with pathologically proven cHCC-CCA were studied. The predominance of hepatocellular carcinoma (HCC)/intrahepatic cholangiocarcinoma (ICC) component of cHCC-CCA was analyzed by histopathology. The proportion of HCC-predominant cHCC-CCA in different LI-RADS category was compared by using Fisher's exact test. Factors affecting tumor recurrence were analyzed by Cox proportional hazard model. Disease-free survival (DFS) was estimated by using Kaplan-Meier survival curve and compared by log-rank test. RESULTS: The study included 37 cHCC-CCA patients (33 men, 4 women; average age, 50.4 ± 11.0 years) and 37 nodules (mean diameter, 6.1 ± 3.9 cm). According to CEUS LI-RADS, 62.2% (23/37), 18.9% (7/37), and 18.9% (7/37) of cHCC-CCA were classified as LR-M, LR-5, and LR-TIV, respectively. The ratio of HCC predominance in LR-5 was 100% (10/10) vs 81.5% (22/27) in the LR-M group (p = 0.591). In our population, LR-5 patients had longer DFS than LR-M and LR-TIV patients combined (median DFS: 18.0 vs 6.4 months, p = 0.016). Multiple lesions (hazard ratio, 3.1; p = 0.007), tumor size (≥ 5 cm, hazard ratio, 4.1; p = 0.003), and CEUS LI-RADS category (LR-M and LR-TIV, hazard ratio, 4.7; p = 0.011) showed independent association with shorter DFS. CONCLUSION: cHCC-CCA characterized as LR-5 on CEUS tend to represent HCC-predominant tumors with significantly longer disease-free survival compared to cHCC-CCA categorized as LR-M and LR-TIV. KEY POINTS: • By using the American College of Radiology contrast-enhanced ultrasound Liver Imaging Reporting and Data System (CEUS LI-RADS), majority (30/37, 81.1%) of cHCC-CCA tumors were classified as LR-M or LR-TIV and only 18.9% (7/30) of cHCC-CCA were categorized as LR-5. • Patients with CEUS LR-5 cHCC-CCA had statistically significant longer disease-free time than those with LR-M and TIV cHCC-CCA (median DFS: 18.0 vs 6.4 months, p = 0.016). • Multiple lesions (hazard ratio, 3.1; p = 0.007), tumor size (≥ 5 cm, hazard ratio, 4.1; p = 0.003), and CEUS LI-RADS category (LR-M and LR-TIV, hazard ratio, 4.7; p = 0.011) showed independent association with shorter DFS.