Although clinical studies have shown promise for targeting programmed cell death protein-1 (PD-1) and ligand (PD-L1) signaling in non-small cell lung cancer (NSCLC), the factors that predict which ...subtype patients will be responsive to checkpoint blockade are not fully understood.
We performed an integrated analysis on the multiple-dimensional data types including genomic, transcriptomic, proteomic, and clinical data from cohorts of lung adenocarcinoma public (discovery set) and internal (validation set) database and immunotherapeutic patients. Gene set enrichment analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups.
We observed that
mutation significantly increased expression of immune checkpoints and activated T-effector and interferon-γ signature. More importantly, the
comutated subgroup manifested exclusive increased expression of PD-L1 and a highest proportion of
Meanwhile,
or
-mutated tumors showed prominently increased mutation burden and specifically enriched in the transversion-high (TH) cohort. Further analysis focused on the potential molecular mechanism revealed that
or
mutation altered a group of genes involved in cell-cycle regulating, DNA replication and damage repair. Finally, immunotherapeutic analysis from public clinical trial and prospective observation in our center were further confirmed that
or
mutation patients, especially those with co-occurring
mutations, showed remarkable clinical benefit to PD-1 inhibitors.
This work provides evidence that
and
mutation in lung adenocarcinoma may be served as a pair of potential predictive factors in guiding anti-PD-1/PD-L1 immunotherapy.
.
Quality control can decrease variations in the performance of colonoscopists and improve the effectiveness of colonoscopy to prevent colorectal cancers. Unfortunately, routine quality control is ...difficult to carry out because a practical method is lacking. The aim of this study was to develop an automatic quality control system (AQCS) and assess whether it could improve polyp and adenoma detection in clinical practice.
First, we developed AQCS based on deep convolutional neural network models for timing of the withdrawal phase, supervising withdrawal stability, evaluating bowel preparation, and detecting colorectal polyps. Next, consecutive patients were prospectively randomized to undergo routine colonoscopies with or without the assistance of AQCS. The primary outcome of the study was the adenoma detection rate (ADR) in the AQCS and control groups.
A total of 659 patients were enrolled and randomized. A total of 308 and 315 patients were analyzed in the AQCS and control groups, respectively. AQCS significantly increased the ADR (0.289 vs 0.165, P < .001) and the mean number of adenomas per procedure (0.367 vs 0.178, P < .001) compared with the control group. A significant increase was also observed in the polyp detection rate (0.383 vs 0.254, P = .001) and the mean number of polyps detected per procedure (0.575 vs 0.305, P < .001). In addition, the withdrawal time (7.03 minutes vs 5.68 minutes, P < .001) and adequate bowel preparation rate (87.34% vs 80.63%, P = .023) were superior for the AQCS group.
AQCS could effectively improve the performance of colonoscopists during the withdrawal phase and significantly increase polyp and adenoma detection. (Clinical trial registration number: NCT03622281.)
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The dynamics, duration, and nature of immunity produced during SARS-CoV-2 infection are still unclear. Here, we longitudinally measured virus-neutralising antibody, specific antibodies against the ...spike (S) protein, receptor-binding domain (RBD), and the nucleoprotein (N) of SARS-CoV-2, as well as T cell responses, in 25 SARS-CoV-2-infected patients up to 121 days post-symptom onset (PSO). All patients seroconvert for IgG against N, S, or RBD, as well as IgM against RBD, and produce neutralising antibodies (NAb) by 14 days PSO, with the peak levels attained by 15-30 days PSO. Anti-SARS-CoV-2 IgG and NAb remain detectable and relatively stable 3-4 months PSO, whereas IgM antibody rapidly decay. Approximately 65% of patients have detectable SARS-CoV-2-specific CD4
or CD8
T cell responses 3-4 months PSO. Our results thus provide critical evidence that IgG, NAb, and T cell responses persist in the majority of patients for at least 3-4 months after infection.
Background and aims
Endoscopic diagnosis of early esophageal squamous cell cancer (ESCC) is complicated and dependent on operators' experience. This study aimed to develop an artificial intelligence ...(AI) model for automatic diagnosis of early ESCC.
Methods
Non‐magnifying and magnifying endoscopic images of normal/noncancerous lesions, early ESCC, and advanced esophageal cancer (AEC) were retrospectively obtained from Qilu Hospital of Shandong University. A total of 10,988 images from 5075 cases were chosen for training and validation. Another 2309 images from 1055 cases were collected for testing. One hundred and four real‐time videos were also collected to evaluate the diagnostic performance of the AI model. The diagnostic performance of the AI model was compared with endoscopists by magnifying images and the assistant efficiency of the AI model for novices was evaluated.
Results
The AI diagnosis for non‐magnifying images showed a per‐patient accuracy, sensitivity, and specificity of 99.5%, 100%, 99.5% for white light imaging, and 97.0%, 97.2%, 96.4% for optical enhancement/iodine straining images. Regarding diagnosis for magnifying images, the per‐patient accuracy, sensitivity, and specificity were 88.1%, 90.9%, and 85.0%. The diagnostic accuracy of the AI model was similar to experts (84.5%, P = 0.205) and superior to novices (68.5%, P = 0.005). The diagnostic performance of novices was significantly improved by AI assistance. When it comes to the diagnosis for real‐time videos, the AI model showed acceptable performance as well.
Conclusions
The AI model could accurately recognize early ESCC among noncancerous mucosa and AEC. It could be a potential assistant for endoscopists, especially for novices.
Nanofluidics derived from low‐dimensional nanosheets and protein nanochannels are crucial for advanced catalysis, sensing, and separation. However, polymer nanofluidics is halted by complicated ...preparation and miniaturized sizes. This work reports the bottom‐up synthesis of modular nanofluidics by confined growth of ultrathin metal–organic frameworks (MOFs) in a polymer membrane consisting of zwitterionic dopamine nanoparticles (ZNPs). The confined growth of the MOFs on the ZNPs reduces the chain entanglement between the ZNPs, leading to stiff interfacial channels enhancing the nanofluidic transport of water molecules through the membrane. As such, the water permeability and solute selectivity of MOF@ZNPM are one magnitude improved, leading to a record‐high performance among all polymer nanofiltration membranes. Both the experimental work and the molecular dynamics simulations confirm that the water transport is shifted from high‐friction‐resistance conventional viscous flow to ultrafast nanofluidic flow as a result of rigid and continuous nanochannels in MOF@ZNPM.
A rigid‐scaffold‐reinforced polymeric nanoparticles’ interfacial channel strategy is proposed for fabricating nanofluidic membranes that exhibit water permeance and dye/salt selectivity that are 1–2 orders of magnitude higher than conventional polymeric membranes. The unprecedented separation performance is due to the paradigm shift of water transport from conventional viscous flow to ultrafast nanofluidic flow in the membrane nanofluidics.
A visible light‐induced Co‐catalyzed highly regio‐ and stereoselective reductive coupling of vinyl azaarenes and alkynes has been developed. Notably, Hünig's base together with simple ethanol has ...been successfully applied as the hydrogen sources instead of commonly used Hantzsch esters in this catalytic photoredox reaction. This approach has considerable advantages for the straightforward synthesis of stereodefined multiple substituted alkenes bearing an azaarene motif, such as excellent regioselectivity (>20 : 1 for >30 examples) and stereoselectivity (>20 : 1 E/Z), broad substrate scope and good functional group compatibility under mild reaction conditions, which has been utilized in the concise synthesis of natural product monomorine I. A reasonable catalytic reaction pathway involving protolysis of the cobaltacyclopentene intermediate has been proposed based on the mechanistic studies.
A novel regio‐ and stereoselective reductive coupling of vinyl azaarenes and alkynes has been developed to access functionalized azaarene compounds bearing stereodefined tri‐substituted alkenes via photoredox cobalt dual catalysis. Simple organic base together with alcohol has been applied as the hydrogen sources instead of commonly used Hantzsch esters in this coupling reaction.
Summary
Glycosylation of monolignols has been found to be widespread in land plants since the 1970s. However, whether monolignol glycosylation is crucial for cell wall lignification and how it exerts ...effects are still unknown. Here, we report the identification of a mutant ugt72b1 showing aggravated and ectopic lignification in floral stems along with arrested growth and anthocyanin accumulation. Histochemical assays and thioacidolysis analysis confirmed the enhanced lignification and increased lignin biosynthesis in the ugt72b1 mutant. The loss of UDP‐glycosyltransferase UGT72B1 function was responsible for the lignification phenotype, as demonstrated by complementation experiments. Enzyme activity analysis indicated that UGT72B1 could catalyze the glucose conjugation of monolignols, especially coniferyl alcohol and coniferyl aldehyde, which was confirmed by analyzing monolignol glucosides of UGT72B1 transgenic plants. Furthermore, the UGT72B1 gene was strongly expressed in young stem tissues, especially xylem tissues. However, UGT72B1 paralogs, such as UGT72B2 and UGT72B3, had weak enzyme activity toward monolignols and weak expression in stem tissues. Transcriptomic profiling showed that UGT72B1 knockout resulted in extensively increased transcript levels of genes involved in monolignol biosynthesis, lignin polymerization and cell wall‐related transcription factors, which was confirmed by quantitative real‐time PCR assays. These results provided evidence that monolignol glucosylation catalyzed by UGT72B1 was essential for normal cell wall lignification, thus offering insight into the molecular mechanism of cell wall development and cell wall lignification.
Significance Statement
Lignin provides mechanical support to plant stems and helps protect plants from pathogen attack. Although monolignol glucosides were reported in planta in the 1970s, whether they were important for cell wall lignification was unknown. Here we characterize a mutant in a UDP‐glycosyl transferase and show that monolignol glucosylation indeed plays an essential role in normal cell wall lignification.
A Co-catalyzed highly regio- and enantioselective reductive coupling of alkynes and aldehydes has been developed under visible light photoredox dual catalysis. A variety of enantioenriched allylic ...alcohols have been obtained by using unsymmetrical internal alkynes and commercially available catalyst, chiral ligand, and reagents. It is noteworthy that this approach has considerable advantages, such as excellent regio- (>95:5 for >40 examples), stereo- (up to >95:5 E/Z), and enantioselectivity (92–99% ee, >35 examples) control, mild reaction conditions, broad substrate scope, and good functional group compatibility, making it a great improvement to enantioselective alkyne–aldehyde reductive coupling reactions.
A new regio- and stereoselective reductive coupling of alkynes and crotononitrile has been developed via visible light organophotoredox cobalt dual catalysis. A variety of enantioenriched homoallylic ...nitriles bearing a stereodefined trisubstituted alkene have been easily synthesized with good to excellent regio- (up to >20:1 rr), stereo- (>20:1 E/Z), and enantioselectivity (up to 98% ee) control under mild conditions. The corresponding nitrile products were smoothly converted into various chiral building blocks. Remarkably, a simple organic base together with water have been utilized as hydrogen sources in this photoinduced reductive reaction.
Autophagy acts as a cellular surveillance mechanism to combat invading pathogens. Viruses have evolved various strategies to block autophagy and even subvert it for their replication and release. ...Here, we demonstrated that ORF3a of the COVID-19 virus SARS-CoV-2 inhibits autophagy activity by blocking fusion of autophagosomes/amphisomes with lysosomes. The late endosome-localized ORF3a directly interacts with and sequestrates the homotypic fusion and protein sorting (HOPS) component VPS39, thereby preventing HOPS complex from interacting with the autophagosomal SNARE protein STX17. This blocks assembly of the STX17-SNAP29-VAMP8 SNARE complex, which mediates autophagosome/amphisome fusion with lysosomes. Expression of ORF3a also damages lysosomes and impairs their function. SARS-CoV-2 virus infection blocks autophagy, resulting in accumulation of autophagosomes/amphisomes, and causes late endosomal sequestration of VPS39. Surprisingly, ORF3a from the SARS virus SARS-CoV fails to interact with HOPS or block autophagy. Our study reveals a mechanism by which SARS-CoV-2 evades lysosomal destruction and provides insights for developing new strategies to treat COVID-19.
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•SARS-CoV-2 virus infection or expression of ORF3a blocks formation of autolysosomes•SARS-CoV-2 ORF3a sequestrates the HOPS component VPS39 on late endosomes•SARS-CoV-2 ORF3a impairs the assembly of the STX17-SNAP29-VAMP8 SNARE complex•SARS virus ORF3a fails to interact with VPS39 or affect autophagy activity
Miao et al. demonstrate that late endosome-localized ORF3a of the COVID-19 virus SARS-CoV-2 sequestrates the HOPS component VPS39. ORF3a blocks autophagosome/amphisome fusion with lysosomes by preventing the assembly of the STX17-SNAP29-VAMP8 SNARE complex. SARS-CoV-2-infected cells also exhibit a defect in autophagosome maturation and sequestration of VPS39 on late endosomes.
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