CDK4/6 inhibitors promote PARP1 degradation and act synergistically with PARP inhibitors in non-small cell lung cancer.

Despite the widespread deregulation of CDK4/6 activity in non-small cell lung cancer (NSCLC), the clinical trials with CDK4/6 inhibitors (CDK4/6is) as a monotherapy have shown poor antitumor activity. However, our preclinical studies have revealed a significant potential for CDK4/6is to collaborate by influencing DNA damage repair pathways during radiotherapy. Given the considerable upregulation of PARP1 expression in NSCLC, we analyzed the efficacy of combined PARP and CDK4/6 inhibition in NSCLC models. Our findings demonstrate that CDK4/6is synergize with PARP inhibitors (PARPis) to inhibit the clonogenic growth of RB-proficient NSCLC models. This synergy is associated with increased accumulation of DNA damage, interrupted cell-cycle checkpoints, and enhanced apoptotic cell death. We showed that CDK4/6is mechanically promote PARP1 protein degradation, leading to decreased availability of DNA repair factors involved in homologous recombination and suppression of DNA repair competency. Furthermore, we showed that PARP trapping is required for this synergy. We then confirmed that combining PARPi and CDK4/6i blocked the growth of NSCLC xenografts in vivo and patient-derived explant models ex vivo. These findings reveal a previously uncharacterized impact of CDK4/6i on PARP1 levels in RB-proficient NSCLC models and the requirement of PARP trapping to render synergy between CDK4/6i and PARPi. Our research suggests that combining CDK4/6i with PARPi could be a promising therapeutic strategy for patients with RB-proficient NSCLC, potentially opening up new and more effective avenues for treatment.

A 1T'-MoTe2/GaN van der Waals Schottky junction for self-powered UV imaging and optical communication.

Schottky-type self-powered UV photodetectors are promising for next-generation imaging systems. Nevertheless, conventional device fabrication using high-energy metal deposition brings unintentional interface defects, leading to deteriorated device performance and inhomogeneities. Emerging two-dimensional (2D) metallic materials offer an alternative pathway to overcoming such limitations because of their naturally passivated surfaces and the ease of combining with mature bulk semiconductors via van der Waals (vdW) integration. Here, we report the controllable preparation of MoTe2 in the pure 1T' phase and the fabrication of a high-performance 1T'-MoTe2/GaN vdW Schottky photodiode. With the reduced interface states and suppressed dark current as low as 20 pA at zero bias, the photodiode exhibits a remarkable UV-to-visible (R350/R400) rejection ratio of 1.6 × 104, a stable photoresponsivity of ∼50 mA W-1 and a detectivity of 3.5 × 1012 Jones under 360 nm illumination. The photocurrent ON/OFF ratio reaches ∼4.9 × 106 under 10.5 mW irradiation (360 nm). In particular, the 1T'-MoTe2/GaN Schottky diode shows excellent weak-light detection capability, which could detect a 3 nW 360 nm laser and the light emission from a lighter with a pronounced Ilight/Idark ratio of ∼2. Finally, the applications of the device in self-powered UV imaging and optical communication are demonstrated. These results reveal the great prospects of 2D/3D integration in multifunctional optoelectronics, which may inspire novel 2D-related devices and expand their applications in widespread fields.

Therapeutic effects of chamomile volatile oil nanoemulsion/Bletilla striata polysaccharides gels on atopic dermatitis.

Atopic dermatitis (AD) is a prevalent chronic skin condition characterized by complex immune responses. Chamomile possesses potent anti-inflammatory properties and has been widely used in treating various skin diseases. This study aimed to assess the therapeutic benefits of chamomile volatile oil nanoemulsion gels (CVO-NEGs) for the treatment of AD. Chamomile volatile oil nanoemulsions (CVO-NEs) were prepared using the phase transition method, yielding spherical nanoparticles with a particle size of 19.07 nm. Subsequently, Bletilla striata polysaccharides were employed to encapsulate CVO-NEs, resulting in the formation of CVO-NEGs. In vivo studies demonstrated that the preparation of CVO-NEGs enhanced the biological activity of volatile oil in AD therapy. Histopathological results indicated that CVO-NEGs reduced skin damage, epidermal thickness, and mast cell infiltration. CVO-NEGs suppressed IgG production and reduced the levels of cytokines, including TNF-α, IL-4, and IFN-γ, in AD mice. Furthermore, flow cytometry revealed that CVO-NEGs were involved in regulating the differentiation of CD4+ T cell subsets. The immune imbalance of Th1/Th2 in AD mice can be controlled, resulting in a reduction in the hypersensitivity reaction caused by excessive Th2 activation. In conclusion, the present study confirms that CVO-NEGs have the potential to serve as an effective alternative treatment for AD.

Care intervention on psychological outcomes among patients admitted to intensive care unit: an umbrella review of systematic reviews and meta-analyses.

BACKGROUND: Numerous studies have explored care interventions to improve the psychological outcome of intensive care unit (ICU) patients, but inconclusive evidence makes it difficult for decision-makers, managers, and clinicians to get familiar with all available literature and find appropriate interventions. This umbrella review aimed to analyze the relationship between care intervention and psychological outcomes of ICU patients based on existing systematic reviews. METHODS: An umbrella review of evidence across systematic reviews and meta-analyses published between 1987 and 2023 was undertaken. We systematically searched reviews that examined the association between care intervention and the improvement of adverse psychological outcomes in ICU patients using PubMed, EMBASE, Web of Science, Cochrane Library, and manual reference screening. The measurement tool (AMSTAR 2) was applied to evaluate the methodological quality of included studies. The excess significance bias, between-study heterogeneity expressed by I2, small-study effect, and evidence class were estimated. RESULTS: A total of 5110 articles were initially identified from the search databases and nine of them were included in the analysis. By applying standardized criteria, only weak evidence was observed in 13 associations, even though most included reviews were of moderate to high methodological quality. These associations pertained to eight interventions (music therapy, early rehabilitation, post-ICU follow-up, ICU diary, information intervention, preoperative education, communication and psychological support, surrogate decision-making) and five psychological outcomes (post-intensive care syndrome, transfer anxiety, post-traumatic stress disorder, anxiety, and depression). Weak or null association was shown among the rest of the associations (e.g., weak association between music therapy and maternal anxiety or stress level). CONCLUSIONS: The evidence of these eight supporting interventions to improve the adverse psychological outcomes of ICU patients and caregivers was weak. Data from more and better-designed studies with larger sample sizes are needed to establish robust evidence.