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Immune checkpoint inhibitors (ICIs) have become a vital part of the therapeutic landscape for non-small cell lung cancer (NSCLC) in recent years benefiting from their remarkable efficacy. However, ICIs are associated with potentially life-threatening immune-related adverse events (irAEs). This study aims to quantify dose dependence and additional influencing factors of both any grade and grade greater than or equal to 3 irAEs in patients with NSCLC treated by ICIs. The trial-level irAE data was collected and pooled from 129 cohorts in 81 clinical studies. A logit-transformed meta-regression model was applied to derive the quantitative relationship of irAE rate and ICI exposure. Programmed cell death-1 (PD-1) or programmed cell death ligand-1 (PD-L1) inhibitors showed no dose dependence in patients with NSCLC, whereas cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitors exhibited a statistically significant dose dependence when used alone or combined with PD-1 or PD-L1 inhibitors. Besides, therapy line and combination of ICIs with chemotherapy or target therapy were significant covariates. Hopefully, the results of this study can improve clinicians' awareness of irAEs and be helpful for clinical decisions during ICI treatment for NSCLC.

The selective oxidation of styrene with highly efficient, environmentally benign, and cost-effective catalysts are of great importance for sustainable chemical processes. Here, we develop an in situ self-assembly strategy to decorate Cu-based metal-organic framework (MOF) Cu-BDC-NH2 nanocrystals on Cu2O octahedra to construct a series of Cu2O@Cu-BDC-NH2 catalysts for selective oxidation of styrene. Using H2O2 as green oxidants, the optimized sample of Cu2O@Cu-BDC-NH2-8h could achieve 85% styrene conversion with 76% selectivity of benzaldehyde under a mild condition of 40 °C. The high performance of the as-prepared heterogeneous catalysts was attributed to the well-designed Cu+/Cu2+ interface between Cu2O and Cu-BDC-NH2 as well as the porous MOF shells composed of the uniformly dispersed Cu-BDC-NH2 nanocrystals. The alkaline properties of Cu2O and the –NH2 modification of MOFs enable the reaction to be carried out in a base-free condition, which simplifies the separation process and makes the catalytic system more environmentally friendly. Besides the Cu2O octahedra (od-Cu2O), the Cu2O cuboctahedrons (cod-Cu2O) were synthesized by adjusting the added polyvinyl pyrrolidone, and the obtained cod-Cu2O@Cu-BDC-NH2 composite also showed good catalytic performance. This work provides a useful strategy for developing highly efficient and environmentally benign heterogeneous catalysts for the selective oxidation of styrene.

Conventional single thermal nature of phase change materials (PCMs) seriously obstructs their frontier applications. Herein, we designed advanced carbon nanotube (CNT) bundles assembled flexible hierarchical framework based phase change material composites for high-performance thermotherapy of allergic rhinitis. Hierarchically interconnected 3D freestanding flexible CNT sponge was constructed via a facile organic solvent-free route using table salt as a sacrificial template. The resulting hierarchical CNT sponge serves as an ideal compatible supporting host and polyethylene glycol (PEG) serves as an excellent thermal energy guest. Subsequently, we designed advanced portable integrated functional mask consisting of outer air purification layer and inner thermal regulation layer for the thermotherapy of allergic rhinitis, in which pristine CNT sponge serves as an excellent particulate matter capturer and PEG-infiltrated CNT sponge serves as a superior thermal regulator. Strikingly, our uniquely constructed flexible CNT sponge-involved composite PCMs assisted by polyvinylidene fluoride (PVDF) harvest high-performance thermotherapy (~33 ​min of the plateau at ~43.5 ​°C). The corresponding medical results (HE staining and Wrights staining) further indicate that our designed thermotherapy mask can significantly reduce the inflammatory injury of nasal mucosa. Additionally, pristine hierarchical CNT sponge guarantees the inhaled air quality and enhances the thermotherapy effect. This synthetic strategy can be scaled up for large-scale production. This novel functional host-guest strategy creates an innovative platform for developing advanced multifunctional PCMs with multiple fascinating peculiarities and desired functional properties and teaches an old dog new tricks.

Owing to the high abundance, good conductivity and excellent tolerance to harsh environment, carbon host materials have recently attracted considerable research interest in the fields of electrochemical hydrogen evolution reaction (HER). However, the deficiency of intrinsic active sites within the carbon host materials substantially gives rise to an inferior HER performance. In this work, atomically dispersed ruthenium active sites are deliberately introduced into the carbon host structure by controlled pyrolysis of Ru-doped ZIF-8. With atomic Ru sites on a unique whisker-like secondary microstructure and a favorable porous texture, the optimal product exhibits a high intrinsic activity as well as robust durability, which especially outperforms the Pt/C benchmarking in alkaline media. A combination of control experiments and theoretical calculations demonstrates that atomically dispersed Ru sites within the carbon host matrix serve as the dominant catalytically active sites, and remarkably optimize the free energy of water molecule dissociation during the Volmer step, thus boosting the HER performance.

Dopamine D1 receptor (D1DR) is proved to be a promising target to prevent tumor metastasis, and our previous studies showed that QAP14, a potent anti-cancer agent, exerted inhibitory effect on lung metastasis via D1DR activation. Therefore, the purpose of the study was to establish count data models to quantitatively characterize the disease progression of lung metastasis and assess the anti-metastatic effect of QAP14. Data of metastatic progression were collected in 4T1 tumor-bearing mice. Generalized Poisson distribution best described the variability of metastasis counts among the individuals. An empirical PK/PD model was developed to establish mathematical relationships between steady plasma concentrations of QAP14 and metastasis growth dynamics. The latency period of metastasis was estimated to be 12 days after tumor implantation. Our model structure also fitted well to other D1DR agonists (fenoldopam and l-stepholidine) which had inhibitory impact on breast cancer lung metastasis likewise. QAP14 40 mg/kg showed the best inhibitory efficacy, for it provided the longest prolongation of metastasis-free periods compared with fenoldopam or l-stepholidine. This study provides a quantitative method to describe the lung metastasis progression of 4T1 allografts, as well as an alternative PD model structure to evaluate anti-metastatic efficacy.

Breast cancer is the second leading cause of cancer-related mortality in women, mainly due to metastasis, which is strongly associated with cancer stemness. Our previous studies showed that the eradication of cancer stem-like cells (CSCs) may be related to the activation of dopamine D1 receptor (D1DR). This study aimed to explicitly demonstrate the target-role of D1DR activation in antimetastatic therapy and to investigate the potential efficacy and the underlying D1DR-related mechanisms of QAP14, a new oral compound. 4T1, MDA-MB-231, and D1DR-knockout 4T1 (4T1-D1DR) cells were selected for in vitro study, while 4T1 and 4T1-D1DR cells were further used to establish a mouse allograft model for in vivo study. Our results showed that D1DR is abundantly expressed in both 4T1 and MDA-MB-231 cells and that knocking out D1DR in 4T1 cells accelerated migration and invasion in vitro as well as lung metastasis in vivo. QAP14 inhibited colony formation, cell motility, mammosphere formation and CSC frequency, induced CSC apoptosis and D1DR expression, and increased cAMP/cGMP levels. Additionally, QAP14 showed inhibitory effects on tumor growth and lung metastasis with acceptable safety in vivo. Knocking out D1DR almost completely abolished the efficacy, confirming that QAP14 exhibits its anti-CSC and antimetastatic effects through D1DR activation. The underlying mechanisms involved suppression of the nuclear factor κB (NF-κB)/protein kinase B (Akt) pathway and consequent downregulation of both epithelial-to-mesenchymal transition (EMT) process and cancer stemness. In summary, our findings suggest a potential candidate compound, QAP14, as well as a potential target, D1DR, for metastatic breast cancer therapy.

Ultrathin Bimetal MOF nanosheets (BMOFNs) are regarded as effective electrocatalyst for Oxygen evolution reaction (OER) because of their abundance of coordinatively unsaturated metal atoms, enhanced mass permeability and coupling effect between bimetals, while the limited conductivity and stability severely hinders their widespread application. Here, we develop an in situ semi-sacrificial template-assisted strategy to grow ultrathin BMOFNs on NiCo-LDH to construct non-noble metal electrocatalysts that are both active and stable. The optimized NiCo-LDH@MOFs heterostructure exhibits a superior electrocatalytic activity with accelerated electronic transfer and significantly enhanced durability of over 300 h. An advanced AFM-IR technology is introduced for the first time to investigate the formation of the 2D-2D heterogeneous structure in NiCo-LDH@MOFs, providing insights into the morphology-structure-composition evolution of the electrocatalyst at a nanoscale. This work demonstrates an in-situ growth strategy to achieve high-performance ultrathin MOF-based electrocatalysts, and provides advanced combinatorial characterization techniques to monitor the material growth process.

The self-renewal and differentiation of cancer stem-like cells (CSCs) leads to cellular heterogeneity, causing one of the greatest challenges in cancer therapy. Growing evidence suggests that CSC-targeting therapy enhances the effect of concomitant antitumour therapy. To gain an in-depth understanding of this enhanced effect, the kinetic profile of estimated CSC frequency (the fraction of CSCs in tumour) was evaluated for in vivo characterization of cellular heterogeneity using sunitinib and dopamine as a paradigm combination therapy. Female MCF-7/Adr xenografted Balb/c nude mice were treated with sunitinib (p.o., 20 mg/kg) and dopamine (i.p., 50 mg/kg), alone or in combination. Estimated CSC frequency and tumour size were measured over time. Mechanistic PK/PD modelling was performed to quantitatively describe the relationship between drug concentration, estimated CSC frequency and tumour size. Sunitinib reduced tumour size by inducing apoptosis of differentiated tumour cells (DTCs) and enriched CSCs by stimulating its proliferation. Dopamine exhibited anti-CSC effects by suppressing the capacity of CSCs and inducing its differentiation. Simulation and animal studies indicated that concurrent administration was superior to sequential administration under current experimental conditions. Alongside tumour size, the current study provides mechanistic insights into the estimation of CSC frequency as an indicator for cellular heterogeneity. This forms the conceptual basis for in vivo characterization of other combination therapies in preclinical cancer studies.

Currently, most reported composite phase change materials (PCMs) are powdery shape, which require secondary processing for practical applications. Although some monolithic composite PCMs have been developed, their flexibility usually undergoes a remarkable reduction or even complete disappearance when supporting material s are infiltrated with PCMs. To solve this problem, we fabricated a flexible supporting material with a folded layer-bridge network structure by dispersing carbon nanotubes (CNTs) in acetic acid solution of chitosan (CS) with poly(vinyl alcohol) (PVA) using a directional freezing method. Then CS/PVA/CNTs (CPC) scaffold was infiltrated with polyethylene glycol (PEG) to prepare PEG@CPC composite PCM. The resulting flexible composite PCM displays excellent mechanical properties, such as high tensile strength of 2.42 MPa and bending resistance of >100 cycles. Moreover, it displays outstanding thermal properties, such as high crystallinity of close to 100% and encapsulation ratio of 92.6 wt%. This work provides a simple method for preparation of flexible monolithic composite PCMs for many potential applications, such as wearable fitting-skin temperature-controlled materials.

Currently, numerous studies are devoted to the pursuit of thermal conductivity enhancement of phase change materials (PCMs). On the contrary, few researches are reported to reduce the thermal conductivity of PCMs. Generally, the PCMs with reduced thermal conductivity have great potential in thermal protection application. Herein, we propose a novel in situ one-step strategy to facilely prepare monolithic silica aerogel-based composite PCMs. The silica aerogels possess low thermal conductivity and are used to encapsulate PCMs to prepare composite PCMs, such as polyethylene glycol (PEG) or octadecanol. Compare with PEG2000@silica aerogel, the resulting monolithic octadecanol@silica aerogel have low thermal conductivity (0.12 W m−1 K−1), high latent heat (127.73 J/g), large compressive strength (11 MPa), good hydrophobicity (contact angle 124°) and superior thermal cycling stability. This monolithic silica aerogel-based composite PCMs could prolong heat preservation duration due to the synergistic effect between low thermal conductivity and high latent heat of composite PCMs, showing potential promise for direct application to the thermal insulation and thermal protection device. More importantly, this in situ one-step synthesis strategy is universal for different types of PCMs.