The cuproptosis-associated 11 gene signature as a predictor for outcomes and response to Bacillus Calmette-Guerin and immune checkpoint inhibitor therapies in bladder carcinoma

Bladder cancer (BC) or carcinoma (BLCA) is predominantly derived from urothelium and includes non-muscle invasive BC (NMIBC) and muscle invasive BC (MIBC). Bacillus Calmette-Guerin (BCG) has long been applied for NMIBC to effectively reduce disease recurrence or progression, whereas immune checkpoint inhibitors (ICIs) were recently introduced to treat advanced BLCA with good efficacy. For BCG and ICI applications, reliable biomarkers are required to stratify potential responders for better personalized interventions, and ideally, they can replace or reduce invasive examinations such as cystoscopy in monitoring treatment efficacy. Here we developed the cuproptosis-associated 11 gene signature (CuAGS-11) model to accurately predict survival and response to BCG and ICI regimens in BLCA patients. In both discovery and validation cohorts where BLCA patients were divided into high- and low-risk groups based on a median CuAGS-11 score as the cutoff, the high-risk group was associated with significantly shortened overall survival (OS) and progression-free survival (PFS) independently. The survival predictive accuracy was comparable between CuAGS-11 and stage, and their combination-based nomograms showed high consistence between predicted and observed OS/PFS. The analysis of 3 BLCA cohorts treated with BCG unveiled lower response rates and higher frequencies of recurrence or progression coupled with shorter survival in CuAGS-11 high-risk groups. In contrast, almost none of patients underwent progression in low-risk groups. In IMvigor210 cohort of 298 BLCA patients treated with ICI Atezolizumab, complete/partial remissions were 3-fold higher accompanied by significantly longer OS in the CuAGS-11 low- than high-risk groups (P = 7.018E-06). Very similar results were obtained from the validation cohort (P = 8.65E-05). Further analyses of Tumor Immune Dysfunction and Exclusion (TIDE) scores revealed that CuAGS-11 high-risk groups displayed robustly higher T cell exclusion scores in both discovery (P = 1.96E-05) and validation (P = 0.008) cohorts. Collectively, the CuAGS-11 score model is a useful predictor for OS/PFS and BCG/ICI efficacy in BLCA patients. For BCG-treated patients, reduced invasive examinations are suggested for monitoring the CuAGS-11 low-risk patients. The present findings thus provide a framework to improve BLCA patient stratification for personalized interventions and to reduce invasive monitoring inspections

Substantially enhanced plasticity of bulk metallic glasses by densifying local atomic packing

Common wisdom to improve ductility of bulk metallic glasses (BMGs) is to introduce local loose packing regions at the expense of strength. Here the authors enhance structural fluctuations of BMGs by introducing dense local packing regions, resulting in simultaneous increase of ductility and strength

Design, Synthesis and Bioactivities of Novel Dichloro-Allyloxy-Phenol-Containing Pyrazole Oxime Derivatives

In this study, in order to find novel biologically active pyrazole oxime compounds, a number of dichloro-allyloxy-phenol-containing pyrazole oximes were designed and synthesized according to the method of active group combination. All of the target compounds were confirmed by 1H-NMR, 13C-NMR and elemental analysis. In addition, bioassays showed that all of the newly synthesized compounds had no acaricidal activity against Tetranychus cinnabarinus and low insecticidal activity against Aphis craccivora at tested concentrations. However, most of them displayed excellent insecticidal activity against Oriental armyworm at a concentration of 500 μg/mL, and some designed compounds still exhibited potent insecticidal activity against Oriental armyworm even at the dose of 20 μg/mL, especially compounds 7f, 7n and 7p had 100%, 90% and 90% inhibition rates, respectively, which were comparable to that of the control pyridalyl

Towards Decision-Friendly AUC: Learning Multi-Classifier with AUCµ

Area Under the ROC Curve (AUC) is a widely used ranking metric in imbalanced learning due to its insensitivity to label distributions. As a well-known multiclass extension of AUC, Multiclass AUC (MAUC, a.k.a. M-metric) measures the average AUC of multiple binary classifiers. In this paper, we argue that simply optimizing MAUC is far from enough for imbalanced multi-classification. More precisely, MAUC only focuses on learning scoring functions via ranking optimization, while leaving the decision process unconsidered. Therefore, scoring functions being able to make good decisions might suffer from low performance in terms of MAUC. To overcome this issue, we turn to explore AUCµ, another multiclass variant of AUC, which further takes the decision process into consideration. Motivated by this fact, we propose a surrogate risk optimization framework to improve model performance from the perspective of AUCµ. Practically, we propose a two-stage training framework for multi-classification, where at the first stage a scoring function is learned maximizing AUCµ, and at the second stage we seek for a decision function to improve the F1-metric via our proposed soft F1. Theoretically, we first provide sufficient conditions that optimizing the surrogate losses could lead to the Bayes optimal scoring function. Afterward, we show that the proposed surrogate risk enjoys a generalization bound in order of O(1/√N). Experimental results on four benchmark datasets demonstrate the effectiveness of our proposed method in both AUCµ and F1-metric

Correction to: Kallistatin inhibits tumour progression and platinum resistance in high-grade serous ovarian cancer

The original article [1] contains errors in Fig. 3C, Results and Discussion

The application of extracellular vesicles in colorectal cancer metastasis and drug resistance: recent advances and trends

Abstract Colorectal cancer (CRC) has high incidence and mortality rates and is one of the most common cancers of the digestive tract worldwide. Metastasis and drug resistance are the main causes of cancer treatment failure. Studies have recently suggested extracellular vesicles (EVs) as a novel mechanism for intercellular communication. They are vesicular particles, which are secreted and released into biological fluids, such as blood, urine, milk, etc., by a variety of cells and carry numerous biologically active molecules, including proteins, nucleic acids, lipids, metabolites, etc. EVs play a crucial part in the metastasis and drug resistance of CRC by delivering cargo to recipient cells and modulating their behavior. An in-depth exploration of EVs might facilitate a comprehensive understanding of the biological behavior of CRC metastasis and drug resistance, which might provide a basis for developing therapeutic strategies. Therefore, considering the specific biological properties of EVs, researchers have attempted to explore their potential as next-generation delivery systems. On the other hand, EVs have also been demonstrated as biomarkers for the prediction, diagnosis, and presumed prognosis of CRC. This review focuses on the role of EVs in regulating the metastasis and chemoresistance of CRC. Moreover, the clinical applications of EVs are also discussed. Graphical Abstrac

α7 Nicotinic acetylcholine receptor: a key receptor in the cholinergic anti-inflammatory pathway exerting an antidepressant effect

Abstract Depression is a common mental illness, which is related to monoamine neurotransmitters and the dysfunction of the cholinergic, immune, glutamatergic, and neuroendocrine systems. The hypothesis of monoamine neurotransmitters is one of the commonly recognized pathogenic mechanisms of depression; however, the drugs designed based on this hypothesis have not achieved good clinical results. A recent study demonstrated that depression and inflammation were strongly correlated, and the activation of alpha7 nicotinic acetylcholine receptor (α7 nAChR)-mediated cholinergic anti-inflammatory pathway (CAP) in the cholinergic system exhibited good therapeutic effects against depression. Therefore, anti-inflammation might be a potential direction for the treatment of depression. Moreover, it is also necessary to further reveal the key role of inflammation and α7 nAChR in the pathogenesis of depression. This review focused on the correlations between inflammation and depression as well-discussed the crucial role of α7 nAChR in the CAP

An anisotropic van der Waals dielectric for symmetry engineering in functionalized heterointerfaces

Abstract Van der Waals dielectrics are fundamental materials for condensed matter physics and advanced electronic applications. Most dielectrics host isotropic structures in crystalline or amorphous forms, and only a few studies have considered the role of anisotropic crystal symmetry in dielectrics as a delicate way to tune electronic properties of channel materials. Here, we demonstrate a layered anisotropic dielectric, SiP2, with non-symmorphic twofold-rotational C 2 symmetry as a gate medium which can break the original threefold-rotational C 3 symmetry of MoS2 to achieve unexpected linearly-polarized photoluminescence and anisotropic second harmonic generation at SiP2/MoS2 interfaces. In contrast to the isotropic behavior of pristine MoS2, a large conductance anisotropy with an anisotropy index up to 1000 can be achieved and modulated in SiP2-gated MoS2 transistors. Theoretical calculations reveal that the anisotropic moiré potential at such interfaces is responsible for the giant anisotropic conductance and optical response. Our results provide a strategy for generating exotic functionalities at dielectric/semiconductor interfaces via symmetry engineering

Valley-dimensionality locking of superconductivity in cubic phosphides

Two-dimensional superconductivity is primarily realized in atomically thin layers through extreme exfoliation, epitaxial growth, or interfacial gating. Apart from their technical challenges, these approaches lack sufficient control over the Fermiology of superconducting systems. Here, we offer a Fermiology-engineering approach, allowing us to desirably tune the coherence length of Cooper pairs and the dimensionality of superconducting states in arsenic phosphides AsxP1−x under hydrostatic pressure. We demonstrate how this turns these compounds into tunable two-dimensional superconductors with a dome-shaped phase diagram even in the bulk limit. This peculiar behavior is shown to result from an unconventional valley-dimensionality locking mechanism, driven by a delicate competition between three-dimensional hole-type and two-dimensional electron-type energy pockets spatially separated in momentum space. The resulting dimensionality crossover is further discussed to be systematically controllable by pressure and stoichiometry tuning. Our findings pave a unique way to realize and control superconducting phases with special pairing and dimensional orders. Valley-dimensionality–locked superconductivity is achieved via orbital selection in cubic AsP alloy under pressure