Copper (Cu)-based antimicrobial compounds (CBACs) have been widely used to control phytopathogens for nearly fourteen decades. Since the first commercialized Bordeaux mixture was introduced, CBACs ...have been gradually developed from highly to slightly soluble reagents and from inorganic to synthetic organic, with nanomaterials being a recent development. Traditionally, slightly soluble CBACs form a physical film on the surface of plant tissues, separating the micro-organisms from the host, then release divalent or monovalent copper ions (Cu
or Cu
) to construct a secondary layer of protection which inhibits the growth of pathogens. Recent progress has demonstrated that the release of a low concentration of Cu
may elicit immune responses in plants. This supports a triple-tiered protection role of CBACs: break contact, inhibit microorganisms, and stimulate host immunity. This spatial defense system, which is integrated both inside and outside the plant cell, provides long-lasting and broad-spectrum protection, even against emergent copper-resistant strains. Here, we review recent findings and highlight the perspectives underlying mitigation strategies for the sustainable utilization of CBACs.
Visual tracking is a fundamental vision task that tries to figure out instances of several object classes from videos and images. It has attracted much attention for providing the basic semantic ...information for numerous applications. Over the past 10 years, visual tracking has made a great progress, but huge challenges still exist in many real-world applications. The facade of a target can be transformed significantly by pose changing, occlusion, and sudden movement, which possibly leads to a sudden target loss. This paper builds a hybrid tracker combining the deep feature method and correlation filter to solve this challenge, and verifies its powerful characteristics. Specifically, an effective visual tracking method is proposed to address the problem of low tracking accuracy due to the limitations of traditional artificial feature models, then rich hiearchical features of Convolutional Neural Networks are used to make the multi-layer features fusion improve the tracker learning accuracy. Finally, a large number of experiments are conducted on benchmark data sets OBT-100 and OBT-50, and show that our proposed algorithm is effective.
In patients with castration-resistant prostate cancer (CRPC), clinical resistances such as androgen receptor (AR) mutation, AR overexpression, and AR splice variants (ARVs) limit the effectiveness of ...second-generation antiandrogens (SGAs). Several strategies have been implemented to develop novel antiandrogens to circumvent the occurring resistance. Here, we found and identified a bifunctional small molecule Z15, which is both an effective AR antagonist and a selective AR degrader. Z15 could directly interact with the ligand-binding domain (LBD) and activation function-1 region of AR, and promote AR degradation through the proteasome pathway. In vitro and in vivo studies showed that Z15 efficiently suppressed AR, AR mutants and ARVs transcription activity, downregulated mRNA and protein levels of AR downstream target genes, thereby overcoming AR LBD mutations, AR amplification, and ARVs-induced SGAs resistance in CRPC. In conclusion, our data illustrate the synergistic importance of AR antagonism and degradation in advanced prostate cancer treatment.
Immunotherapy has revolutionized cancer treatment, but most patients are refractory to immunotherapy or acquire resistance, with the underlying mechanisms remaining to be explored.
We characterized ...the transcriptomes of ~92,000 single cells from 3 pre-treatment and 12 post-treatment patients with non-small cell lung cancer (NSCLC) who received neoadjuvant PD-1 blockade combined with chemotherapy. The 12 post-treatment samples were categorized into two groups based on pathologic response: major pathologic response (MPR; n = 4) and non-MPR (NMPR; n = 8).
Distinct therapy-induced cancer cell transcriptomes were associated with clinical response. Cancer cells from MPR patients exhibited a signature of activated antigen presentation via major histocompatibility complex class II (MHC-II). Further, the transcriptional signatures of FCRL4+FCRL5+ memory B cells and CD16+CX3CR1+ monocytes were enriched in MPR patients and are predictors of immunotherapy response. Cancer cells from NMPR patients exhibited overexpression of estrogen metabolism enzymes and elevated serum estradiol. In all patients, therapy promoted expansion and activation of cytotoxic T cells and CD16+ NK cells, reduction of immunosuppressive Tregs, and activation of memory CD8+T cells into an effector phenotype. Tissue-resident macrophages were expanded after therapy, and tumor-associated macrophages (TAMs) were remodeled into a neutral instead of an anti-tumor phenotype. We revealed the heterogeneity of neutrophils during immunotherapy and identified an aged CCL3+ neutrophil subset was decreased in MPR patients. The aged CCL3+ neutrophils were predicted to interact with SPP1+ TAMs through a positive feedback loop to contribute to a poor therapy response.
Neoadjuvant PD-1 blockade combined with chemotherapy led to distinct NSCLC tumor microenvironment transcriptomes that correlated with therapy response. Although limited by a small patient sample size subjected to combination therapy, this study provides novel biomarkers to predict therapy response and suggests potential strategies to overcome immunotherapy resistance.
IL-1α is closely related to the development and metastasis of cancer, and its polymorphisms have been reported affecting the susceptibility of malignancy tumors, yet the conclusions are ...controversial. Present an overall meta-analysis was performed to reach more general findings. Relevant literature was searched from Google Scholar, Web of Science, PubMed, EMBASE, CNKI database and Wanfang database, and the association among polymorphism and cancer risk was appraised by counting ORs and 95% CIs of overall and stratification analysis. The date from 15,586 cases and 18,430 controls in 40 publications were enrolled. There is significantly upregulated risk leads by rs3783553 in all genetic models, while the same tendency was found in all cancer types. The results also suggest a high risk of cancer susceptibility in patients carried rs1800587 polymorphism, of which draw out form allelic and homozygote models in overall studies, especially for cervical cancer. However, there are no significant results in analysis of rs17561. In a word, IL1A SNPs play an essential role in upregulating cancer susceptibility, and current analysis provides detail date for further study in the future.
Recently, a newly programmed cell death has been discovered, namely cuproptosis. It is considered a novel copper-dependent cell death model. Long non-coding RNA (lncRNA) influence the prognosis of ...bladder cancer. In this study, we established a scoring system based on 7 cuproptosis-related lncRNA to predict the prognosis and immune landscape of bladder cancer (BCa).
Gene expression and clinical data of 431 tissues were downloaded from The Cancer Genome Atlas (TCGA), including 19 normal samples and 419 cancer samples. All samples were randomly categorized into train and test cohorts. Cuproptosis-related lncRNA were distinguished. Then we conduct univariate COX and multivariate COX regression, paralleled with LASSO regression to cultivate a cuproptosis-related lncRNA risk model. Kaplan-Meier curves, scatter diagram, C-index, ROC curves, nomogram, PCA analysis and univariate and multivariate Cox regression were used to test the accuracy of risk model and to predict patient survival. Additional, gene mutation status between high- and low-risk groups was calculated.
GO and KEGG were used to access the DEGs (different expression genes)-related pathway.
The ssGSEA and ESTIMATE algorithms were used to assess the immune function in different tumor samples. Besides, patient's response to immunotherapy and drug susceptibility were also been estimated.
7 cuproptosis-related lncRNA (LINC01184, LINC00513, LINC02443, SMARCA5-AS1, BDNF-AS, SOD2-OT1, HYI-AS1) were selected to construct the risk model in the train cohort. This model can well predict the overall survival (OS) in test group and entire cohort with different stage. Despite no significant different is observed in gene mutation between high- and low-risk group, different immune infiltration, different survival and sensitivity to drugs are discovered.
We established a novel cuproptosis-related lncRNA risk model which can predict the outcome and immunotherapy response with satisfactory predictive effects. This risk model can provide a new insight into prognostic evaluation and may have potential to guide comprehensive treatment in bladder cancer.
Afatinib, an irreversible ErbB-family blocker, could improve the survival of advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer patients (NSCLCm+). This phase II trial ...(NCT04201756) aimed to assess the feasibility of neoadjuvant Afatinib treatment for stage III NSCLCm+. Forty-seven patients received neoadjuvant Afatinib treatment (40 mg daily). The primary endpoint was objective response rate (ORR). Secondary endpoints included pathological complete response (pCR) rate, pathological downstaging rate, margin-free resection (R0) rate, event-free survival, disease-free survival, progression-free survival, overall survival, treatment-related adverse events (TRAEs). The ORR was 70.2% (95% CI: 56.5% to 84.0%), meeting the pre-specified endpoint. The major pathological response (MPR), pCR, pathological downstaging, and R0 rates were 9.1%, 3.0%, 57.6%, and 87.9%, respectively. The median survivals were not reached. The most common TRAEs were diarrhea (78.7%) and rash (78.7%). Only three patients experienced grade 3/4 TRAEs. Biomarker analysis and tumor microenvironment dynamics by bulk RNA sequencing were included as predefined exploratory endpoints. CISH expression was a promising marker for Afatinib response (AUC = 0.918). In responders, compared to baseline samples, increasing T-cell- and B-cell-related features were observed in post-treatment tumor and lymph-node samples, respectively. Neoadjuvant Afatinib is feasible for stage III NSCLC+ patients and leads to dynamic changes in the tumor microenvironment.
Subduction channels are commonly occupied by deformed and metamorphosed basaltic rocks, together with clastic and pelagic sediments, which form a zone up to several kilometers thick to depths of at ...least 40 km. At temperatures above ~ 350 °C (corresponding to depths of > 25–35 km), the subduction zone undergoes a transition to aseismic behavior, and much of the relative motion is accommodated by ductile deformation in the subduction channel. Microstructures in metagreywacke suggest deformation occurs mainly by solution-redeposition creep in quartz. Interlayered metachert shows evidence for dislocation creep at relatively low stresses (8–13 MPa shear stress). Metachert is likely to be somewhat stronger than metagreywacke, so this value may be an upper limit for the shear stress in the channel as a whole. Metabasaltic rocks deform mainly by transformation-assisted diffusional creep during low-temperature metamorphism and, when dry, are somewhat stronger than metachert. Quartz flow laws for dislocation and solution-redeposition creep suggest strain rates of ~ 10
−12
s
−1
at 500 °C and 10 MPa shear stress: this is sufficient to accommodate a 100 mm/yr. convergence rate within a 1 km wide ductile shear zone.
The up-dip transition into the seismic zone occurs through a region where deformation is still distributed over a thickness of several kilometers, but occurs by a combination of microfolding, dilational microcracking, and solution-redeposition creep. This process requires a high fluid flux, released by dehydration reactions down-dip, and produces a highly differentiated deformational fabric with alternating millimeter-scale quartz and phyllosilicate-rich bands, and very abundant quartz veins. Bursts of dilational microcracking in zones 100–200 m thick may cause cyclic fluctuations in fluid pressure and may be associated with episodic tremor and slow slip events. Shear stress estimates from dislocation creep microstructures in dynamically recrystallized metachert are ~ 10 MPa.
This trial aimed to analyse the safety, effectiveness and transcriptomic characteristics of neoadjuvant toripalimab plus chemotherapy in II-III non-small-cell lung cancer (NSCLC).
Patient eligibility ...mainly involved treatment-naive, clinical stage II-III and wild-type EGFR/ALK NSCLC. The patients received 2-4 cycles of toripalimab (240 mg q3w) plus carboplatin-based chemotherapy. After the second treatment cycle, all patients were re-evaluated by a multidisciplinary team. Candidates eligible for surgery underwent surgery; otherwise, patients received the remaining treatment cycles. The primary endpoints were safety and major pathological response (MPR). Secondary endpoints were R0 resection rate, progression-free survival (PFS) and overall survival (OS). RNA sequencing of baseline and post-treatment samples was conducted to explore the transcriptomic characteristics of the therapeutic response.
In total, 50 eligible patients were enrolled, including 12 (24.0%) with resectable disease (RD) and 38 (76.0%) with potentially resectable disease (PRD). Treatment-related adverse events (TRAEs) were recorded in 48 cases (96.0%). Severe TRAEs occurred in 3 (6.0%) cases, including myelosuppression, drug-induced liver injury and death related to haemoptysis. The objective response rate (ORR) was 76.0%, with 8 (16.0%) patients having a complete response (CR), 30 (60.0%) partial response (PR), 10 (20.0%) stable disease (SD) and 2 (4.0%) progressive disease (PD). Surgery could be achieved in 12 (100%) patients with RD and 25 (65.8%) with PRD; 1 (2.0%) with PRD refused surgery. Therefore, R0 resection was performed for all 36 (100%) patients who underwent surgery; 20 (55.6%) achieved MPR, including 10 (27.8%) with a complete pathological response (pCR). The CHI3L1 (chitinase-3-like protein 1) immunohistochemistry (IHC) expression of baseline tumour samples could predict the therapeutic response (AUC=0.732), OS (P=0.017) and PFS (P=0.001). Increased PD-1 expression, T cell abundance and immune-related pathway enrichment were observed in post-treatment samples compared to baseline in the response group (CR+PR) but not in the non-response group (SD+PD).
Neoadjuvant toripalimab plus chemotherapy was safe and effective, with a high MPR and manageable TRAEs for II-III NSCLC, even converting initially PRD to RD. Disparate transcriptomic characteristics of therapeutic efficiency were observed, and CHI3L1 expression predicted therapeutic response and survival.
ChiCTR1900024014, June 22, 2019.
In this paper, we developed a novel strategy of preparing doxorubicin (DOX) nanocrystal (NC) exerting spherical particles with a diameter of 102 nm, which experienced following coating of chondroitin ...sulphate derivative (CSOA) shell via electrostatic and hydrophobic interactions. Such multifunctional outerwear resulted in drug nanocapsules with high drug loading content up to 70% and high colloidal stability under physiological conditions. It exhibited accelerated drug release behaviour when dispersing in hyaluronidase (HAase) containing medium or incubated with cancer cells. CSOA/NCs were effectively taken up by cancer cells via CD44 receptor-mediated endocytosis, but were rarely internalised into normal fibroblasts. With the comparison of typical drug-loaded micelles system (DOX/PEG-PCL), CSOA/NCs showed greater inhibition to cancer cells due to the targeted and sensitive drug delivery.
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