Clinicopathological characteristics and prognosis of synchronous brain metastases from non-small cell lung cancer compared with metachronous brain metastases.

Purpose: Brain metastasis (BM) from non-small cell lung cancer (NSCLC) is a serious complication severely affecting patients' prognoses. We aimed to compare the clinicopathological features and prognosis of synchronous and metachronous BM from NSCLC. Methods: Clinical data of 461 patients with brain metastases from NSCLC who visited the Cancer Hospital of China Medical University from 2005 to 2017 were retrospectively collected. We analyzed the pathophysiological characteristics of synchronous and metachronous BM from NSCLC and survival rates of the patients. Propensity score matching analysis was used to reduce bias between groups. In addition, we used the Kaplan-Meier method for survival analysis, log-rank test to compare survival rates, and Cox proportional hazards regression model for multivariate prognosis analysis. Results: Among 461 patients with BM, the number of people who met the inclusion criteria was 400 cases, and after 1:2 propensity score matching,130 had synchronous BM and 260 had metachronous BM. The survival time was longer for metachronous BM in driver mutation-negative patients with squamous cell carcinoma than synchronous BM. Conversely, metachronous and synchronous BM with gene mutations and adenocarcinoma showed no differences in survival time. Multivariate analysis showed that metachronous BM was an independent prognostic factor for overall survival. Furthermore, the pathological type squamous cell carcinoma and Karnofsky Performance Status score <80 were independent risk factors affecting overall survival. Conclusion: BM status is an independent factor influencing patient outcome. Moreover, synchronous and metachronous BM from NSCLC differ in gene mutation profile, pathological type, and disease progression and hence require different treatments.

From intramuscular to nasal: unleashing the potential of nasal spray vaccines against coronavirus disease 2019.

Coronavirus disease 2019, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected 700 million people worldwide since its outbreak in 2019. The current pandemic strains, including Omicron and its large subvariant series, exhibit strong transmission and stealth. After entering the human body, the virus first infects nasal epithelial cells and invades host cells through the angiotensin-converting enzyme 2 receptor and transmembrane serine protease 2 on the host cell surface. The nasal cavity is an important body part that protects against the virus. Immunisation of the nasal mucosa produces immunoglobulin A antibodies that effectively neutralise viruses. Saline nasal irrigation, a type of physical therapy, can reduce the viral load in the nasal cavity and prevent viral infections to some extent. As a commonly used means to fight SARS-CoV-2, the intramuscular (IM) vaccine can induce the human body to produce a systemic immune response and immunoglobulin G antibody; however, the antibody is difficult to distribute to the nasal mucosa in time and cannot achieve a good preventive effect. Intranasal (IN) vaccines compensate for the shortcomings of IM vaccines, induce mucosal immune responses, and have a better effect in preventing infection. In this review, we discuss the nasal defence barrier, the harm caused by SARS-CoV-2, the mechanism of its invasion into host cells, nasal cleaning, IM vaccines and IN vaccines, and suggest increasing the development of IN vaccines, and use of IN vaccines as a supplement to IM vaccines.

Clinical factors and major pathological response after neoadjuvant chemoimmunotherapy in potentially resectable lung squamous cell carcinoma.

Objective: Major pathological response (MPR) helps evaluate the prognosis of patients with lung squamous cell carcinoma (LUSC). However, the clinical factors that affect the achievement of MPR after neoadjuvant chemoimmunotherapy (NCIO) in patients with LUSC remain unclear. This study aimed to explore the clinical factors affecting the MPR after NCIO in patients with potentially resectable LUSC. Methods: This retrospective study included patients with stage IIB-IIIC LUSC who underwent surgical resection after receiving NCIO at a center between March 2020 and November 2022. In addition to the postoperative pathological remission rate, sex, age, body mass index (BMI), smoking history, TNM stage, hematological and imaging test results, and other indicators were examined before NCIO. According to the pathological response rate of the surgically removed tumor tissue, the patients were split into MPR and non-MPR groups. Results: In total, 91 LUSC patients who met the study's eligibility criteria were enrolled: 32 (35%) patients in the non-MPR group and 59 (65%) in the MPR group, which included 43 cases of pathological complete remission (pCR). Pre-treatment lymphocyte level (LY) (odds ratio [OR] =5.997), tumor burden (OR=0.958), N classification (OR=15.915), radiographic response (OR=11.590), pulmonary atelectasis (OR=5.413), and PD-L1 expression (OR=1.028) were independently associated with MPR (all P < 0.05). Based on these six independent predictors, we developed a nomogram model of prediction having an area under the curve (AUC) of 0.914 that is simple to apply clinically to predict the MPR. The MPR group showed greater disease-free survival (DFS) than the non-MPR group, according to the survival analysis (P < 0.001). Conclusion: The MPR rate of NCIO for potentially resectable LUSC was 65%. LY, tumor burden, N classification, radiographic response, pulmonary atelectasis, and PD-L1 expression in patients with LUSC before NCIO were the independent and ideal predictors of MPR. The developed nomogram demonstrated a good degree of accuracy and resilience in predicting the MPR following NCIO, indicating that it is a useful tool for assuring customized therapy for patients with possibly resectable LUSC.

Calcitonin gene-related peptide-modulated macrophage phenotypic alteration regulates angiogenesis in early bone healing.

OBJECTIVES: This study aimed to investigate the effect of calcitonin gene-related peptide (CGRP) on the temporal alteration of macrophage phenotypes and macrophage-regulated angiogenesis duringearlybonehealing and preliminarily elucidate the mechanism. METHODS: In vivo, the rat mandibular defect models were established with inferior alveolar nerve transection (IANT) or CGRP receptor antagonist injection. Radiographicandhistologic assessments for osteogenesis, angiogenesis, and macrophage phenotypic alteration within bone defects were performed. In vitro, the effect and mechanism of CGRP on macrophage polarization and phenotypic alteration were analyzed. Then the conditioned medium (CM) from CGRP-treated M1 or M2 macrophages was used to culture human umbilical vein endothelial cells (HUVECs), and the CGRP's effect on macrophage-regulated angiogenesis was detected. RESULTS: Comparable changes following IANT and CGRP blockade within bone defects were observed, including the suppression of early osteogenesis and angiogenesis, the prolonged M1 macrophage infiltration and the prohibited transition toward M2 macrophages around vascular endothelium. In vitro experiments showed that CGRP promoted M2 macrophage polarization while upregulating the expression of interleukin 6 (IL-6), a major cytokine that facilitates the transition from M1 to M2-dominant stage, in M1 macrophages via the activation of Yes-associated protein 1. Moreover, CGRP-treated macrophage-CM showed an anabolic effect on HUVECs angiogenesis compared with macrophage-CM and might prevail over the direct effect of CGRP on HUVECs. CONCLUSIONS: Collectively, our results reveal the effect of CGRP on M1 to M2 macrophage phenotypic alteration possibly via upregulating IL-6 in M1 macrophages, and demonstrate the macrophage-regulated pro-angiogenic potential of CGRP in early bone healing.

Langmuir-Blodgett Film Formed by Amphiphilic Molecules for Facile and Rapid Construction of Zinc-Iodine Cell.

Zinc-iodine batteries (ZIBs) are promising candidates for ecofriendly, safe, and low-cost energy storage systems, but polyiodide shuttling and the complex cathode fabrication procedures have severely hindered their broader commercial usage. Herein, a protocol is developed using phospholipid-like oleylamine molecules for scalable production of Langmuir-Blodgett films, which allows the facile preparation of ZIB cathodes in less than 1 min. The resulting inhomogeneous cathode allows for the continuous conversion of iodine. Moreover, the amine group of the oleylamine molecule at the cathode is capable of producing [OA*I+]I3- charge-transfer complexes with iodine, which facilitates the rapid migration of iodine and results in a highly reversible iodine conversion process. Consequently, the as-prepared ZIBs can deliver over 2000 cycles at 0.5 mA cm-2 with a capacity retention of 75.3%. This work presents a novel, straightforward, and efficient method for the rapid construction of ZIBs.

Value of Bax and Bcl2 expression in peripheral blood mononuclear cells for clinical prognosis of patients with chronic heart failure.

To investigate the expression of Bax and Bcl2 protein in peripheral blood mononuclear cells (PBMC) of patients with chronic heart failure (CHF), and to analyze their value for predicting major adverse cardiovascular event (MACE) in CHF patients. A total of 154 fasting venous blood samples from CHF patients were collected in our hospital from January 2017 to June 2019, and they were divided into 2 group according to whether MACE occurred during 3 years follow-up, MACE group and No-MACE group. Levels of Bax and Bcl2 protein expression in PBMC of CHF patients using enzyme-linked immunosorbent assay (ELISA), and then evaluated the predictive power of Bax and Bcl2 expression for MACE using logistic regression analysis and ROC curve. 62 (40.26%) of 154 CHF patients occurred MACE during follow-up, and there were significant differences in age, diabetes, LVEF, LDL-C and NYHA grade between MACE group and No-MACE group. Levels of Bax protein expression in PBMC of CHF patients in MACE group were significantly higher than those in No-MACE group, while levels of Bcl2 protein expression were significantly lower than those in No-MACE group, and Bax and Bcl2 protein levels increased and decreased with NYHA grades in MACE group and No-MACE group, respectively. Results of univariate and multivariate logistic regression analysis showed that Bax (OR, 1.026; 95% CI, 1.003-1.049; P = .027) and Bcl2 levels (OR, 0.952; 95% CI, 0.908-0.998; P = .041) were independent predictive factors for MACE in CHF patients. In addition, Bax and Bcl2 levels could be used to differentiate CHF patients at risk for MACE with an AUC of 0.744 (95% CI: 0.660-0.827) and an AUC of 0.743 (95% CI: 0.667-0.819), respectively. Levels of Bax and Bcl2 protein in PBMC could be used as independent predictive factors for MACE in CHF patients.

TET2 modulates spatial relocalization of heterochromatin in aged hematopoietic stem and progenitor cells.

DNA methylation deregulation at partially methylated domains (PMDs) represents an epigenetic signature of aging and cancer, yet the underlying molecular basis and resulting biological consequences remain unresolved. We report herein a mechanistic link between disrupted DNA methylation at PMDs and the spatial relocalization of H3K9me3-marked heterochromatin in aged hematopoietic stem and progenitor cells (HSPCs) or those with impaired DNA methylation. We uncover that TET2 modulates the spatial redistribution of H3K9me3-marked heterochromatin to mediate the upregulation of endogenous retroviruses (ERVs) and interferon-stimulated genes (ISGs), hence contributing to functional decline of aged HSPCs. TET2-deficient HSPCs retain perinuclear distribution of heterochromatin and exhibit age-related clonal expansion. Reverse transcriptase inhibitors suppress ERVs and ISGs expression, thereby restoring age-related defects in aged HSPCs. Collectively, our findings deepen the understanding of the functional interplay between DNA methylation and histone modifications, which is vital for maintaining heterochromatin function and safeguarding genome stability in stem cells.

Expanding PROTACtable genome universe of E3 ligases.

Proteolysis-targeting chimera (PROTAC) and other targeted protein degradation (TPD) molecules that induce degradation by the ubiquitin-proteasome system (UPS) offer new opportunities to engage targets that remain challenging to be inhibited by conventional small molecules. One fundamental element in the degradation process is the E3 ligase. However, less than 2% amongst hundreds of E3 ligases in the human genome have been engaged in current studies in the TPD field, calling for the recruiting of additional ones to further enhance the therapeutic potential of TPD. To accelerate the development of PROTACs utilizing under-explored E3 ligases, we systematically characterize E3 ligases from seven different aspects, including chemical ligandability, expression patterns, protein-protein interactions (PPI), structure availability, functional essentiality, cellular location, and PPI interface by analyzing 30 large-scale data sets. Our analysis uncovers several E3 ligases as promising extant PROTACs. In total, combining confidence score, ligandability, expression pattern, and PPI, we identified 76 E3 ligases as PROTAC-interacting candidates. We develop a user-friendly and flexible web portal ( https://hanlaboratory.com/E3Atlas/ ) aimed at assisting researchers to rapidly identify E3 ligases with promising TPD activities against specifically desired targets, facilitating the development of these therapies in cancer and beyond.

Magnetically assisted soft milli-tools for occluded lumen morphology detection.

Methodologies based on intravascular imaging have revolutionized the diagnosis and treatment of endovascular diseases. However, current methods are limited in detecting, i.e., visualizing and crossing, complicated occluded vessels. Therefore, we propose a miniature soft tool comprising a magnet-assisted active deformation segment (ADS) and a fluid drag-driven segment (FDS) to visualize and cross the occlusions with various morphologies. First, via soft-bodied deformation and interaction, the ADS could visualize the structure details of partial occlusions with features as small as 0.5 millimeters. Then, by leveraging the fluidic drag from the pulsatile flow, the FDS could automatically detect an entry point selectively from severe occlusions with complicated microchannels whose diameters are down to 0.2 millimeters. The functions have been validated in both biologically relevant phantoms and organs ex vivo. This soft tool could help enhance the efficacy of minimally invasive medicine for the diagnosis and treatment of occlusions in various circulatory systems.

Molecular mechanisms of tumor resistance to radiotherapy.

BACKGROUND: Cancer is the most prevalent cause of death globally, and radiotherapy is considered the standard of care for most solid tumors, including lung, breast, esophageal, and colorectal cancers and glioblastoma. Resistance to radiation can lead to local treatment failure and even cancer recurrence. MAIN BODY: In this review, we have extensively discussed several crucial aspects that cause resistance of cancer to radiation therapy, including radiation-induced DNA damage repair, cell cycle arrest, apoptosis escape, abundance of cancer stem cells, modification of cancer cells and their microenvironment, presence of exosomal and non-coding RNA, metabolic reprogramming, and ferroptosis. We aim to focus on the molecular mechanisms of cancer radiotherapy resistance in relation to these aspects and to discuss possible targets to improve treatment outcomes. CONCLUSIONS: Studying the molecular mechanisms responsible for radiotherapy resistance and its interactions with the tumor environment will help improve cancer responses to radiotherapy. Our review provides a foundation to identify and overcome the obstacles to effective radiotherapy.

Cholesteric Liquid Crystal Polymeric Coatings for Colorful Artificial Muscles and Motile Humidity Sensor Skin Integrated with Magnetic Composites.

Structural colorful cholesterics show impressive susceptibility to external stimulation, leading to applications in electro/mechano-chromic devices. However, out-of-plane actuation of structural colorful actuators based on cholesterics and the integration with other stimulation remains underdeveloped. Herein, colorful actuators and motile humidity sensors are developed using humidity-responsive cholesteric liquid crystal networks (CLCNs) and magnetic composites. The developed colorful actuator can exhibit synergistic out-of-plane shape morphing and color change in response to humidity, with CLCNs as colorful artificial muscles. Through the integration with magnetic control, the motile sensor can be navigated to open and confined spaces with the aid of friction to detect local relative humidity. The integration of multi-stimulation actuation of cholesteric magnetic actuators will expand the research frontier of structural colorful actuators and motile sensors for confined spaces.

Quantitative characterization of cell physiological state based on dynamical cell mechanics for drug efficacy indication.

Cell mechanics is essential to cell development and function, and its dynamics evolution reflects the physiological state of cells. Here, we investigate the dynamical mechanical properties of single cells under various drug conditions, and present two mathematical approaches to quantitatively characterizing the cell physiological state. It is demonstrated that the cellular mechanical properties upon the drug action increase over time and tend to saturate, and can be mathematically characterized by a linear time-invariant dynamical model. It is shown that the transition matrices of dynamical cell systems significantly improve the classification accuracies of the cells under different drug actions. Furthermore, it is revealed that there exists a positive linear correlation between the cytoskeleton density and the cellular mechanical properties, and the physiological state of a cell in terms of its cytoskeleton density can be predicted from its mechanical properties by a linear regression model. This study builds a relationship between the cellular mechanical properties and the cellular physiological state, adding information for evaluating drug efficacy.

Neutrophil elastase: From mechanisms to therapeutic potential.

Neutrophil elastase (NE), a major protease in the primary granules of neutrophils, is involved in microbicidal activity. NE is an important factor promoting inflammation, has bactericidal effects, and shortens the inflammatory process. NE also regulates tumor growth by promoting metastasis and tumor microenvironment remodeling. However, NE plays a role in killing tumors under certain conditions and promotes other diseases such as pulmonary ventilation dysfunction. Additionally, it plays a complex role in various physiological processes and mediates several diseases. Sivelestat, a specific NE inhibitor, has strong potential for clinical application, particularly in the treatment of coronavirus disease 2019 (COVID-19). This review discusses the pathophysiological processes associated with NE and the potential clinical applications of sivelestat.

A versatile jellyfish-like robotic platform for effective underwater propulsion and manipulation.

Underwater devices are critical for environmental applications. However, existing prototypes typically use bulky, noisy actuators and limited configurations. Consequently, they struggle to ensure noise-free and gentle interactions with underwater species when realizing practical functions. Therefore, we developed a jellyfish-like robotic platform enabled by a synergy of electrohydraulic actuators and a hybrid structure of rigid and soft components. Our 16-cm-diameter noise-free prototype could control the fluid flow to propel while manipulating objects to be kept beneath its body without physical contact, thereby enabling safer interactions. Its against-gravity speed was up to 6.1 cm/s, substantially quicker than other examples in literature, while only requiring a low input power of around 100 mW. Moreover, using the platform, we demonstrated contact-based object manipulation, fluidic mixing, shape adaptation, steering, wireless swimming, and cooperation of two to three robots. This study introduces a versatile jellyfish-like robotic platform with a wide range of functions for diverse applications.

Engineering of NEMO as calcium indicators with large dynamics and high sensitivity.

Genetically encoded calcium indicators (GECIs) are indispensable tools for real-time monitoring of intracellular calcium signals and cellular activities in living organisms. Current GECIs face the challenge of suboptimal peak signal-to-baseline ratio (SBR) with limited resolution for reporting subtle calcium transients. We report herein the development of a suite of calcium sensors, designated NEMO, with fast kinetics and wide dynamic ranges (>100-fold). NEMO indicators report Ca2+ transients with peak SBRs around 20-fold larger than the top-of-the-range GCaMP6 series. NEMO sensors further enable the quantification of absolution calcium concentration with ratiometric or photochromic imaging. Compared with GCaMP6s, NEMOs could detect single action potentials in neurons with a peak SBR two times higher and a median peak SBR four times larger in vivo, thereby outperforming most existing state-of-the-art GECIs. Given their high sensitivity and resolution to report intracellular Ca2+ signals, NEMO sensors may find broad applications in monitoring neuronal activities and other Ca2+-modulated physiological processes in both mammals and plants.

Dynamic Characterization of Single Cells Based on Temporal Cellular Mechanical Properties.

The mechanical properties of cells play important roles in regulating the physiological activities of cells and reflect the state of macro-organisms. Although many approaches are available for investigating the mechanical properties of cells, the fluidity of cytoplasm across cell boundaries makes characterizing the dynamics of mechanical properties of single cells exceedingly difficult. In this study, we present a single cell characterization method by modelling the dynamics of cellular mechanical properties measured with an atomic force microscope (AFM). The mechanical dynamics of a single cell system was described by a linear model with a mechanical stimulus as virtual input and mechanical property parameters as outputs. The dynamic mechanical properties of a single cell were characterized by the system matrix of the single cell system. The method was used to classify different types of cells, and the experimental results show that the proposed method outperformed conventional methods by achieving an average classification accuracy of over 90%. The developed method can be used to classify different cancer types according to the mechanical properties of tumour cells, which is of great significance for clinically assisted pathological diagnosis.

Direct modulation index: A measure of phase amplitude coupling for neurophysiology data.

Neural communication across different spatial and temporal scales is a topic of great interest in clinical and basic science. Phase-amplitude coupling (PAC) has attracted particular interest due to its functional role in a wide range of cognitive and motor functions. Here, we introduce a novel measure termed the direct modulation index (dMI). Based on the classical modulation index, dMI provides an estimate of PAC that is (1) bound to an absolute interval between 0 and +1, (2) resistant against noise, and (3) reliable even for small amounts of data. To highlight the properties of this newly-proposed measure, we evaluated dMI by comparing it to the classical modulation index, mean vector length, and phase-locking value using simulated data. We ascertained that dMI provides a more accurate estimate of PAC than the existing methods and that is resilient to varying noise levels and signal lengths. As such, dMI permits a reliable investigation of PAC, which may reveal insights crucial to our understanding of functional brain architecture in key contexts such as behaviour and cognition. A Python toolbox that implements dMI and other measures of PAC is freely available at https://github.com/neurophysiological-analysis/FiNN.

Flexible Wearable Sensors in Medical Monitoring.

The popularity of health concepts and the wave of digitalization have driven the innovation of sensors in the medical field. Such continual development has made sensors progress in the direction of safety, flexibility, and intelligence for continuous monitoring of vital signs, which holds considerable promise for changing the way humans live and even treat diseases. To this end, flexible wearable devices with high performance, such as high sensitivity, high stability, and excellent biodegradability, have attracted strong interest from scientists. Herein, a review of flexible wearable sensors for temperature, heart rate, human motion, respiratory rate, glucose, and pH is highlighted. In addition, engineering issues are also presented, focusing on material selection, sensor fabrication, and power supply. Finally, potential challenges facing current technology and future directions of wearable sensors are also discussed.