MET exon 14 skipping mutation drives cancer progression and recurrence via activation of SMAD2 signalling.

BACKGROUND: c-Met encoded by the proto-oncogene MET, also known as hepatocyte growth factor (HGF) receptor, plays a crucial role in cellular processes. MET exon 14 skipping alteration (METΔ14EX) is a newly discovered MET mutation. SMAD2 is an important downstream transcription factor in TGF-ß pathway. Unfortunately, the mechanisms by which METΔ14EX leads to oncogenic transformation are scarcely understood. The relationship between METΔ14EX and SMAD2 has not been studied yet. METHODS: We generate METΔ14EX models by CRISPR-Cas9. In vitro transwell, wound-healing, soft-agar assay, in vivo metastasis and subcutaneous recurrence assay were used to study the role of METΔ14EX in tumour progression. RNA-seq, Western blotting, co-immunoprecipitation (CO-IP) and immunofluorescent were performed to explore the interaction between c-Met and SMAD2. RESULTS: Our results demonstrated that METΔ14EX, independent of HGF, can prolong the constitutive activation of c-Met downstream signalling pathways by impeding c-Met degradation and facilitating tumour metastasis and recurrence. Meanwhile, METΔ14EX strengthens the interaction between c-Met and SMAD2, promoting SMAD2 phosphorylation. Therapeutically, MET inhibitor crizotinib impedes METΔ14EX-mediated tumour metastasis by decreasing SMAD2 phosphorylation. CONCLUSIONS: These data elucidated the previously unrecognised role of METΔ14EX in cancer progression via activation of SMAD2 independent of TGF-ß, which helps to develop more effective therapies for such patients. METΔ14EX alteration significantly triggers tumour progression via activation of SMAD2 signalling that are involved in activating tumour invasion, metastasis and recurrence. On the left, in the MET wild-type (METWT), the juxtamembrane (JM) domain is involved in the regulation of tyrosine kinase activity, receptor degradation, and caspase cleavage. On the right, the METΔ14EX mutation leads to the loss of the juxtamembrane domain, resulting in an abnormal MET protein lacking a CBL-binding site. This causes the accumulation of truncated MET receptors followed by constitutive activation of the MET signalling pathway. Thus, the METΔ14EX-mutated protein has strong binding and phosphorylation to SMAD2, which results in the phosphorylation of a large number of SMAD2/3 proteins that combine with SMAD4 to form a complex in the nucleus, activating downstream signalling pathways, such as EMT and ECM remodelling, resulting in tumour progression and recurrence. TF transcription factor.

Pyroelectric-Effect-Assisted Near-Infrared-Driven Photoelectrochemical Biosensor Based on Exponential DNA Amplifier for MicroRNA Detection.

Although near-infrared responsive photoelectrochemical (PEC) biosensors have less damage to biological components compared to UV-visible light, they still reveal an inferior response due to the rapid recombination of photogenerated electron-hole. In this study, a near-infrared-driven PEC biosensor is fabricated for microRNA (miRNA) detection via integrating photoelectricity and pyroelectricity. Upon the introduction of target miRNA-21, the exponential DNA amplifier is triggered based on enzyme-assisted strand displacement amplification (SDA), releasing multiple Ag2S reporter probes to hybridize with capture probes immobilized on a CdS-2-mercaptobenzimidazole (2MBI)-modified photoelectrode. As a result, under the stimulation of NIR, the photoelectric conversion of Ag2S NPs generates the photocurrents. In addition, due to the strong hole acceptor ability of MBI, the pyroelectric effect of CdS-2MBI nanocomposites is enhanced, which generates highly pyroelectro-induced charge separation efficiency and induces the pyroelectric current benefited from the spontaneous polarization of CdS-2MBI caused by the temperature variation under the function of Ag2S nanoheaters. Impressively, this PEC biosensor has achieved the sensitive and selective determination of miRNA-21 with a detection limit as low as 54 fM. Overall, this NIR-driven PEC biosensor based on pyroelectric and photoelectric effects opens up a new horizon for bioanalysis and early disease diagnosis.

Mechanisms of Resistance to Tyrosine Kinase Inhibitors in ROS1 Fusion-Positive Nonsmall Cell Lung Cancer.

BACKGROUND: ROS1 fusion-positive (ROS1+) nonsmall cell lung cancer (NSCLC) patients are highly sensitive to tyrosine kinase inhibitor (TKI) treatments. However, acquired TKI resistance remains the major hurdle preventing patients from experiencing prolonged benefits. METHODS: 107 advanced or metastatic ROS1+ NSCLC patients who progressed on crizotinib and lorlatinib were recruited. Tissue and plasma samples were collected at baseline (N = 50), postcrizotinib (N = 91), and postlorlatinib (N = 21), which were all subject to the 139-gene targeted next-generation DNA sequencing. Molecular dynamics modeling was performed to investigate the effects of ROS1 mutations on binding to different TKIs. RESULTS: In patients with postcrizotinib and postlorlatinib samples, an accumulation of on- and off-target resistance alterations after multiple TKI treatments was observed. ROS1 G2032R and MET amplification were the most common on-target and off-target alterations, respectively. Patients with CD74-ROS1 and SLC34A2-ROS1 had longer progression-free survival (PFS) (P < 0.001) and higher rates of resistance mutations (on-target, P = 0.001; off-target, P = 0.077) than other ROS1 fusion variants following crizotinib treatment. Ten distinct on-target resistance mutations were detected after TKI therapies, of which 4 were previously unreported (ROS1 L2010M, G1957A, D1988N, L1982V). Molecular dynamics simulations showed that all 4 mutations were refractory to crizotinib, while G1957A, D1988N, and L1982V were potentially sensitive to lorlatinib and entrectinib. CONCLUSIONS: This study provided a comprehensive portrait of TKI-resistance mechanisms in ROS1+ NSCLC patients. Using in silico simulations of TKI activity, novel secondary mutations that may confer TKI resistance were identified and may support clinical therapeutic decision-making.

Antizyme inhibitor family: biological and translational research implications.

Metabolism of polyamines is of critical importance to physiological processes. Ornithine decarboxylase (ODC) antizyme inhibitors (AZINs) are capable of interacting with antizymes (AZs), thereby releasing ODC from ODC-AZs complex, and promote polyamine biosynthesis. AZINs regulate reproduction, embryonic development, fibrogenesis and tumorigenesis through polyamine and other signaling pathways. Dysregulation of AZINs has involved in multiple human diseases, especially malignant tumors. Adenosine-to-inosine (A-to-I) RNA editing is the most common type of post-transcriptional nucleotide modification in humans. Additionally, the high frequencies of RNA-edited AZIN1 in human cancers correlates with increase of cancer cell proliferation, enhancement of cancer cell stemness, and promotion of tumor angiogenesis. In this review, we summarize the current knowledge on the various contribution of AZINs related with potential cancer promotion, cancer stemness, microenvironment and RNA modification, especially underlying molecular mechanisms, and furthermore explored its promising implication for cancer diagnosis and treatment.

Glyco-signatures in patients with advanced lung cancer during anti-PD-1/PD-L1 immunotherapy.

Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1/programmed cell death ligand-1 (PD-1/PD-L1) have significantly prolonged the survival of advanced/metastatic patients with lung cancer. However, only a small proportion of patients can benefit from ICIs, and clinical management of the treatment process remains challenging. Glycosylation has added a new dimension to advance our understanding of tumor immunity and immunotherapy. To systematically characterize anti-PD-1/PD-L1 immunotherapy-related changes in serum glycoproteins, a series of serum samples from 12 patients with metastatic lung squamous cell carcinoma (SCC) and lung adenocarcinoma (ADC), collected before and during ICIs treatment, are firstly analyzed with mass-spectrometry-based label-free quantification method. Second, a stratification analysis is performed among anti-PD-1/PD-L1 responders and non-responders, with serum levels of glycopeptides correlated with treatment response. In addition, in an independent validation cohort, a large-scale site-specific profiling strategy based on chemical labeling is employed to confirm the unusual characteristics of IgG N-glycosylation associated with anti-PD-1/PD-L1 treatment. Unbiased label-free quantitative glycoproteomics reveals serum levels' alterations related to anti-PD-1/PD-L1 treatment in 27 out of 337 quantified glycopeptides. The intact glycopeptide EEQFN 177STYR (H3N4) corresponding to IgG4 is significantly increased during anti-PD-1/PD-L1 treatment (FC=2.65, P=0.0083) and has the highest increase in anti-PD-1/PD-L1 responders (FC=5.84, P=0.0190). Quantitative glycoproteomics based on protein purification and chemical labeling confirms this observation. Furthermore, obvious associations between the two intact glycopeptides (EEQFN 177STYR (H3N4) of IgG4, EEQYN 227STFR (H3N4F1) of IgG3) and response to treatment are observed, which may play a guiding role in cancer immunotherapy. Our findings could benefit future clinical disease management.

Plasma extracellular vesicle transcriptomics identifies CD160 for predicting immunochemotherapy efficacy in lung cancer.

Better biomarkers are needed to improve the efficacy of immune checkpoint inhibitors in lung adenocarcinoma (LUAD) treatment. We investigated the plasma extracellular vesicle (EV)-derived long RNAs (exLRs) in unresectable/advanced LUAD to explore biomarkers for immunochemotherapy. Seventy-four LUAD patients without targetable mutations receiving first-line anti-programmed cell death 1 (PD-1) immunochemotherapy were enrolled. Their exLRs were profiled through plasma EV transcriptome sequencing. Biomarkers were analyzed against response rate and survival using pre- and post-treatment samples in the retrospective cohort (n = 36) and prospective cohort (n = 38). The results showed that LUAD patients demonstrated a distinct exLR profile from the healthy individuals (n = 56), and T-cell activation-related pathways were enriched in responders. Among T-cell activation exLRs, CD160 exhibited a strong correlation with survival. In the retrospective cohort, the high baseline EV-derived CD160 level correlated with prolonged progression-free survival (PFS) (P < 0.001) and overall survival (OS) (P = 0.005), with an area under the curve (AUC) of 0.784 for differentiating responders from non-responders. In the prospective cohort, the CD160-high patients also showed prolonged PFS (P = 0.003) and OS (P = 0.014) and a promising AUC of 0.648. The predictive value of CD160 expression was validated by real-time quantitative PCR. We also identified the dynamics of EV-derived CD160 for monitoring therapeutic response. The elevated baseline CD160 reflected a higher abundance of circulating NK cells and CD8+ -naïve T cells, suggesting more active host immunity. In addition, increased CD160 levels of tumors also correlated with a favorable prognosis in LUAD patients. Together, plasma EV transcriptome analysis revealed the role of the baseline CD160 level and early post-treatment CD160 dynamics for predicting the response to anti-PD-1 immunochemotherapy in LUAD patients.

Efficacy and safety of pralsetinib in patients with advanced RET fusion-positive non-small cell lung cancer.

BACKGROUND: Pralsetinib is a potent, selective RET inhibitor targeting oncogenic RET alterations. As part of the global, phase 1/2 ARROW trial (NCT03037385), the efficacy and safety of pralsetinib in Chinese patients with advanced RET fusion-positive non-small cell lung cancer (NSCLC) were evaluated. METHODS: Adult patients with advanced, RET fusion-positive NSCLC with or without prior platinum-based chemotherapy were enrolled into two cohorts receiving 400-mg once-daily oral pralsetinib. Primary end points were objective response rates assessed by blinded independent central review and safety. RESULTS: Of 68 patients enrolled, 37 had received prior platinum-based chemotherapy (48.6% with ≥3 prior systemic regimens) and 31 were treatment-naïve. As of March 4, 2022 (data cutoff), of the patients with measurable lesions at baseline, a confirmed objective response was observed in 22 (66.7%; 95% confidence interval [CI], 48.2-82.0) of 33 pretreated patients, including 1 (3.0%) complete response and 21 (63.6%) partial responses; and in 25 (83.3%; 95% CI, 65.3-94.4) of 30 treatment-naïve patients, including two (6.7%) complete responses and 23 (76.7%) partial responses. Median progression-free survival was 11.7 months (95% CI, 8.7-not estimable) in pretreated patients and 12.7 months (95% CI, 8.9-not estimable) in treatment-naïve patients. The most common grade 3/4 treatment-related adverse events in 68 patients were anemia (35.3%) and decreased neutrophil count (33.8%). Eight (11.8%) patients discontinued pralsetinib because of treatment-related adverse events. CONCLUSION: Pralsetinib showed robust and durable clinical activity with a well-tolerated safety profile in Chinese patients with RET fusion-positive NSCLC. CLINICAL TRIAL REGISTRATION: NCT03037385.

Metabolic alterations in patients with Helicobacter pylori-related gastritis: The H. pylori-gut microbiota-metabolism axis in progression of the chronic inflammation in the gastric mucosa.

PURPOSE: To characterize the serum metabolism in patients with Helicobacter pylori-positive and H. pylori-negative gastritis. METHODS: Clinical data and serum gastric function parameters, PGI (pepsinogen I), PGII, PGR (PGI/II), and G-17 (gastrin-17) of 117 patients with chronic gastritis were collected, including 57 H. pylori positive and 60 H. pylori negative subjects. Twenty cases in each group were randomly selected to collect intestinal mucosa specimens and serum samples. The gut microbiota profiles were generated by 16S rRNA gene sequencing, and the serum metabolites were analyzed by a targeted metabolomics approach based on liquid chromatography-mass spectrometry (LC-MS) technology. RESULTS: Altered expression of 20 metabolites, including isovaleric acid, was detected in patients with HPAG. Some taxa of Bacteroides, Fusobacterium, and Prevotella in the gut microbiota showed significant correlations with differentially expressed metabolites between H. pylori positive and H. pylori negative individuals. As a result, an H. pylori-gut microbiota-metabolism (HGM) axis was proposed. CONCLUSION: Helicobacter pylori infection may influence the progression of mucosal diseases and the emergence of other complications in the host by altering the gut microbiota, and thus affecting the host serum metabolism.

Infrared spectra of the SARS-CoV-2 spike receptor-binding domain: Molecular dynamics simulations.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread around the world rapidly, which seriously threatens to human health and safety. The rapid detection of the virus in the early stage is very important to prevent the cross infection and transmission. It is also a key link in the post-treatment examination. This paper has explored the infrared (IR) spectra of spike protein receptor-binding domain (RBD) for SARS-CoV-2 using molecular dynamics simulations, and the absorption bands are assigned. The calculated IR spectra of water and insulin are compared with that measured in the related literatures. The results showed that O-H stretching vibration generated a strong absorption band located around 3591 cm-1, the oscillator strength of 310 K is slightly higher than that at 298 K. The absorption peaks have a small red shift or blue shift with the change of temperature. As a theoretical basis for the optical detection of SARS-CoV-2 virus, this work will play a positive role in promoting the development of new virus detection technology.

Identification of the key genes of tuberculosis and construction of a diagnostic model via weighted gene co-expression network analysis.

BACKGROUND: Tuberculosis (TB) is an infectious disease with high mortality, and mining key genes for TB diagnosis is vital to raise the survival rate of patients. METHODS: The whole microarray datasets GSE83456 (training set) and GSE19444 (validation set) of TB patients were downloaded from the Gene Expression Omnibus (GEO) database. Differential expression was conducted on genes between TB and normal samples (unconfirmed TB) in GSE83456 to yield TB-related differentially expressed genes (DEGs). DEGs were subjected to weighted gene co-expression network analysis (WGCNA) and clustered to form distinct gene modules. The immune scores of 25 kinds of immune cells were obtained by single-sample gene set enrichment analysis (ssGSEA) of TB samples, and Pearson correlation analysis was carried out between the 25 immune scores and diverse gene modules. The gene modules significantly associated with immune cells were retained as Target modules. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed on the genes in the modules (p-value <0.05). The protein-protein interaction (PPI) network was established utilizing the STRING database for genes in the Target module, and the selected key genes were intersected with immune-related genes in the ImmPort database. The obtained immune-related module genes were used for subsequent least absolute shrinkage and selection operator (LASSO) regression analysis and diagnostic models were constructed. Finally, the receiver operating characteristic (ROC) curve was utilized to validate the diagnostic model. RESULTS: The turquoise and yellow modules had a high correlation with macrophages. LASSO regression analysis of immune-related genes in TB was carried on to finally construct a 5-gene diagnostic model composed of C5, GRN, IL1B, IL23A, and TYMP. As demonstrated by the ROC curves, the diagnostic efficiency of this diagnostic model was 0.957 and 0.944 in the training and validation sets, respectively. Therefore, the immune-related 5-gene model had a good diagnostic function for TB. CONCLUSION: We identified 5 immune-related diagnostic markers that may play an important role in TB, and verified that this immune-related key gene model had a good diagnostic performance.

Study on Fluorescence Recognition of Fe3+, Cr2O72- and p-Nitrophenol by a Cadmium Complex and Related Mechanism.

The effective detection of environmental pollutants is very important to the sustainable development of human health and the environment. A luminescent Cd(II) coordination complex, {[Cd(dbtdb)(1,2,4-H3btc)]·0.5H2O}n (1) (dbtdb = 1-(2,3,5,6-tetramethyl-4-((2-(thiazol-4-yl)-2H-benzo[d]imidazol-3(3aH)-yl)methyl)benzyl)-2,7a-dihydro-2-(thiazol-4-yl)-1H-benzo[d]imidazole, 1,2,4-H3btc = 1,2,4-benzenetricarboxylic acid), was obtained by hydrothermal reactions. Complex 1 has a chain structure decorated with uncoordinated Lewis basic O and S donors and provides good sensing of Fe3+, Cr2O72-, and p-nitrophenol with fluorescence quenching through an energy transfer process. The calculated binding constants were 3.3 × 103 mol-1 for Fe3+, 2.36 × 104 mol-1 for Cr2O72-, and 9.3 × 103 mol-1 for p-nitrophenol, respectively. These results show that 1 is a rare multiresponsive sensory material for efficient detection of Fe3+, Cr2O72-, and p-nitrophenol.

Rh-Endostatin Plus Irinotecan/Cisplatin as Second-Line Therapy for Advanced Esophageal Squamous Cell Carcinoma: An Open-Label, Phase II Study.

BACKGROUND: This open-label, phase II study aimed to investigate the efficacy and safety of recombinant human endostatin (Rh-endostatin) plus irinotecan/cisplatin as second-line treatment in patients with advanced esophageal squamous cell carcinoma (ESCC). METHODS: Eligible patients received 15mg/m2 Rh-endostatin as a continuous intravenous pump infusion (7 continuous days), 60mg/m2 irinotecan (days 1 and 8), and 60mg/m2 cisplatin (day 1) every 3 weeks. The primary endpoint was progression-free survival (PFS). RESULTS: A total of 50 patients were assessable for efficacy and safety analysis. The median follow-up was 10.97 months (95%CI: 7.03-19.42) as the data cutoff. Median PFS was 4.01 months (95% CI: 3.19-5.49), and median overall survival (OS) was 12.32 months (95% CI: 8.21-17.45); 13 (26%; 95% CI: 15.87-39.55) of 50 patients had an objective response, and 31 (62%; 95% CI: 48.15-74.14) had disease control. Grade 3 or greater treatment-related adverse events (AEs) occurred in 12 (24.0%) patients, and no deaths were reported. The common grade 3 or greater AEs were leucopenia (18.0%) and neutropenia (16.0%). Five (10%) patients discontinued treatment because of AEs. CONCLUSION: Rh-endostatin plus irinotecan/cisplatin showed promising anti-tumor activity in advanced ESCC patients with a good safety profile in the second-line setting, which warrants further study in this population. (ClinicalTrials.gov identifier: NCT03797625).

Evolution of the CBL and CIPK gene families in Medicago: genome-wide characterization, pervasive duplication, and expression pattern under salt and drought stress.

BACKGROUND: Calcineurin B-like proteins (CBLs) are ubiquitous Ca2+ sensors that mediate plant responses to various stress and developmental processes by interacting with CBL-interacting protein kinases (CIPKs). CBLs and CIPKs play essential roles in acclimatization of crop plants. However, evolution of these two gene families in the genus Medicago is poorly understood. RESULTS: A total of 68 CBL and 135 CIPK genes have been identified in five genomes from Medicago. Among these genomes, the gene number of CBLs and CIPKs shows no significant difference at the haploid genome level. Phylogenetic and comprehensive characteristic analyses reveal that CBLs and CIPKs are classified into four clades respectively, which is validated by distribution of conserved motifs. The synteny analysis indicates that the whole genome duplication events (WGDs) have contributed to the expansion of both families. Expression analysis demonstrates that two MsCBLs and three MsCIPKs are specifically expressed in roots, mature leaves, developing flowers and nitrogen fixing nodules of Medicago sativa spp. sativa, the widely grown tetraploid species. In particular, the expression of these five genes was highly up-regulated in roots when exposed to salt and drought stress, indicating crucial roles in stress responses. CONCLUSIONS: Our study leads to a comprehensive understanding of evolution of CBL and CIPK gene families in Medicago, but also provides a rich resource to further address the functions of CBL-CIPK complexes in cultivated species and their closely related wild relatives.

Transcriptomic analysis and validation reveal the pathogenesis and a novel biomarker of acute exacerbation of chronic obstructive pulmonary disease.

BACKGROUND: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is the main factor that leads to the deterioration of the disease. Currently, the diagnosis of AECOPD mainly relies on clinical manifestations, good predictors or biomarkers are lacking. We aim to reveal specific biomarkers and potential pathogenesis of AECOPD and provide a research basis for the diagnosis and treatment. METHODS: Four patients with AECOPD, four patients with stable COPD, and five control subjects were enrolled for RNA sequencing and KEGG analysis. The mRNA level of target genes was verified by quantitative real-time PCR (qPCR) with an expanded sample size (30 patients with AECOPD, 27 patients with stable COPD, and 35 control subjects). ELISA and immunofluorescence were used to identify the target proteins. Furthermore, the expression and function of WNT/ß-catenin signaling pathway were assessed in animal models of COPD. RESULTS: RNA sequencing showed that 54 genes were up-regulated and 111 genes were down-regulated in the AECOPD. Differentially expressed genes were mainly enriched in WNT signaling pathway, et al. QPCR revealed that multi-genes of the WNT/ß-catenin signaling were significantly down-regulated in AECOPD (P < 0.05), and ß-catenin protein was significantly decreased in plasma of AECOPD and stable COPD (P < 0.01), while phosphorylated ß-catenin was significantly up-regulated in peripheral blood mononuclear cells of AECOPD (P < 0.05). Similarly, WNT ligands, WNT receptors, and downstream signaling molecules were down-regulated, with an increased phosphorylated ß-catenin protein in animal models of COPD. Activation of WNT/ß-catenin signaling pathway by lithium chloride reduced the expression of phosphorylated ß-catenin and ameliorated the COPD-like airway inflammation in mice. CONCLUSION: WNT/ß-catenin signaling pathway is down-regulated in AECOPD patients and in animal models of COPD. Increased expression of phosphorylated ß-catenin in the blood might be a potential biomarker of AECOPD. Activation of WNT/ß-catenin pathway may also represent a therapeutic target for AECOPD.

Construction of a ZnIn2S4/Au/CdS Tandem Heterojunction for Highly Efficient CO2 Photoreduction.

Photocatalytic CO2 reduction technology is of great importance to alleviate energy crisis and environmental pollution; however, it remains a serious challenge due to the fast recombination of carriers. In this study, we report a three-dimensional structure of a ZnIn2S4/Au/CdS composite photocatalyst for the CO2 reduction reaction, where Au nanoparticles (NPs) are evenly anchored on the surface of ZnIn2S4 by photodeposition and Au NPs are wrapped around by CdS. In ZnIn2S4/Au/CdS composite photocatalysts, Au NPs act as a bridge to construct a "semiconductor-metal-semiconductor" tandem electron transfer mechanism (ZnIn2S4 → Au → CdS) heterojunction, which greatly promotes the transfer of photogenerated electrons. It is worth noting that Au NPs, as a local surface plasmon resonance (LSPR) effect excited source to generate excited-state electrons, further improve the photoreduction CO2 activity. Under UV-vis light irradiation, the CO yield of ZnIn2S4/Au/CdS can reach 63.07 µmol·g-1·h-1, which is higher than that of 6.37 µmol·g-1·h-1 for pure ZnIn2S4, 0.93 µmol·g-1·h-1 for CdS, 8.9 µmol·g-1·h-1 for ZnIn2S4/CdS, 31.04 µmol·g-1·h-1 for ZnIn2S4/Au, and 5.37 µmol·g-1·h-1 for CdS/Au. In addition, the ternary ZnIn2S4/Au/CdS composite photocatalyst has good cyclic stability. This study broadens the idea of designing photocatalysts with good carrier separation efficiency.

Substituent, Solvent, and Dispersion Effects on the Zwitterionic Character and Dimerization Thermochemistry of the Group 6 Fulvene Metal Tricarbonyl Complexes.

Dimerizations of fulvene metal tricarbonyl complexes of the type (C5H4CRR')M(CO)3 (R, R' = MeO, Me, H; M = Cr, Mo, W) to form a metal-metal bond and a new carbon-carbon bond, thereby giving binuclear cyclopentadienyl metal carbonyl derivatives, are predicted to be thermochemically favored but to have significant activation energies ranging from ΔE = 19 to 42 kcal/mol. However, the introduction of dimethylamino but not methoxy substituents onto the exocyclic carbon atom changes the situation drastically so that the monomers [C5H4CH(NMe2)]M(CO)3 and [C5H4C(NMe2)2]M(CO)3 become strongly thermochemically favored, lying ΔE = 43 kcal/mol (M = W) to 63 kcal/mol (M = Cr) below their corresponding dimers. In such dimethylamino-substituted (fulvene)M(CO)3 derivatives, the M-C distance to the exocyclic fulvene carbon is lengthened beyond the bonding distance to give a zwitterionic structure with a pentahapto fulvene ligand. Such M-C distances in (fulvene)M(CO)3 complexes, which have preferred zwitterionic structures, increase with increasing solvent polarity (i.e., dielectric constant) until a saturation point is reached.

Dietary Cinnamaldehyde Enhances Growth Performance, Digestion, Immunity, and Lipid Metabolism in Juvenile Fat Greenling (Hexagrammos otakii).

Fat greenling (Hexagrammos otakii) is a kind of economic fish that is widely consumed by human, and its intensive farming technology is making important progress. However, high-density farming may cause the occurrence of diseases in H. otakii. Cinnamaldehyde (CNE) is a new feed additive for aquatic animals and has a positive effect on disease resistance. In the study, dietary CNE was evaluated on the growth performance, digestion, immune response, and lipid metabolism of juvenile H. otakii (6.21 ± 0.19 g). Six experimental diets were formulated containing CNE at levels of 0, 200, 400, 600, 800, and 1000 mg/kg for 8 weeks. The percent weight gain (PWG), specific growth rate (SGR), survival (SR), and feeding rate (FR) were significantly increased by including CNE in fish diets regardless of the inclusion level (P < 0.05). The feed conversion ratio (FCR) was significantly decreased among the groups fed CNE supplemented diets (P < 0.05). A significant decrease in hepatosomatic index (HSI) was observed in fish fed 400 mg/kg-1000 mg/kg CNE compared to the control diet (P < 0.05). Fish-fed diets containing 400 mg/kg and 600 mg/kg CNE had a higher level of crude protein in muscles than the control diet (P < 0.05). Moreover, the activities of lipase (LPS) and pepsin (PEP) in the intestinal were markedly increased in juvenile H. otakii-fed dietary CNE (P < 0.05). Apparent digestibility coefficient (ADC) of dry matter, protein, and lipid was significantly increased with CNE supplement (P < 0.05). The activities of catalase (CAT) and acid phosphatase (ACP) in the liver were markedly enhanced by including CNE in juvenile H. otakii diets compared with the control (P < 0.05). The activities of superoxide dismutase (SOD) and alkaline phosphatase (AKP) in the liver were markedly enhanced in juvenile H. otakii treated with CNE supplements 400 mg/kg-1000 mg/kg (P < 0.05). Additionally, the levels of total protein (TP) in the serum were markedly increased by including CNE in juvenile H. otakii diets compared with the control (P < 0.05). In the CNE200, CNE400, and CNE600 groups, albumin (ALB) levels in the serum were markedly higher compared with that in the control (P < 0.05). In the CNE200 and CNE400 groups, the levels of immunoglobulin G (IgG) in the serum were significantly increased compared with that the control group (P < 0.05). The juvenile H. otakii-fed dietary CNE had lower triglycerides (TG) and total cholesterol (TCHO) levels in the serum than fish-fed CNE-free diets (P < 0.05). The gene expression of peroxisome proliferator-activated receptor alpha (PPAR-α), hormone-sensitive lipase (HSL), and carnitine O-palmitoyltransferase 1 (CPT1) in the liver was significantly increased by including CNE in fish diets regardless of the inclusion level (P < 0.05). However, fatty acid synthase (FAS), peroxisome proliferator-activated receptor gamma (PPAR-γ), and acetyl-CoA carboxylase alpha (ACCα) in the liver were markedly decreased with CNE supplements 400 mg/kg-1000 mg/kg (P < 0.05). The glucose-6-phosphate1-dehydrogenase (G6PD) gene expression levels in the liver were markedly decreased compared with the control (P < 0.05). The optimal supplementation level of CNE was shown by curve equation analysis to be 590.90 mg/kg.

Dual-function chimeric antigen receptor T cells targeting c-Met and PD-1 exhibit potent anti-tumor efficacy in solid tumors.

Purpose Programmed cell death 1 (PD-1), which is upregulated under the continuous induction of the tumor microenvironment, causes chimeric antigen receptor (CAR)-T cell hypofunction via interaction with programmed death ligand 1 (PD-L1). This study aimed to construct CAR-T cells that are resistant to PD-1 inhibition to improve the effect of CAR-T cells in solid tumors. Methods We constructed a type of dual-function CAR-T cell that targets tumor-associated antigen c-Met and blocks the binding of PD-1 with PD-L1. The expression of c-Met, PD-L1, and inhibitory receptors was measured using flow cytometry. The cytotoxicity, cytokine release, and differentiation level of CAR-T cells were determined using lactate dehydrogenase release assay, enzyme-linked immunosorbent assay, and flow cytometry, respectively. The levels of p-Akt, p-MAPK, caspase-3, and Bcl2 were detected by western blot. The in vivo anti-tumor effect was evaluated using tumor xenograft models. Results Dual-function CAR-T cells could mediate enhanced active signals upon encountering target antigens and had targeted cytotoxicity to target cells. However, the cytotoxicity of c-Met-CAR-PD-1+ T cells was impaired due to the interaction of PD-1 with PD-L1. By blocking the binding of PD-1 and PD-L1, the novel dual-function CAR-PD-1+ T cells could maintain cytotoxicity to PD-L1+ tumor cells. In tumor tissue, the dual-function CAR-T cells showed lower inhibitory receptor expression and lower differentiation characteristics, which resulted in potent anti-tumor effects and prolonged survival in PD-L1+ tumor xenograft models compared to single-target CAR-T cells. Conclusion These results confirm that the novel dual-function CAR-T cells exhibit stronger anti-tumor activity against solid tumors than traditional single-target CAR-T cells and present a new approach that enhance the activity of CAR-T cells in solid tumors.

On-chip monolithic Fourier transform spectrometers assisted by cGAN spectral prediction.

Silicon photonic spatial heterodyne Fourier transform spectrometers (SH-FTSs) are attractive with chip-scale monolithic arrays of imbalanced Mach-Zehnder interferometers; however, there exist optical path difference (OPD) errors from the inevitable fabrication imperfection, which will severely distort the retrieved spectra. In this Letter, we propose that a predictive model can be created for rapid and accurate spectral recovery based on the conditional generative adversarial network (cGAN) featuring strong input-on-output supervision, instead of both complicated physical OPD modification and time-consuming iterative spectral calculation. As a demonstration, cGAN spectral prediction was performed for our previously presented dual-polarized SH-FTS with large OPD errors [Opt. Lett.44, 2923 (2019)OPLEDP0146-959210.1364/OL.44.002923]. Due to the strong noise-resistant capability, the cGAN-predicted spectra can stay reliable, even though the signal-to-noise ratio of acquired interferograms dramatically drops from 1000 to 100, implying a lower limit of detection.

Dynamic monitor of CT scan within short interval in invasive pulmonary aspergillosis for nonneutropenic patients: a retrospective analysis in two centers.

BACKGROUND: In nonneutropenic patients with underlying respiratory diseases (URD), invasive pulmonary aspergillosis (IPA) is a life-threatening disease. Yet establishing early diagnosis in those patients remains quite a challenge. METHODS: A retrospective series of nonneutropenic patients with probable or proven IPA were reviewed from January 2014 to May 2018 in Department of Respiratory Medicine of two Chinese hospitals. Those patients were suspected of IPA and underwent lung computed tomography (CT) scans twice within 5-21 days. The items required for IPA diagnosis were assessed by their host factors, mycological findings and CT scans according to the European Organization for Research and Treatment of Cancer (EORTC) and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (MSG) criteria (EORTC/MSG criteria). RESULTS: Together with the risk factors, mycological findings and nonspecific radiological signs on first CT, ten patients were suspected of IPA. With the appearance of cavities on second CT scan in the following days, all patients met the criteria of probable or possible IPA. Except one patient who refused antifungal treatment, nine patients received timely antifungal treatment and recovered well. One of the nine treated IPA cases was further confirmed by pathology, one was confirmed by biopsy. CONCLUSIONS: Dynamic monitor of CT scan provided specific image evidences for IPA diagnosis. This novel finding might provide a noninvasive and efficient strategy in IPA diagnosis with URD.