Dysfunction of STING Autophagy Degradation in Senescent Nucleus Pulposus Cells Accelerates Intervertebral Disc Degeneration.

The pathogenesis of Intervertebral Disc Degeneration (IDD) is complex and multifactorial, with cellular senescence of nucleus pulposus (NP) cells and inflammation playing major roles in the progression of IDD. The stimulator of interferon genes (STING) axis is a key mediator of inflammation during infection, cellular stress, and tissue damage. Here, we present a progressive increase in STING in senescent NP cells with the degradation disorder. The STING degradation function in normal NP cells can prevent IDD. However, the dysfunction of STING degradation through autophagy causes the accumulation and high expression of STING in senescent NP cells as well as inflammation continuous activation together significantly promotes IDD. In senescent NP cells and intervertebral discs (IVDs), we found that STING autophagy degradation was significantly lower than that of normal NP cells and IVDs when STING was activated by 2'3'-cGAMP. Also, the above phenomenon was found in STINGgt/gt, cGAS-/- mice with models of age-induced, lumbar instability-induced IDD as well as found in the rat caudal IVD puncture models. Taken together, we suggested that the promotion of STING autophagy degradation in senescent NP Cells demonstrated a potential therapeutic modality for the treatment of IDD.

COL8A1 is a potential prognostic biomarker associated with migration, proliferation, and tumor microenvironment in glioma.

Glioblastoma (GBM) is a common primary central nervous system tumor. The molecular mechanisms of glioma are unknown, and the prognosis is poor. Therefore, exploring the underlying mechanisms and screening for new prognostic markers and therapeutic targets is crucial. We utilized the weighted gene co-expression network analysis (WGCNA), Differentially Expressed Genes (DEGs), and LASSO-COX analysis to identify three target genes. Next, we constructed and evaluated a prognostic model, screening out COL8A1 as a risk gene. Through a sequence of cellular functional experiments, in vivo studies, and RNA sequencing, we delved into exploring the functional effects and molecular mechanisms of COL8A1 on GBM cells. Finally, the correlation between COL8A1 and tumor immune cells and different inflammatory responses was analyzed. Immunohistochemistry experiments revealed the influence of COL8A1 on macrophage polarization. The COL8A1 expression level was associated with the grade, prognosis, and tumor microenvironment (TME) of glioma. Functional experiments showed that COL8A1 inhibited GBM cell apoptosis and promoted migration, invasion, and proliferation in vitro and in vivo. We also found that COL8A1 promotes the epithelial-mesenchymal transition process and may mediate the activation of the ERK pathway through SHC1. In addition, immune infiltration analysis showed that COL8A1 was closely associated with macrophages in glioma tissues, significantly suppressing the signaling of M1-like -type macrophages and enhancing the signaling of M2-like -type macrophages. COL8A1 was first found to be associated with prognosis, progression, and immune microenvironment of glioma and may serve as a new marker of prognosis and a therapeutic target.

Release of damaged mitochondrial DNA: A novel factor in stimulating inflammatory response.

Mitochondrial DNA (mtDNA) is a circular double-stranded genome that exists independently of the nucleus. In recent years, research on mtDNA has significantly increased, leading to a gradual increase in understanding of its physiological and pathological characteristics. Reactive oxygen species (ROS) and other factors can damage mtDNA. This damaged mtDNA can escape from the mitochondria to the cytoplasm or extracellular space, subsequently activating immune signaling pathways, such as NLR family pyrin domain protein 3 (NLRP3), and triggering inflammatory responses. Numerous studies have demonstrated the involvement of mtDNA damage and leakage in the pathological mechanisms underlying various diseases including infectious diseases, metabolic inflammation, and immune disorders. Consequently, comprehensive investigation of mtDNA can elucidate the pathological mechanisms underlying numerous diseases. The prevention of mtDNA damage and leakage has emerged as a novel approach to disease treatment, and mtDNA has emerged as a promising target for drug development. This article provides a comprehensive review of the mechanisms underlying mtDNA-induced inflammation, its association with various diseases, and the methods used for its detection.

Microglial gp91phox-mediated neuroinflammation and ferroptosis contributes to learning and memory deficits in rotenone-treated mice.

Apart from dopaminergic neurotoxicity, exposure to rotenone, a commonly used insecticide in agriculture, also adversely affects hippocampal and cortical neurons, resulting in cognitive impairments in mice. We recently established a role of microglia-mediated neuroinflammation in rotenone-elicited deficits of cognition, yet the mechanisms remain elusive. Here, we investigated the involvement of NADPH oxidase 2 (NOX2) catalytic subunit gp91phox in rotenone-induced cognitive deficits and the associated mechanisms. Our study demonstrated that rotenone exposure elevated expression of gp91phox and phosphorylation of the NOX2 cytosolic subunit p47phox, along with NADPH depletion in the hippocampus and cortex of mice, indicating NOX2 activation. Specific knockdown of gp91phox in microglia via adeno-associated virus delivery resulted in reduced microglial activation, proinflammatory gene expression and improved learning and memory capacity in rotenone-intoxicated mice. Genetic deletion of gp91phox also reversed rotenone-elicited cognitive dysfunction in mice. Furthermore, microglial gp91phox knockdown attenuated neuronal damage and synaptic loss in mice. This intervention also suppressed iron accumulation, disruption of iron-metabolism proteins and iron-dependent lipid peroxidation and restored the balance of ferroptosis-related parameters, including GPX4, SLC711, PTGS2, and ACSL4 in rotenone-lesioned mice. Intriguingly, pharmacological inhibition of ferroptosis with liproxstatin-1 conferred protection against rotenone-induced neurodegeneration and cognitive dysfunction in mice. In summary, our findings underscored the contribution of microglial gp91phox-dependent neuroinflammation and ferroptosis to learning and memory dysfunction in rotenone-lesioned mice. These results provided valuable insights into the pathogenesis of cognitive deficits associated with pesticide-induced Parkinsonism, suggesting potential therapeutic avenues for intervention.

A general quantum algorithm for numerical integration.

Quantum algorithms have shown their superiority in many application fields. However, a general quantum algorithm for numerical integration, an indispensable tool for processing sophisticated science and engineering issues, is still missing. Here, we first proposed a quantum integration algorithm suitable for any continuous functions that can be approximated by polynomials. More impressively, the algorithm achieves quantum encoding of any integrable functions through polynomial approximation, then constructs a quantum oracle to mark the number of points in the integration area and finally converts the statistical results into the phase angle in the amplitude of the superposition state. The quantum algorithm introduced in this work exhibits quadratic acceleration over the classical integration algorithms by reducing computational complexity from O(N) to O(√N). Our work addresses the crucial impediments for improving the generality of quantum integration algorithm, which provides a meaningful guidance for expanding the superiority of quantum computing.

Impact of Preseason Climate Factors on Vegetation Photosynthetic Phenology in Mid-High Latitudes of the Northern Hemisphere.

During the period preceding the vegetation growing season (GS), temperature emerges as the pivotal factor determining phenology in northern terrestrial ecosystems. Despite extensive research on the impact of daily mean temperature (Tmean) during the preseason period, the influence of diurnal temperature range (DTR) on vegetation photosynthetic phenology (i.e., the impact of the plant photosynthetic cycle on seasonal time scale) has largely been neglected. Using a long-term vegetation photosynthetic phenology dataset and historical climate data, we examine vegetation photosynthetic phenology dynamics and responses to climate change across the mid-high latitudes of the Northern Hemisphere from 2001 to 2020. Our data reveal an advancing trend in the start of the GS (SOS) by -0.15 days per year (days yr-1), affecting 72.1% of the studied area. This is particularly pronounced in western Canada, Alaska, eastern Asia, and latitudes north of 60°N. Conversely, the end of the GS (EOS) displays a delaying trend of 0.17 days yr-1, impacting 62.4% of the studied area, especially northern North America and northern Eurasia. The collective influence of an earlier SOS and a delayed EOS has resulted in the notably prolonged length of the GS (LOS) by 0.32 days yr-1 in the last two decades, affecting 70.9% of the studied area, with Eurasia and western North America being particularly noteworthy. Partial correlation coefficients of the SOS with preseason Tmean, DTR, and accumulated precipitation exhibited negative values in 98.4%, 93.0%, and 39.2% of the study area, respectively. However, there were distinct regional variations in the influence of climate factors on the EOS. The partial correlation coefficients of the EOS with preseason Tmean, DTR, and precipitation were positive in 58.6%, 50.1%, and 36.3% of the region, respectively. Our findings unveil the intricate mechanisms influencing vegetation photosynthetic phenology, holding crucial significance in understanding the dynamics of carbon sequestration within terrestrial ecosystems amidst climate change.

Heterogeneity of immune cells and their communications unveiled by transcriptome profiling in acute inflammatory lung injury.

Background: Acute Respiratory Distress Syndrome (ARDS) or its earlier stage Acute lung injury (ALI), is a worldwide health concern that jeopardizes human well-being. Currently, the treatment strategies to mitigate the incidence and mortality of ARDS are severely restricted. This limitation can be attributed, at least in part, to the substantial variations in immunity observed in individuals with this syndrome. Methods: Bulk and single cell RNA sequencing from ALI mice and single cell RNA sequencing from ARDS patients were analyzed. We utilized the Seurat program package in R and cellmarker 2.0 to cluster and annotate the data. The differential, enrichment, protein interaction, and cell-cell communication analysis were conducted. Results: The mice with ALI caused by pulmonary and extrapulmonary factors demonstrated differential expression including Clec4e, Retnlg, S100a9, Coro1a, and Lars2. We have determined that inflammatory factors have a greater significance in extrapulmonary ALI, while multiple pathways collaborate in the development of pulmonary ALI. Clustering analysis revealed significant heterogeneity in the relative abundance of immune cells in different ALI models. The autocrine action of neutrophils plays a crucial role in pulmonary ALI. Additionally, there was a significant increase in signaling intensity between B cells and M1 macrophages, NKT cells and M1 macrophages in extrapulmonary ALI. The CXCL, CSF3 and MIF, TGFß signaling pathways play a vital role in pulmonary and extrapulmonary ALI, respectively. Moreover, the analysis of human single-cell revealed DCs signaling to monocytes and neutrophils in COVID-19-associated ARDS is stronger compared to sepsis-related ARDS. In sepsis-related ARDS, CD8+ T and Th cells exhibit more prominent signaling to B-cell nucleated DCs. Meanwhile, both MIF and CXCL signaling pathways are specific to sepsis-related ARDS. Conclusion: This study has identified specific gene signatures and signaling pathways in animal models and human samples that facilitate the interaction between immune cells, which could be targeted therapeutically in ARDS patients of various etiologies.

Practice and Effect Evaluation of Preoperative Management Strategy for Patients Undergoing Day Arthroscopic Surgery Based on Evidence-Based Concept.

Objective: To improve the preoperative management of patients undergoing day arthroscopy. Methods: Based on the evidence-based concept, the preoperative management strategy of daytime arthroscopic surgery was practiced, and the implementation effect of patients undergoing daytime arthroscopic surgery before and after evidence application was compared. The evidence-based strategies adopted in this study include: informed consent,seven aspects: anesthesia assessment, health education, prohibition of drinking and eating, preoperative medication guidance, surgical arrangement, and emergency management. Results: After applying evidence-based strategies, significant improvements were observed in various quality indicators, including reduced waiting time, reduced surgical cancellations, increased patient satisfaction, and reduced unplanned hospitalization rates. Conclusion: Based on the evidence-based concept, the practice of preoperative management strategies for patients undergoing daytime arthroscopic surgery optimizes the daytime surgical process from the strict implementation of patient health education and evaluation, as well as the establishment of compliant and reasonable surgical schedules and emergency mechanisms. This improves the preoperative management behavior of daytime surgery, enhances the patient's medical experience, and enhances the quality of daytime surgical care, providing a good basis for management and decision-making.

Novel IL-4/HB-EGF-dependent crosstalk between eosinophils and macrophages controls liver regeneration after ischaemia and reperfusion injury.

OBJECTIVE: Previous studies indicate that eosinophils are recruited into the allograft following orthotopic liver transplantation and protect from ischaemia reperfusion (IR) injury. In the current studies, we aim to explore whether their protective function could outlast during liver repair. DESIGN: Eosinophil-deficient mice and adoptive transfer of bone marrow-derived eosinophils (bmEos) were employed to investigate the effects of eosinophils on tissue repair and regeneration after hepatic IR injury. Aside from exogenous cytokine or neutralising antibody treatments, mechanistic studies made use of a panel of mouse models of eosinophil-specific IL-4/IL-13-deletion, cell-specific IL-4rα-deletion in liver macrophages and hepatocytes and macrophage-specific deletion of heparin-binding epidermal growth factor-like growth factor (hb-egf). RESULT: We observed that eosinophils persisted over a week following hepatic IR injury. Their peak accumulation coincided with that of hepatocyte proliferation. Functional studies showed that eosinophil deficiency was associated with a dramatic delay in liver repair, which was normalised by the adoptive transfer of bmEos. Mechanistic studies demonstrated that eosinophil-derived IL-4, but not IL-13, was critically involved in the reparative function of these cells. The data further revealed a selective role of macrophage-dependent IL-4 signalling in liver regeneration. Eosinophil-derived IL-4 stimulated macrophages to produce HB-EGF. Moreover, macrophage-specific hb-egf deletion impaired hepatocyte regeneration after IR injury. CONCLUSION: Together, these studies uncovered an indispensable role of eosinophils in liver repair after acute injury and identified a novel crosstalk between eosinophils and macrophages through the IL-4/HB-EGF axis.

Systematic investigation of the Borrelia miyamotoi spirochetes in ticks, wildlife and domestic animal hosts in Yunnan province, Southwest China.

Background: Borrelia miyamotoi is a spirochete species transmitted via hard ticks. Following its discovery in Japan, this pathogen has been detected around the world, and is increasingly confirmed as a human pathogen causing febrile disease, namely relapsing fever. Its presence has been confirmed in the Northeast China. However, there is little information regarding the presence of B. miyamotoi and other hard-tick-borne relapsing fever spirochetes in southern China including Yunnan province, where tick and animal species are abundant and many people both inhabit and visit for recreation. Methods: For the present study, we collected samples of ticks, wildlife, and domestic animal hosts from different counties in Yunnan province. Nucleic acids from samples were extracted, and the presence of B. miyamotoi and other relapsing fever spirochetes was confirmed using polymerase chain reaction (PCR) for the 16S rRNA specific target gene fragment. The positive samples were then amplified for partial genome of the flaB and glpQ genes. Statistical differences in its distribution were analyzed by SPSS 20 software. Sequence of partial 16S rRNA, flaB and glpQ genome were analyzed and phylogenetic trees were constructed. Results: A total of 8260 samples including 2304 ticks, 4120 small mammals and 1836 blood of domestic animal hosts were collected for screening for infection of B. miyamotoi and other relapsing fever spirochetes. Cattle and sheep act as the main hosts and Rhipicephalus microplus, Haemaphysalis nepalensis, H. kolonini and Ixodes ovatus were identified as the important vector host with high prevalence or wide distribution. Only one Mus caroli (mouse) and one Sorex alpinus (shrew) were confirmed positive for relapsing fever spirochetes. Evidence of vertical transmission in ticks was also confirmed. Two known strains of B. miyamotoi and one novel relapsing fever spirochetes, B. theileri-like agent, were confirmed and described with their host adaptation, mutation, and potential risk of spreading and spillover for human beings. Conclusions: Our results provide new evidence of relapsing fever spirochetes in vector and animal hosts in Yunnan province based on large sample sizes, and offer guidance on further investigation, surveillance and monitoring of this pathogen.

Engineering Interconnected Nanofluidic Channel in a Hydrogel Supernetwork toward K+ Ion Accelerating Transport and Efficient Sensing.

Ion transportation via the mixed mechanisms of hydrogels underpins ultrafast biological signal transmission in nature, and its application to the rapid and sensitive sensing detection of human specific ions is of great interest for the field of medical science. However, current research efforts are still unable to achieve transmission results that are comparable to those of bioelectric signals. Herein, 3D interconnected nanochannels based on poly(pyrrole-co-dopamine)/poly(vinyl alcohol) (P(Py-co-DA)/PVA) supernetwork conductive hydrogels are designed and fabricated as stimuli-responsive structures for K+ ions. Distinct from conventional configurations, which exhibit rapid electron transfer and permeability to biosubstrates, interconnected nanofluidic nanochannels collaborated with the P(Py-co-DA) conductive polymer in the supernetwork conductive hydrogel significantly improve conductivity (88.3 mS/cm), ion transport time (0.1 s), and ion sensitivity (74.6 mV/dec). The faster ion response time is attributed to the synergism of excellent conductivity originating from the P(Py-co-DA) polymer and the electronic effect in the interconnected nanofluidic channels. Furthermore, the supernetwork conductive hydrogel demonstrates K+ ion selectivity relative to other cations in biofluids such as Na+, Mg2+, and Ca2+. The DFT calculation indicates that the small solvation energy and low chemical transfer resistance are the main reasons for the excellent K+ ion selectivity. Finite element analysis (FEA) simulations further support these experimental results. Consequently, the P(Py-co-DA)/PVA supernetwork conductive hydrogels enriched with the 3D interconnected nanofluidic channels developed in this work possess excellent sensing of K+ ions. This strategy provides great insight into efficient ion sensing in traditional biomedical sensing that has not been explored by previous researchers.

Klebsiella pneumoniae infections after liver transplantation: Drug resistance and distribution of pathogens, risk factors, and influence on outcomes.

BACKGROUND: Liver transplantation (LT) is the only curative treatment for end-stage liver disease. However, LT recipients are susceptible to infection, which is the leading cause of early mortality after LT. Klebsiella pneumoniae infections (KPIs) in the bloodstream are common in LT recipients. We hypothesized that KPIs and carbapenem-resistant Klebsiella pneumoniae (CRKP) infections may affect the outcomes of LT recipients. AIM: To assess KPI incidence, timing, distribution, drug resistance, and risk factors following LT and its association with outcomes. METHODS: This retrospective study included 406 patients undergoing LT at The Third Xiangya Hospital of Central South University, a tertiary hospital, from January 2015 to January 2023. We investigated the risk factors for KPIs and assessed the impact of KPIs and CRKP infections on the prognosis of LT recipients using logistic regression analysis. RESULTS: KPI incidence was 7.9% (n = 32), with lung/thoracic cavity the most frequent site of infection; the median time from LT to KPI onset was 7.5 d. Of 44 Klebsiella pneumoniae isolates, 43 (97.7%) and 34 (77.3%) were susceptible to polymyxin B or ceftazidime/avibactam and tigecycline, respectively; > 70% were resistant to piperacillin/ tazobactam, ceftazidime, cefepime, aztreonam, meropenem, and levofloxacin. Female sex [odds ratio (OR) = 2.827, 95% confidence interval (CI): 1.256-6.364; P = 0.012], pre-LT diabetes (OR = 2.794, 95%CI: 1.070-7.294; P = 0.036), day 1 post-LT alanine aminotransferase (ALT) levels ≥ 1500 U/L (OR = 3.645, 95%CI: 1.671-7.950; P = 0.001), and post-LT urethral catheter duration over 4 d (OR = 2.266, 95%CI: 1.016-5.054; P = 0.046) were risk factors for KPI. CRKP infections, but not KPIs, were risk factors for 6-month all-cause mortality post-LT. CONCLUSION: KPIs occur frequently and rapidly after LT. Risk factors include female sex, pre-LT diabetes, increased post-LT ALT levels, and urethral catheter duration. CRKP infections, and not KPIs, affect mortality.

Effect of free and bound proanthocyanidins from Chinese quince on heterocyclic aromatic amine formation and quality in fried chicken.

The abilities of Chinese quince free proanthocyanidins (FP) and bound proanthocyanidins (BP) at different levels (0.1%, 0.15%, and 0.3%) to mitigate heterocyclic aromatic amine (HAA) formation in fried chicken patties were investigated for the first time and compared with vitamin C (Vc). FP and BP reduced HAAs in a dose-dependent manner. Significantly, high concentrations of FP (0.3%) resulted in a reduction of PhIP, harman, and norharman levels by 59.84%, 22.91%, and 38.21%, respectively, in chicken patties. The addition of proanthocyanidins significantly (p < 0.05) reduced the weight loss of fried chicken patties. Furthermore, a positive correlation was observed among pH, weight loss, and total HAA formation in all three groups (FP, BP, and Vc). Multivariate analysis showed that FP had a more pronounced effect than BP from the perspective of enhancing the quality of fried chicken patties and reducing the formation of HAAs. These results indicate that proanthocyanidins, both BP and FP, but especially FP, from Chinese quince can inhibit the formation of carcinogenic HAAs when added to protein-rich foods that are subsequently fried.

SEEI: spherical evolution with feedback mechanism for identifying epistatic interactions.

BACKGROUND: Detecting epistatic interactions (EIs) involves the exploration of associations among single nucleotide polymorphisms (SNPs) and complex diseases, which is an important task in genome-wide association studies. The EI detection problem is dependent on epistasis models and corresponding optimization methods. Although various models and methods have been proposed to detect EIs, identifying EIs efficiently and accurately is still a challenge. RESULTS: Here, we propose a linear mixed statistical epistasis model (LMSE) and a spherical evolution approach with a feedback mechanism (named SEEI). The LMSE model expands the existing single epistasis models such as LR-Score, K2-Score, Mutual information, and Gini index. The SEEI includes an adaptive spherical search strategy and population updating strategy, which ensures that the algorithm is not easily trapped in local optima. We analyzed the performances of 8 random disease models, 12 disease models with marginal effects, 30 disease models without marginal effects, and 10 high-order disease models. The 60 simulated disease models and a real breast cancer dataset were used to evaluate eight algorithms (SEEI, EACO, EpiACO, FDHEIW, MP-HS-DHSI, NHSA-DHSC, SNPHarvester, CSE). Three evaluation criteria (pow1, pow2, pow3), a T-test, and a Friedman test were used to compare the performances of these algorithms. The results show that the SEEI algorithm (order 1, averages ranks = 13.125) outperformed the other algorithms in detecting EIs. CONCLUSIONS: Here, we propose an LMSE model and an evolutionary computing method (SEEI) to solve the optimization problem of the LMSE model. The proposed method performed better than the other seven algorithms tested in its ability to identify EIs in genome-wide association datasets. We identified new SNP-SNP combinations in the real breast cancer dataset and verified the results. Our findings provide new insights for the diagnosis and treatment of breast cancer. AVAILABILITY AND IMPLEMENTATION: https://github.com/scutdy/SSO/blob/master/SEEI.zip .

Seven oral traditional Chinese medicine combined with chemotherapy for the treatment of non-small cell lung cancer: a network meta-analysis.

CONTEXT: Traditional Chinese medicines (TCMs) have emerged as potential adjuvant therapies to treat non-small cell lung cancer. More direct comparative studies must be conducted among various oral TCMs. OBJECTIVE: This network meta-analysis evaluates the efficacy and safety of seven oral TCMs combined with chemotherapy in treating NSCLC. METHODS: The analysis included Zilongjin, Banmao, Hongdoushan, Huachansu, Kanglaite, Xihuang, and Pingxiao TCMs. Randomized-controlled trials (RCTs) were identified from the following databases: China National Infrastructure, Wanfang, PubMed, Embase, and the Cochrane Library up to April 2023. Two researchers independently extracted data. RESULTS: Sixty-eight RCTs (5,099 patients) were included. Compared to chemotherapy, Banmao capsules [odds ratio (OR) = 2.69, 95% confidence interval (CI) 1.96-3.69)] and Huachansu tablets [OR = 2.35, 95%CI (1.81, 3.05)] ranked in the top two in terms of increasing disease control rate. The two main TCMs to improve the objective response rate were Banmao capsules [OR = 3.49, 95%CI (2.17, 5.60)] and Zilongjin tablets [OR = 2.62, 95%CI (1.92, 3.57)]. Zilongjin tablets [OR = 3.47, 95%CI (2.14, 5.63)] and Huachansu tablets [OR = 3.30, 95%CI (1.65, 6.60)] were ranked as the top two in improving Karnofsky performance status. Hongdoushan capsules (SUCRA = 18.8%) and Banmao capsules (SUCRA = 19.8%) were the top two in reducing gastrointestinal toxicity. Zilongjin tablets (SUCRA = 18.9%) and Banmao capsules (SUCRA = 26.6%) were the top two to reduce liver and kidney toxicity. Hongdoushan capsules (SUCRA = 15.7%) and Huachansu tablets (SUCRA = 16.8%) ranked the top two in reducing thrombocytopenia. Banmao capsules (SUCRA = 14.3%) and Zilongjin tablets (SUCRA = 26.3%) were the top two decreasing leukopenia. CONCLUSIONS: Combining oral TCMs with platinum-based chemotherapy has shown superior efficacy compared to platinum-based chemotherapy alone in treating NSCLC.

PCDH11X mutation as a potential biomarker for immune checkpoint therapies in lung adenocarcinoma.

Immune checkpoint inhibitors (ICIs) have achieved impressive success in lung adenocarcinoma (LUAD). However, the response to ICIs varies among patients, and predictive biomarkers are urgently needed. PCDH11X is frequently mutated in LUAD, while its role in ICI treatment is unclear. In this study, we curated genomic and clinical data of 151 LUAD patients receiving ICIs from three independent cohorts. Relations between PCDH11X and treatment outcomes of ICIs were examined. A melanoma cohort collected from five published studies, a pan-cancer cohort, and non-ICI-treated TCGA-LUAD cohort were also examined to investigate whether PCDH11X mutation is a specific predictive biomarker for LUAD ICI treatment. Among the three ICI-treated LUAD cohorts, PCDH11X mutation (PCDH11X-MUT) was associated with better clinical response compared to wild-type PCDH11X (PCDH11X-WT). While in ICI-treated melanoma cohort, the pan-cancer cohort excluding LUAD, and the non-ICI-treated TCGA-LUAD cohort, no significant differences in overall survival (OS) were observed between the PCDH11X-MUT and PCDH11X-WT groups. PCDH11X mutation was associated with increased PD-L1 expression, tumor mutation burden (TMB), neoantigen load, DNA damage repair (DDR) mutations, and hot tumor microenvironment in TCGA-LUAD cohort. Our findings suggested that the PCDH11X mutation might serve as a specific biomarker to predict the efficacy of ICIs for LUAD patients. Considering the relatively small sample size of ICI-treated cohorts, future research with larger cohorts and prospective clinical trials will be essential for validating and further exploring the role of PCDH11X mutation in the context of immunotherapy outcomes in LUAD. KEY MESSAGES: PCDH11X mutation is associated with better clinical response compared to wild type PCDH11X in three ICIs-treated LUAD cohorts. In ICIs-treated melanoma cohort, the pan-cancer cohort excluding LUAD, and non-ICIs-treated TCGA-LUAD cohorts PCDH11X mutation is not associated with better clinical response, suggesting PCDH11X mutation might be a specific biomarker to predict the efficacy of ICIs treatment for LUAD patients. PCDH11X mutation is associated with increased PD-L1 expression, tumor mutation burden, and neoantigen load in TCGA-LUAD cohort. PCDH11X mutation is associated with hot tumor microenvironment in TCGA-LUAD cohort.

Post-Assembly Polymerization of Discrete Anion-Coordinated Triple Helicate.

Hierarchical self-assembly has been recently employed in the construction of anion-coordination-driven gel materials. However, the post-assembly modification strategy, which may be a highly efficient strategy to realize the functionalization of discrete 'aniono' supramolecular architectures, has not been employed yet. Herein we report the first example of anion-coordination-driven gel material cross-linked by well-defined 'aniono' triple helicate through post-assembly polymerization. The obtained gel shows self-healing property and excellent compatibility with various surfaces, including glass, rubber, leaf, PP, and metal. The viscoelastic gel constructed through the post-assembly modification strategy enriches the method to construct the anion-coordination-driven smart materials.

Neoadjuvant chemotherapy may be the best neoadjuvant therapy modality for non-metastatic pancreatic cancer: a population based study.

Objective: Currently, there are no studies showing which neoadjuvant therapy modality can provide better prognosis for patients after pancreatic cancer surgery. This study explores the optimal neoadjuvant therapy model by comparing the survival differences between patients with non-metastatic pancreatic cancer (cT1-4N0-1M0) who received neoadjuvant chemotherapy (NACT) and neoadjuvant chemoradiotherapy (NARCT). Methods: We retrospectively analyzed the clinical data of 723 patients with cT1-4N0-1M0 pancreatic cancer who received neoadjuvant therapy before surgery from the Surveillance, Epidemiology, and End Results (SEER) database. After propensity score matching (PSM), we compared the effects of NACT and NARCT on overall survival (OS) and cancer-specific survival (CSS) in patients with non-metastatic pancreatic cancer, and then performed subgroup analyze. Finally, we used univariate and multivariate Cox regression analysis to explore potential risk factors for OS and CSS in patients with non-metastatic pancreatic cancer treated with preoperative neoadjuvant therapy. Result: Before PSM, mOS (30.0 months VS 26.0 months, P=0.122) and mCSS (30.0 months VS 26.0 months, P=0.117) were better in patients with non-metastatic pancreatic cancer treated with NACT compared with NARCT, but this was not statistically significant (P>0.05). After PSM, mOS (30.0 months VS 25.0 months, P=0.032) and mCSS (33.0 months VS 26.0 months, P=0.028) were better in patients with non-metastatic pancreatic cancer treated with NACT compared with NARCT, and this difference was statistically significant (P<0.05). Multivariate Cox regression analysis results showed that age, lymph node positivity, and NARCT were independent adverse prognostic factors for OS and CSS in patients with non-metastatic pancreatic cancer. Conclusion: The study results show that compared with NARCT, NACT is the best preoperative neoadjuvant therapy mode for patients with non-metastatic pancreatic cancer. This result still needs to be confirmed by more prospective randomized controlled trials.