Tamm-cavity terahertz detector.

Efficiently fabricating a cavity that can achieve strong interactions between terahertz waves and matter would allow researchers to exploit the intrinsic properties due to the long wavelength in the terahertz waveband. Here we show a terahertz detector embedded in a Tamm cavity with a record Q value of 1017 and a bandwidth of only 469 MHz for direct detection. The Tamm-cavity detector is formed by embedding a substrate with an Nb5N6 microbolometer detector between an Si/air distributed Bragg reflector (DBR) and a metal reflector. The resonant frequency can be controlled by adjusting the thickness of the substrate layer. The detector and DBR are fabricated separately, and a large pixel-array detector can be realized by a very simple assembly process. This versatile cavity structure can be used as a platform for preparing high-performance terahertz devices and opening up the study of the strong interactions between terahertz waves and matter.

Application of New Polymer Soil Amendment in Ecological Restoration of High-Steep Rocky Slope in Seasonally Frozen Soil Areas.

In seasonally frozen soil areas, high-steep rocky slopes resulting from open-pit mining and slope cutting during road construction undergo slow natural restoration, making ecological restoration generally challenging. In order to improve the problems of external soil attachment and long-term vegetation growth in the ecological restoration of high-steep rocky slopes in seasonally frozen areas, this study conducted a series of experiments through the combined application of polyacrylamide (PAM) and carboxymethyl cellulose (CMC) to assess the effects of soil amendments on soil shear strength, water stability, freeze-thaw resistance, erosion resistance, and vegetation growth. This study showed that the addition of PAM-CMC significantly increased the shear resistance and cohesion of the soil, as well as improving the water stability, freeze-thaw resistance, and erosion resistance, but the internal friction angle of the soil was not significantly increased after reaching a certain content. Moderate amounts of PAM-CMC can extend the survival of vegetation, but overuse may cause soil hardening and inhibit vegetation growth by limiting air permeability. It was observed by a scanning electron microscope (SEM) that the gel membrane formed by PAM-CMC helped to "bridge" and bind the soil particles. After discussion and analysis, the optimum application rate of PAM-CMC was 3%, which not only improved the soil structure but also ensured the growth of vegetation in the later stage under the optimum application rate. Field application studies have shown that 3% PAM-CMC-amended soil stably attaches to high-steep rocky slopes, with stable vegetation growth, and continues to grow after five months of freeze-thaw action, with no need for manual maintenance after one year.

Weakened connection between spring leaf-out and autumn senescence in the Northern Hemisphere.

Vegetation autumn phenology is critical in regulating the ecosystem carbon cycle and regional climate. However, the dominant drivers of autumn senescence and their temporal shifts under climate change remain poorly understood. Here, we conducted a multi-factor analysis considering both direct climatic controls and biological carryover effects from start-of-season (SOS) and seasonal peak vegetation activities on the end-of-season (EOS) to fill these knowledge gaps. Combining satellite and ground observations across the northern hemisphere, we found that carryover effects from early-to-peak vegetation activities exerted greater influence on EOS than the direct climatic controls on nearly half of the vegetated land. Unexpectedly, the carryover effects from SOS on EOS have significantly weakened over recent decades, accompanied by strengthened climatic controls. Such results indicate the weakened constraint of leaf longevity on senescence due to prolonged growing season in response to climate change. These findings underscore the important role of biological carryover effects in regulating vegetation autumn senescence under climate change, which should be incorporated into the formulation and enhancement of phenology modules utilized in land surface models.

[Effects of different exercise modes on neuromuscular junction and metabolism of skeletal muscle-related proteins in aging rats].

The present study aimed to explore the effects of different exercise modes on neuromuscular junction (NMJ) and metabolism of skeletal muscle-related proteins in aging rats. Ten from 38 male Sprague-Dawley (SD) rats (3-month-old) were randomly selected into young (Y) group, while the rest were raised to 21 months old and randomly divided into elderly control (O), endurance exercise (EN) and resistance exercise (R) groups. After 8 weeks of corresponding exercises training, the gastrocnemius muscles of rats were collected, and the expression of S100B in Schwann cells was detected by immunofluorescence staining. Western blot was used to detect the protein expression levels of agglutinate protein (Agrin), low-density lipoprotein receptor-related protein 4 (Lrp4), muscle- specific kinase protein (MuSK), downstream tyrosine kinase 7 (Dok7), phosphorylated protein kinase B (p-Akt), phosphorylated mammalian target rapamycin (p-mTOR), and phosphorylated forkhead box O1 (p-FoxO1) in rat gastrocnemius muscles. The results showed that, endurance and resistance exercises increased the wet weight ratio of gastrocnemius muscle in the aging rats. The protein expression of S100B in the R group was significantly higher than those in the O and EN groups. Proteins related to NMJ function, including Agrin, Lrp4, MuSK, and Dok7 were significantly decreased in the O group compared with those in the Y group. Resistance exercise up-regulated these four proteins in the aging rats, whereas endurance exercise could not reverse the protein expression levels of Lrp4, MuSK and Dok7. Regarding skeletal muscle-related proteins, the O group showed down-regulated p-Akt, and p-mTOR protein expression levels and up-regulated p-FoxO1 protein expression level, compared to the Y group. Resistance and endurance exercises reversed the changes in p-mTOR and p-FoxO1 protein expression in the aging rats. These findings demonstrate that both exercise modes can enhance NMJ function, increase protein synthesis and reduce the catabolism of skeletal muscle-related proteins in aging rats, with resistance exercise showing a more pronounced effect.

Terahertz Sensing of L-Valine and L-Phenylalanine Solutions.

To detect and differentiate two essential amino acids (L-Valine and L-Phenylalanine) in the human body, a novel asymmetrically folded dual-aperture metal ring terahertz metasurface sensor was designed. A solvent mixture of water and glycerol with a volume ratio of 2:8 was proposed to reduce the absorption of terahertz waves by reducing the water content. A sample chamber with a controlled liquid thickness of 15 µm was fabricated. And a terahertz time-domain spectroscopy (THz-TDS) system, which is capable of horizontally positioning the samples, was assembled. The results of the sensing test revealed that as the concentration of valine solution varied from 0 to 20 mmol/L, the sensing resonance peak shifted from 1.39 THz to 1.58 THz with a concentration sensitivity of 9.98 GHz/mmol∗L-1. The resonance peak shift phenomenon in phenylalanine solution was less apparent. It is assumed that the coupling enhancement between the absorption peak position of solutes in the solution and the sensing peak position amplified the terahertz localized electric field resonance, which resulted in the increase in frequency shift. Therefore, it could be shown that the sensor has capabilities in performing the marker sensing detection of L-Valine.

Emerging Role of Sorting Nexin 17 in Human Health and Disease.

The distortion of the cellular membrane transport pathway has a profound impact on cell dynamics and can drive serious physiological consequences during the process of cell sorting. SNX17 is a member of the Sorting Nexin (SNX) family and plays a crucial role in protein sorting and transport in the endocytic pathway. SNX17, SNX27, and SNX31 belong to the SNX-FERM subfamily and possess the FERM domain, which can assist in endocytic transport and lysosomal degradation. The binding partners of SNX27 have been discovered to number over 100, and SNX27 has been linked to the development of Alzheimer's disease progression, tumorigenesis, cancer progression, and metastasis. However, the role and potential mechanisms of SNX17 in human health and disease remain poorly understood, and the function of SNX17 has not been fully elucidated. In this review, we summarize the structure and basic functions of SNX protein, focusing on providing current evidence of the role and possible mechanism of SNX17 in human neurodegenerative diseases and cardiovascular diseases.

A detailed overview of quercetin: implications for cell death and liver fibrosis mechanisms.

Background: Quercetin, a widespread polyphenolic flavonoid, is known for its extensive health benefits and is commonly found in the plant kingdom. The natural occurrence and extraction methods of quercetin are crucial due to its bioactive potential. Purpose: This review aims to comprehensively cover the natural sources of quercetin, its extraction methods, bioavailability, pharmacokinetics, and its role in various cell death pathways and liver fibrosis. Methods: A comprehensive literature search was performed across several electronic databases, including PubMed, Embase, CNKI, Wanfang database, and ClinicalTrials.gov, up to 10 February 2024. The search terms employed were "quercetin", "natural sources of quercetin", "quercetin extraction methods", "bioavailability of quercetin", "pharmacokinetics of quercetin", "cell death pathways", "apoptosis", "autophagy", "pyroptosis", "necroptosis", "ferroptosis", "cuproptosis", "liver fibrosis", and "hepatic stellate cells". These keywords were interconnected using AND/OR as necessary. The search focused on studies that detailed the bioavailability and pharmacokinetics of quercetin, its role in different cell death pathways, and its effects on liver fibrosis. Results: This review details quercetin's involvement in various cell death pathways, including apoptosis, autophagy, pyroptosis, necroptosis, ferroptosis, and cuproptosis, with particular attention to its regulatory influence on apoptosis and autophagy. It dissects the mechanisms through which quercetin affects these pathways across different cell types and dosages. Moreover, the paper delves into quercetin's effects on liver fibrosis, its interactions with hepatic stellate cells, and its modulation of pertinent signaling cascades. Additionally, it articulates from a physical organic chemistry standpoint the uniqueness of quercetin's structure and its potential for specific actions in the liver. Conclusion: The paper provides a detailed analysis of quercetin, suggesting its significant role in modulating cell death mechanisms and mitigating liver fibrosis, underscoring its therapeutic potential.

An adaptive discretized RNN algorithm for posture collaboration motion control of constrained dual-arm robots.

Although there are many studies on repetitive motion control of robots, few schemes and algorithms involve posture collaboration motion control of constrained dual-arm robots in three-dimensional scenes, which can meet more complex work requirements. Therefore, this study establishes the minimum displacement repetitive motion control scheme for the left and right robotic arms separately. On the basis of this, the design mentality of the proposed dual-arm posture collaboration motion control (DAPCMC) scheme, which is combined with a new joint-limit conversion strategy, is described, and the scheme is transformed into a time-variant equation system (TVES) problem form subsequently. To address the TVES problem, a novel adaptive Taylor-type discretized recurrent neural network (ATT-DRNN) algorithm is devised, which fundamentally solves the problem of calculation accuracy which cannot be balanced well with the fast convergence speed. Then, stringent theoretical analysis confirms the dependability of the ATT-DRNN algorithm in terms of calculation precision and convergence rate. Finally, the effectiveness of the DAPCMC scheme and the excellent convergence competence of the ATT-DRNN algorithm is verified by a numerical simulation analysis and two control cases of dual-arm robots.

Decoding chromosome organization using CheC-PLS: chromosome conformation by proximity labeling and long-read sequencing.

Genomic approaches have provided detailed insight into chromosome architecture. However, commonly deployed techniques do not preserve connectivity-based information, leaving large-scale genome organization poorly characterized. Here, we developed CheC-PLS: a proximity-labeling technique that indelibly marks, and then decodes, protein-associated sites. CheC-PLS tethers dam methyltransferase to a protein of interest, followed by Nanopore sequencing to identify methylated bases - indicative of in vivo proximity - along reads >100kb. As proof-of-concept we analyzed, in budding yeast, a cohesin-based meiotic backbone that organizes chromatin into an array of loops. Our data recapitulates previously obtained association patterns, and, importantly, exposes variability between cells. Single read data reveals cohesin translocation on DNA and, by anchoring reads onto unique regions, we define the internal organization of the ribosomal DNA locus. Our versatile technique, which we also deployed on isolated nuclei with nanobodies, promises to illuminate diverse chromosomal processes by describing the in vivo conformations of single chromosomes.

Association between low cognitive performance and diabetes-related health indicators across racial and ethnic groups in adults with diabetes.

AIM: To examine the associations between low cognitive performance (LCP) and diabetes-related health indicators (including body mass index [BMI], HbA1c, systolic blood pressure [SBP], low-density lipoprotein [LDL] and self-reported poor physical health) and whether these associations vary across racial/ethnic subgroups. METHODS: We identified adults aged 60 years or older with self-reported diabetes from the 2011-2014 National Health and Nutrition Examination Survey. Individuals with cognitive test scores in the lowest quartile were defined as having LCP. We used regression models to measure the associations of LCP with diabetes-related biometrics (BMI, HbA1c, SBP and LDL); and self-reported poor physical health. Moreover, we explored potential variations in these associations across racial/ethnic subgroups. RESULTS: Of 873 (261 with LCP) adults with diabetes, LCP was associated with higher HbA1c, SBP and LDL (adjusted difference: 0.41%, 5.01 mmHg and 5.08 mg/dL, respectively; P < .05), and greater odds of reporting poor physical health (adjusted odds ratio: 1.59, P < .05). The association between LCP and HbA1c was consistent across racial/ethnic groups, and notably pronounced in Hispanic and Other. BMI worsened with LCP, except for non-Hispanic Black. Excluding the Other group, elevated SBP was observed in people with LCP, with Hispanic showing the most significant association. LDL levels were elevated with LCP for Hispanic and Other. Physical health worsened with LCP for both non-Hispanic Black and Hispanic. CONCLUSIONS: We quantified the association between LCP and diabetes-related health indicators. These associations were more pronounced in Hispanic and Other racial/ethnic groups.

Edible bird's nest regulates glucose and lipid metabolic disorders via the gut-liver axis in obese mice.

Edible bird's nest (EBN) is a traditional food known for its nourishing and functional properties and is found to be involved in anti-oxidation, anti-aging, and anti-influenza mechanisms, immune regulation, and improving cardiovascular diseases, among others. However, the potential of EBN to improve glycolipid metabolism disorders in high-fat-diet induced obesity and the underlying mechanisms remain unexplored. We examined the effects of EBN on glycolipid metabolism in obese mice fed a high-fat diet. Male C57BL/6J mice were fed a high-fat diet for 8 weeks to establish an obesity model. The obese mice were selected and divided into six groups: two model control groups (normal and high-fat diets) and four intervention groups [Neu5Ac and low-, medium-, and high-dose EBN], with 12 mice in each group. After 10 weeks of continuous gavage intervention, only mice in the high-dose EBN intervention group had lower body weight and total fat content, especially visceral fat. Meanwhile, intervention with three doses of EBN reduced serum FBG, TC, LDL, Ox-LDL, IL-1ß, IL-6, and TNF-α levels and increased serum HDL levels and energy expenditure. Using the high dosage as a paradigm, EBN intervention increased the sialic acid content in LDL, decreased TMAO in the liver, and increased GLP-1 levels in sera. EBN increased the colonic abundances of Akkermansia, Lactobacillus, and Desulfovibrio and reduced those of Lysinibacillus and Bacillus. The changes in the microbial community contribute to increasing colonic bile acids, reducing lipopolysaccharide synthesis to protect the intestinal barrier, and lowering inflammation levels. Changes were also observed in colonic transcripts and metabolites and liver gene transcripts and metabolites, which were mainly enriched in pathways of glycolipid metabolism, immune function amelioration, inflammatory signal mitigation, circadian rhythm, bile acid metabolism and insulin resistance. Therefore, EBN may enhance the gut microbiota and intestinal immunity, relieve chronic inflammation levels in serum, improve antioxidant capacity and circadian rhythm in the liver, promote bile acid metabolism, and decrease lipid absorption and lipid synthesis via the gut-liver axis. Consequently, this may reduce blood lipid and fat accumulation as well as improve islet function and reduce blood glucose levels.

Overall survival benefits of cancer drugs initially approved by the US Food and Drug Administration on the basis of immature survival data: a retrospective analysis.

BACKGROUND: New cancer drugs can be approved by the US Food and Drug Administration (FDA) on the basis of surrogate endpoints while data on overall survival are still incomplete or immature, with too few deaths for meaningful analysis. We aimed to evaluate whether clinical trials with immature survival data generated evidence of overall survival benefit during the period after marketing authorisation, and where that evidence was reported. METHODS: In this retrospective analysis, we searched Drugs@FDA to identify cancer drug indications approved between Jan 1, 2001, and Dec 31, 2018, on the basis of immature survival data. We systematically collected publicly available data on postapproval overall survival results in labelling (Drugs@FDA), journal publications (MEDLINE via PubMed), and clinical trial registries (ClinicalTrials.gov). The primary outcome was availability of statistically significant overall survival benefits during the period after marketing authorisation (until March 31, 2023). Additionally, we evaluated the availability and timing of overall survival findings in labelling, journal publications, and ClinicalTrials.gov records. FINDINGS: During the study period, the FDA granted marketing authorisation to 223 cancer drug indications, 95 of which had overall survival as an endpoint. 39 (41%) of these 95 indications had immature survival data. After a minimum of 4·3 years of follow-up during the period after marketing authorisation (and median 8·2 years [IQR 5·3-12·0] since FDA approval), additional survival data from the pivotal trials became available in either revised labelling or publications, or both, for 38 (97%) of 39 indications. Additional data on overall survival showed a statistically significant benefit in 12 (32%) of 38 indications, whereas mature data yielded statistically non-significant overall survival findings for 24 (63%) indications. Statistically significant evidence of overall survival benefit was reported in either labelling or publications a median of 1·5 years (IQR 0·8-2·3) after initial approval. The median time to availability of statistically non-significant overall survival results was 3·3 years (2·2-4·5). The availability of overall survival results on ClinicalTrials.gov varied considerably. INTERPRETATION: Fewer than a third of indications approved with immature survival data showed a statistically significant overall survival benefit after approval. Notable inconsistencies in timing and availability of information after approval across different sources emphasise the need for better reporting standards. FUNDING: None.

Improvements in the health-related quality-of-life benefit of cancer drugs approved in China, 2005-2020: an observational study.

Background: Health-related quality of life (HRQoL), along with overall survival (OS), is a critical study endpoint for measuring the clinical benefits of cancer drugs. Previous studies have examined the OS benefit of new cancer drugs approved in China. However, their HRQoL benefits have not been systematically evaluated. We aimed to characterise the measurement and improvement of HRQoL associated with cancer drugs approved in China. Methods: This mixed-methods study comprises of a literature review and a cross-sectional study, including all antineoplastic agents approved in China between January 1, 2005 and December 31, 2020. A systematic search was conducted on December 31, 2023 to extract HRQoL information of identified drugs. We extracted information on the characteristics of HRQoL assessment and statistically significant HRQoL gains compared with the control treatment. Findings: A total of 64 novel cancer drugs, corresponding to 115 cancer indications, supported by randomised clinical trials were approved in China between 2005 and 2020. Among the indications, 78 (67.8%) used HRQoL as an endpoint in the pivotal trial. By December 31, 2023, after a median follow-up of 5.3 (range, 3.0-18.8) years from approval, HRQoL information was available for more than half of the indications (75, 65.2%). Thirty-three indications (28.7%) reported statistically significant improvement in HRQoL, with 22 (19.1%) also having documented OS benefit. Approximately one-third of the indications (39, 33.9%) showed no difference in HRQoL, with 21 (18.3%) having documented OS gains. Three indications (2.6%) reported worsening HRQoL. The most commonly used HRQoL measurements were individual disease-specific instruments (62 of 75, 82.7%) while the most frequently employed analysis metric was the mean change scores from baseline (56 of 75, 74.7%). Interpretation: Fewer than one-third of cancer indications approved in China had shown HRQoL improvements. There was considerable heterogeneity in the analysis and reporting of HRQoL benefits associated with new cancer drugs approved in China. These findings emphasise the important role of HRQoL evaluation and analysis in clinical research and the necessity of improving the standardization of HRQoL assessment. Funding: National Natural Science Foundation of China (72274004).

Highly stable power control for chip-based continuous-variable quantum key distribution system.

Quantum key distribution allows secret key generation with information theoretical security. It can be realized with photonic integrated circuits to benefit the tiny footprints and the large-scale manufacturing capacity. Continuous-variable quantum key distribution is suitable for chip-based integration due to its compatibility with mature optical communication devices. However, the quantum signal power control compatible with the mature photonic integration process faces difficulties on stability, which limits the system performance and causes the overestimation of a secret key rate that opens practical security loopholes. Here, a highly stable chip-based quantum signal power control scheme based on a biased Mach-Zehnder interferometer structure is proposed, theoretically analyzed, and experimentally implemented with standard silicon photonic techniques. Simulations and experimental results show that the proposed scheme significantly improves the system stability, where the standard deviation of the secret key rate is suppressed by an order of magnitude compared with the system using traditional designs, showing a promising and practicable way to realize a highly stable continuous-variable quantum key distribution system on chip.

Cancer drug indication approvals in China and the United States: a comparison of approval times and clinical benefit, 2001-2020.

Background: Perceived delays in cancer drug approvals have been a major concern for policymakers in China. Policies have been implemented to accelerate the launch of new cancer drugs and indications. This study aimed to assess similarities and differences between China and the United States in the approvals, timing, and clinical benefit evidence of cancer drug indications between 2001 and 2020. Methods: This study retrospectively identified all cancer drugs and indications approved in both China and the United States from January 1st, 2001 to December 31, 2020, and described differences in approval times as well as in submission and review times. Information on the availability of overall survival benefit evidence by December 31, 2020, was collected. Univariate and multiple logistic regression analyses were used to assess whether evidence of benefit and other factors affected the propensity and timing of approvals of cancer drug indications in China. Findings: Between 2001 and 2020, 229 indications corresponding to 145 cancer drugs approved in the United States were identified. Of those, 80 indications (34.9%) were also approved in China by the end of 2020. Cancer drug indications were approved in China at a median of 1273.5 days after approval in the United States. The median submission and review time differences for cancer drug indications in China were 1198.0 days and 180.0 days respectively. Submission time differences accounted for most of the approval time differences (p < 0.001). Indications supported by overall survival benefit evidence had shorter median review time differences (145.0 days) than those without such evidence (235.0 days, p = 0.008). Indications with overall survival benefit evidence were 3.94 times more likely to be approved in China compared to those without such evidence (p = 0.001), controlling for approval year, cancer type, and the prevalence of cancer by site. Interpretation: FDA-approved cancer drug indications demonstrating a survival benefit were more likely to receive approvals in China with shorter regulatory review times compared to indications without such evidence. Given that manufacturer submission times were the main driver of cancer drug approval times in China, factors influencing submission timing should be explored. Funding: No funding.

Development and Improvement of a Piezoelectrically Driven Miniature Robot.

In this paper, we proposed a miniature quadrupedal piezoelectric robot with a mass of 1.8 g and a body length of 4.6 cm. The robot adopts a novel spatial parallel mechanism as its transmission. Each leg of the robot has two degrees of freedom (DOFs): swing and lift. The trajectory necessary for walking is achieved by the appropriate phasing of these two DOFs. A new manufacturing method for piezoelectric actuators was developed. During the stacking process, discrete patterned PZT pieces are used to avoid dielectric failure caused by laser cutting. Copper-clad FR-4 is used as the solder pad instead of copper foil, making the connection between the pad and the actuator more reliable. The lift powertrain of the robot was modeled and the link length of the powertrain was optimized based on the model. The maximum output force of each leg can reach 26 mN under optimized design parameters, which is 1.38 times the required force for successful walking. The frequency response of the powertrain was measured and fitted to the second-order system, which enabled increased leg amplitudes near the powertrain resonance of approximately 70 Hz with adjusted drive signals. The maximum speed of the robot without load reached 48.66 cm/s (10.58 body lengths per second) and the payload capacity can reach 5.5 g (3.05 times its mass) near the powertrain resonance.

Causal associations of immune cells with benign prostatic hyperplasia: insights from a Mendelian randomization study.

BACKGROUND: Previous research has focused on the association between immune cells and the development of benign prostatic hyperplasia (BPH). Nevertheless, the causal relationships in this context remain uncertain. METHODS: This study employed a comprehensive and systematic two-sample Mendelian randomization (MR) analysis to determine the causal relationships between immunophenotypes and BPH. We examined the causal associations between 731 immunophenotypes and the risk of BPH by utilizing publicly available genetic data. Integrated sensitivity analyses were performed to validate the robustness, assess heterogeneity, and examine horizontal pleiotropy in the results. RESULTS: We discovered that 38 immunophenotypes have a causal effect on BPH. Subsequently, four of these immunophenotypes underwent verification using weighted median, weighted mode, and inverse variance weighted (IVW) algorithms, which included CD19 on CD24+ CD27+, CD19 on naive-mature B cell, HLA DR on CD14- CD16+ and HLA DR+ T cell%lymphocyte. Furthermore, BPH exhibited a significant association with three immunophenotypes: CD19 on IgD+ CD38dim (ß = -0.152, 95% CI = 0.746-0.989, P = 0.034), CD19 on IgD+ (ß = -0.167, 95% CI = 0.737-0.973, P = 0.019), and CD19 on naive-mature B cell (ß = -0.166, 95% CI = 0.737-0.972, P = 0.018). CONCLUSIONS: Our study provides valuable insights for future clinical investigations by establishing a significant association between immune cells and BPH.

Redoxhigh phenotype mediated by KEAP1/STK11/SMARCA4/NRF2 mutations diminishes tissue-resident memory CD8+ T cells and attenuates the efficacy of immunotherapy in lung adenocarcinoma.

Metabolism reprogramming within the tumor microenvironment (TME) can have a profound impact on immune cells. Identifying the association between metabolic phenotypes and immune cells in lung adenocarcinoma (LUAD) may reveal mechanisms of resistance to immune checkpoint inhibitors (ICIs). Metabolic phenotypes were classified by expression of metabolic genes. Somatic mutations and transcriptomic features were compared across the different metabolic phenotypes. The metabolic phenotype of LUAD is predominantly determined by reductase-oxidative activity and is divided into two categories: redoxhigh LUAD and redoxlow LUAD. Genetically, redoxhigh LUAD is mainly driven by mutations in KEAP1, STK11, NRF2, or SMARCA4. These mutations are more prevalent in redoxhigh LUAD (72.5%) compared to redoxlow LUAD (17.4%), whereas EGFR mutations are more common in redoxlow LUAD (19.0% vs. 0.7%). Single-cell RNA profiling of pre-treatment and post-treatment samples from patients receiving neoadjuvant chemoimmunotherapy revealed that tissue-resident memory CD8+ T cells are responders to ICIs. However, these cells are significantly reduced in redoxhigh LUAD. The redoxhigh phenotype is primarily attributed to tumor cells and is positively associated with mTORC1 signaling. LUAD with the redoxhigh phenotype demonstrates a lower response rate (39.1% vs. 70.8%, p = 0.001), shorter progression-free survival (3.3 vs. 14.6 months, p = 0.004), and overall survival (12.1 vs. 31.2 months, p = 0.022) when treated with ICIs. The redoxhigh phenotype in LUAD is predominantly driven by mutations in KEAP1, STK11, NRF2, and SMARCA4. This phenotype diminishes the number of tissue-resident memory CD8+ T cells and attenuates the efficacy of ICIs.

Correlation of distribution characteristics and dynamic changes of gut microbiota with the efficacy of immunotherapy in EGFR-mutated non-small cell lung cancer.

BACKGROUND: The effects of gut microbiota and metabolites on the responses to immune checkpoint inhibitors (ICIs) in advanced epidermal growth factor receptor (EGFR) wild-type non-small cell lung cancer (NSCLC) have been studied. However, their effects on EGFR-mutated (EGFR +) NSCLC remain unknown. METHODS: We prospectively recorded the clinicopathological characteristics of patients with advanced EGFR + NSCLC and assessed potential associations between the use of antibiotics or probiotics and immunotherapy efficacy. Fecal samples were collected at baseline, early on-treatment, response and progression status and were subjected to metagenomic next-generation sequencing and ultra-high-performance liquid chromatography-mass spectrometry analyses to assess the effects of gut microbiota and metabolites on immunotherapy efficacy. RESULTS: The clinical data of 74 advanced EGFR + NSCLC patients were complete and 18 patients' fecal samples were dynamically collected. Patients that used antibiotics had shorter progression-free survival (PFS) (mPFS, 4.8 vs. 6.7 months; P = 0.037); probiotics had no impact on PFS. Two dynamic types of gut microbiota during immunotherapy were identified: one type showed the lowest relative abundance at the response time point, whereas the other type showed the highest abundance at the response time point. Metabolomics revealed significant differences in metabolites distribution between responders and non-responders. Deoxycholic acid, glycerol, and quinolinic acid were enriched in responders, whereas L-citrulline was enriched in non-responders. There was a significant correlation between gut microbiota and metabolites. CONCLUSIONS: The use of antibiotics weakens immunotherapy efficacy in patients with advanced EGFR + NSCLC. The distribution characteristics and dynamic changes of gut microbiota and metabolites may indicate the efficacy of immunotherapy in advanced EGFR + NSCLC.

Prevalence of aggressive care among patients with cancer near the end of life: a systematic review and meta-analysis.

Background: Aggressive care near patients' end-of-life (EOL) entails limited therapeutic values, high costs, and compromised quality of life (QoL). In this study, we aimed to estimate the global prevalence of aggressive care in patients with cancer and explore potential subgroup differences. Methods: We searched PubMed, Embase, and the Cochrane Library from database inception to Feb 16, 2024. Eligible studies reported the prevalence of aggressive EOL care using at least one quantifiable measure. Random-effects models were used to derive the pooled prevalence and subgroup analyses were performed to investigate differences in the prevalence of aggressive care across regions, the country's level of economic development, tumor types, ages, and sample sizes. This review is registered with PROSPERO, number CRD42023467839. Findings: A total of 129 studies were included in this systematic review, of which 118 (91.5%) were from high-income countries. Studies were mostly conducted in the Americas (60, 46.5%), Europe (34, 26.4%), and Western Pacific (31, 24.0%). Measures of aggressive care were inconsistent across studies, with the most commonly used measure being the use of chemotherapy in the last 14 days of life (DOLs) (n = 87, 67.4%) and intensive care unit (ICU) stay in the last 30 DOLs (n = 87, 67.4%). The prevalence of the five claims-based measures of aggressive care, i.e., chemotherapy in the last 14 DOLs, ICU stay in the last 30 DOLs, repeated hospital admission in the last 30 DOLs, repeated emergency room (ER) visit in the last 30 DOLs, and hospice care <3 days before death were 11.6% (95% CI, 9.8%-13.4%), 14.4% (95% CI, 11.8%-17.0%), 17.9% (95% CI, 14.4%-21.4%), 14.8% (95% CI, 12.0%-17.6%), and 14.4% (95% CI, 11.2%-17.6%), respectively. Regional differences were statistically significant in the prevalence of ICU stay and repeated hospital admission in the last 30 DOLs (p < 0.01; p = 0.03). Patients with hematologic malignancies were more likely to receive aggressive care than those with solid tumors, as seen in their higher rates of chemotherapy in the last 14 DOLs (21.7% versus 11.6%; p = 0.03), ICU stay in the last 30 DOLs (25.5% versus 10.8%; p < 0.01), and hospice care <3 days before death (26.7% versus 14.2%; p < 0.01). In addition, the prevalence of chemotherapy in the last 14 DOLs (26.2%; p < 0.01) and repeated hospital admission in the last 30 DOLs (31.4%; p < 0.01) were highest among pediatric patients with cancer. Interpretation: This meta-analysis found that aggressive EOL care was common in patients with cancer, regardless of the definition used, and varied by regions and populations. It is necessary to be aware of the global burden of aggressive care for patients with cancer near their EOL and take prompt action to address it. Funding: National Natural Science Foundation of China (Grant No. 72274004).