Time trends in surgical provision and cancer-specific outcomes in patients with stage T2-3 kidney cancer: a SEER-based study.

Background and objective: Surgery is the primary therapy that crucially affects the survival of patients with kidney cancer (KC). However, pertinent surgical decision criteria for individuals with stage T2-3 KC are lacking. This study aimed to display the practical choices and evolving trends of surgical procedures and elucidate their implied value. Methods: Through the Surveillance, Epidemiology, and End Results (SEER) dataset, the levels and evolving trends of different surgical methods were examined to determine cancer-specific risk of death (CSRD). Additionally, stratification analysis and survival rate analysis were performed to explore the effectiveness of partial nephrectomy (PN). Results: In this study, 9.27% of patients opted for PN. Interestingly, an upward trend was observed in its decision, with an average annual percentage change (AAPC) of 7.0 (95% CI: 4.8-9.3, P < 0.05). Patients who underwent PN and were in a relatively less severe condition exhibited more favorable CSRD levels (0.17-0.36 vs. 0.50-0.67) and an improvement trend compared with those who underwent radical nephrectomy (RN) (AAPC: -1.9 vs. -0.8). Further analysis showed that the levels of CSRD and survival rates for patients opting for different surgical methods followed a similar pattern. Conclusions: This study showed that RN was still the most common surgical method. Patients with stage T2-3 KC had an increasing preference for PN and exhibited more favorable cancer-related survival outcomes, which underscores the need for further investigation and validation.

Hsa-LINC02418/mmu-4930573I07Rik regulated by METTL3 dictates anti-PD-L1 immunotherapeutic efficacy via enhancement of Trim21-mediated PD-L1 ubiquitination.

BACKGROUND: Limited response to programmed death ligand-1 (PD-L1)/programmed death 1 (PD-1) immunotherapy is a major hindrance of checkpoint immunotherapy in non-small cell lung cancer (NSCLC). The abundance of PD-L1 on the tumor cell surface is crucial for the responsiveness of PD-1/PD-L1 immunotherapy. However, the negative control of PD-L1 expression and the physiological significance of the PD-L1 inhibition in NSCLC immunotherapy remain obscure. METHODS: Bioinformatics analysis was performed to profile and investigate the long non-coding RNAs that negatively correlated with PD-L1 expression and positively correlated with CD8+T cell infiltration in NSCLC. Immunofluorescence, in vitro PD-1 binding assay, T cell-induced apoptosis assays and in vivo syngeneic mouse models were used to investigate the functional roles of LINC02418 and mmu-4930573I07Rik in regulating anti-PD-L1 therapeutic efficacy in NSCLC. The molecular mechanism of LINC02418-enhanced PD-L1 downregulation was explored by immunoprecipitation, RNA immunoprecipitation (RIP), and ubiquitination assays. RIP, luciferase reporter, and messenger RNA degradation assays were used to investigate the m6A modification of LINC02418 or mmu-4930573I07Rik expression. Bioinformatics analysis and immunohistochemistry (IHC) verification were performed to determine the significance of LINC02418, PD-L1 expression and CD8+T cell infiltration. RESULTS: LINC02418 is a negative regulator of PD-L1 expression that positively correlated with CD8+T cell infiltration, predicting favorable clinical outcomes for patients with NSCLC. LINC02418 downregulates PD-L1 expression by enhancing PD-L1 ubiquitination mediated by E3 ligase Trim21. Both hsa-LINC02418 and mmu-4930573I07Rik (its homologous RNA in mice) regulate PD-L1 therapeutic efficacy in NSCLC via Trim21, inducing T cell-induced apoptosis in vitro and in vivo. Furthermore, METTL3 inhibition via N6-methyladenosine (m6A) modification mediated by YTHDF2 reader upregulates hsa-LINC02418 and mmu-4930573I07Rik. In patients with NSCLC, LINC02418 expression is inversely correlated with PD-L1 expression and positively correlated with CD8+T infiltration. CONCLUSION: LINC02418 functions as a negative regulator of PD-L1 expression in NSCLC cells by promoting the degradation of PD-L1 through the ubiquitin-proteasome pathway. The expression of LINC02418 is regulated by METTL3/YTHDF2-mediated m6A modification. This study illuminates the underlying mechanisms of PD-L1 negative regulation and presents a promising target for improving the effectiveness of anti-PD-L1 therapy in NSCLC.

A neutron beam monitor based on ceramic gas electron multiplier with high spatial resolution for low flux measurements.

Neutron scattering instruments play an important role in studying the inner structure of materials. A neutron beam monitor is a detector commonly used in a neutron scattering instrument. The detection efficiency for most neutron beam monitors is quite low (10-4-10-6). However, in some experiments with a low neutron flux, such as small angle neutron scattering (SANS) and inelastic neutron scattering experiments, a neutron beam monitor with a higher detection efficiency (∼1% for thermal neutrons) is required to reduce the duration of the experiment. To meet this requirement, a ceramic gas electron multiplier-based neutron beam monitor equipped with a 1 µm 10B4C neutron converter was developed in this study. Its performance was determined both experimentally and in simulations. The detection efficiency in the wavelength range of 1.8-5.5 Å was measured experimentally and was confirmed by the simulation results. An algorithm based on event selection and position reconstruction was developed to improve the spatial resolution to about 1 mm full-width-half-maximum. The wavelength spectrum was measured in beamline 20 (BL20) and agreed well with the results obtained using a commercial monitor. The maximum counting rate was 1.3 MHz. The non-uniformity over the whole 100 × 100 mm2 active area was determined to be 1.4%. Due to the excellent performance of this monitor, it has been used in several neutron instruments, such as the SANS and the High-Energy Direct-Geometry Inelastic Spectrometer instruments in the China spallation neutron source.

Magnetron sputtering system for depositing boron carbide film use as neutron detection.

Boron carbide (B4C) films used as neutron conversion layers were investigated in this paper to replace the traditional 3He detectors due to their shortage. A magnetron sputtering system was developed for depositing large-size B4C films with the 1500 × 400 mm2 uniform-area. B4C films at the micron scale were deposited on aluminum (Al), float glass (SiO2), and silicon (Si) substrates with an inserting adhesion layer. The key characteristics, including surface morphology, thickness nonuniformity, purity, and neutron efficiency of B4C films, were characterized using atomic force microscopy, scanning electron microscopy, grazing incidence x-ray reflectivity, x-ray photoelectron spectroscopy, and neutron radiation metrology. The experimental results indicate that the deposition thickness nonuniformity across a 1500 × 400 mm2 area was better than ±3%. The stoichiometric ratio of boron atoms and carbon atoms (B/C) is 5.18, with 6 at. % O and 0.79 at. % N concentrations. The measured neutron detection efficiency of a 3 µm 10B4C film for 25 meV neutrons was 3.3 ± 0.3(sys)%, which is close to the simulated results (3.4%). The results show that the B4C neutron conversion layer is a promising substitute for 3He for neutron detection in the future.

Comprehensive analysis of the immunogenic cell death-related signature for predicting prognosis and immunotherapy efficiency in patients with lung adenocarcinoma.

BACKGROUND: Although immunotherapy has been considered as a potent strategy for lung adenocarcinoma (LUAD), only a small part of patients was served as potentially clinical benefiters. Immunogenic cell death (ICD), a type of regulated cell death (RCD), which enable to reshape the tumor immune microenvironment and contribute to the immunotherapy efficiency. Developing a novel ICD-based signature may be a potential strategy to differentiate prognosis of patients with LUAD and predict efficacy of immunotherapy. METHODS: In this study, 34 ICD-related genes (ICDRGs) were identified and analyzed in LUAD samples from the Cancer Genome Atlas (TCGA). 572 patients with LUAD were divided into two distinct clusters according to ICDRGs expression levels. Patients were subsequently classified into two distinct gene subtypes based on differentially expressed genes (DEGs) analyzed between two ICD-related clusters. We further developed and validated a novel ICD-related score (ICDRS) followed by comprehensive investigation about the landscape of the prognosis, immune-based features, immunotherapautic responses and sensitivity of target drugs in patients with LUAD. RESULTS: After confirming transcriptomic aberrations and appraising prognostic value of ICDRGs, two ICD-associated subtypes were initially determined by consensus clustering in accordance with differentially expressional levels of ICDRGs. It was shown that patients in the ICD high-subtype possessed the superior clinical prognosis, abundant immune cell infiltration and higher involvement in immune-related signaling compared with the ICD low-subtype. A signature of ICD-related score (ICDRS) was further established and validated, which was served as an independent prognostic indicator for LUAD patients. These comprehensive results revealed that the high-score patients represented better clinical prognosis, higher immune infiltration-related characteristics, stronger expression of immune checkpoints, and better response to immune checkpoint inhibitor therapy and multiple targeted drugs. To further verify our analysis, we selected TLR4 as the representative of ICDRGs and evaluated its expression on the lung normal cells and cancer cells in vitro. Then, relative animal experiments were performed in vivo, with results of that the stimulation of TLR4 suppressed the growth of lung cancer. CONCLUSIONS: In conclusion, our comprehensive analysis of ICDRGs in LUAD demonstrated their function in serving as a biomarker of predicting prognosis and clinical effects of immunotherapy and targeted drugs, which is meaningful to improve our understanding of ICDRGs and brought inspirations about evaluating prognosis and developing effective therapeutic strategies to patients with LUAD.

Associations of polygenic risk scores with risks of stroke and its subtypes in Chinese.

BACKGROUND AND PURPOSE: Previous studies, mostly focusing on the European population, have reported polygenic risk scores (PRSs) might achieve risk stratification of stroke. We aimed to examine the association strengths of PRSs with risks of stroke and its subtypes in the Chinese population. METHODS: Participants with genome-wide genotypic data in China Kadoorie Biobank were split into a potential training set (n=22 191) and a population-based testing set (n=72 150). Four previously developed PRSs were included, and new PRSs for stroke and its subtypes were developed. The PRSs showing the strongest association with risks of stroke or its subtypes in the training set were further evaluated in the testing set. Cox proportional hazards regression models were used to estimate the association strengths of different PRSs with risks of stroke and its subtypes (ischaemic stroke (IS), intracerebral haemorrhage (ICH) and subarachnoid haemorrhage (SAH)). RESULTS: In the testing set, during 872 919 person-years of follow-up, 8514 incident stroke events were documented. The PRSs of any stroke (AS) and IS were both positively associated with risks of AS, IS and ICH (p<0.05). The HR for per SD increment (HRSD) of PRSAS was 1.10 (95% CI 1.07 to 1.12), 1.10 (95% CI 1.07 to 1.12) and 1.13 (95% CI 1.07 to 1.20) for AS, IS and ICH, respectively. The corresponding HRSD of PRSIS was 1.08 (95% CI 1.06 to 1.11), 1.08 (95% CI 1.06 to 1.11) and 1.09 (95% CI 1.03 to 1.15). PRSICH was positively associated with the risk of ICH (HRSD=1.07, 95% CI 1.01 to 1.14). PRSSAH was not associated with risks of stroke and its subtypes. The addition of current PRSs offered little to no improvement in stroke risk prediction and risk stratification. CONCLUSIONS: In this Chinese population, the association strengths of current PRSs with risks of stroke and its subtypes were moderate, suggesting a limited value for improving risk prediction over traditional risk factors in the context of current genome-wide association study under-representing the East Asian population.

[Lamin B1 regulates the growth of hepatocellular carcinoma cells by influencing telomerase activity].

Lamin B1 (LMNB1) is highly expressed in liver cancer tissues, and its influence and mechanism on the proliferation of hepatocellular carcinoma cells were explored by knocking down the expression of the protein. In liver cancer cells, siRNAs were used to knock down LMNB1. Knockdown effects were detected by Western blotting. Changes in telomerase activity were detected by telomeric repeat amplification protocol assay (TRAP) experiments. Telomere length changes were detected by quantitative real-time polymerase chain reaction (qPCR). CCK8, cloning formation, transwell and wound healing were performed to detect changes in its growth, invasion and migration capabilities. The lentiviral system was used to construct HepG2 cells that steadily knocked down LMNB1. Then the changes of telomere length and telomerase activity were detected, and the cell aging status was detected by SA-ß-gal senescence staining. The effects of tumorigenesis were detected by nude mouse subcutaneous tumorigenesis experiments, subsequent histification staining of tumors, SA-ß-gal senescence staining, fluorescence in situ hybridization (FISH) for telomere analysis and other experiments. Finally, the method of biogenesis analysis was used to find the expression of LMNB1 in clinical liver cancer tissues, and its relationship with clinical stages and patient survival. Knockdown of LMNB1 in HepG2 and Hep3B cells significantly reduced telomerase activity, cell proliferation, migration and invasion abilities. Experiments in cells and tumor formation in nude mice had demonstrated that stable knockdown of LMNB1 reduced telomerase activity, shortened telomere length, senesced cells, reduced cell tumorigenicity and KI-67 expression. Bioinformatics analysis showed that LMNB1 was highly expressed in liver cancer tissues and correlated with tumor stage and patient survival. In conclusion, LMNB1 is overexpressed in liver cancer cells, and it is expected to become an indicator for evaluating the clinical prognosis of liver cancer patients and a target for precise treatment.

Minimal improvement in coronary artery disease risk prediction in Chinese population using polygenic risk scores: evidence from the China Kadoorie Biobank.

BACKGROUND: Several studies have reported that polygenic risk scores (PRSs) can enhance risk prediction of coronary artery disease (CAD) in European populations. However, research on this topic is far from sufficient in non-European countries, including China. We aimed to evaluate the potential of PRS for predicting CAD for primary prevention in the Chinese population. METHODS: Participants with genome-wide genotypic data from the China Kadoorie Biobank were divided into training ( n = 28,490) and testing sets ( n = 72,150). Ten previously developed PRSs were evaluated, and new ones were developed using clumping and thresholding or LDpred method. The PRS showing the strongest association with CAD in the training set was selected to further evaluate its effects on improving the traditional CAD risk-prediction model in the testing set. Genetic risk was computed by summing the product of the weights and allele dosages across genome-wide single-nucleotide polymorphisms. Prediction of the 10-year first CAD events was assessed using hazard ratios (HRs) and measures of model discrimination, calibration, and net reclassification improvement (NRI). Hard CAD (nonfatal I21-I23 and fatal I20-I25) and soft CAD (all fatal or nonfatal I20-I25) were analyzed separately. RESULTS: In the testing set, 1214 hard and 7201 soft CAD cases were documented during a mean follow-up of 11.2 years. The HR per standard deviation of the optimal PRS was 1.26 (95% CI:1.19-1.33) for hard CAD. Based on a traditional CAD risk prediction model containing only non-laboratory-based information, the addition of PRS for hard CAD increased Harrell's C index by 0.001 (-0.001 to 0.003) in women and 0.003 (0.001 to 0.005) in men. Among the different high-risk thresholds ranging from 1% to 10%, the highest categorical NRI was 3.2% (95% CI: 0.4-6.0%) at a high-risk threshold of 10.0% in women. The association of the PRS with soft CAD was much weaker than with hard CAD, leading to minimal or no improvement in the soft CAD model. CONCLUSIONS: In this Chinese population sample, the current PRSs minimally changed risk discrimination and offered little improvement in risk stratification for soft CAD. Therefore, this may not be suitable for promoting genetic screening in the general Chinese population to improve CAD risk prediction.

Association between pneumonia hospitalisation and long-term risk of cardiovascular disease in Chinese adults: A prospective cohort study.

Background: Lower respiratory tract infections, including pneumonia, have been associated with short-term increased risk of cardiovascular disease (CVD). However, there is only limited evidence about the long-term impact of pneumonia on the cardiovascular system beyond one year. Methods: We conducted a prospective matched cohort study based on data from the China Kadoorie Biobank study of 482,017 adults who were enrolled between June 25, 2004, and July 15, 2008, and were free of CVD at baseline and before pneumonia hospitalization. A total of 24,060 patients hospitalised with pneumonia were identified until December 31, 2018, and were matched on age, sex, urban or rural areas, and decile of the frailty index to 223,875 controls. We used the piecewise Cox proportional hazards model to estimate the hazard ratios (HRs) and their 95% confidence intervals (CIs) for pre-specified incident CVD outcomes, including ischaemic heart disease (IHD), arrhythmia, heart failure (HF), ischaemic stroke (IS), and hemorrhagic stroke (HS), at various time intervals through 10 years after pneumonia hospitalization. Findings: Of the 247,935 pneumonia cases and controls included, the mean age (standard deviation) was 53.5 (10.4), and 40.8% (101,159) were men. During follow-up, 2389 (9.9%) pneumonia cases developed IHD, 489 (2.0%) cases developed arrhythmia, 545 (2.3%) cases developed HF, 1764 (7.3%) cases developed IS, and 348 (1.4%) cases developed HS. After adjustment for sociodemographic characteristics, lifestyle factors, health status and medication, underlying conditions, and family history of CVD, the elevated CVD risk was highest within the first 30 days after pneumonia hospitalisation, with subsequent risk reductions varying by subtypes. The elevated risk remained until the eighth year after pneumonia hospitalisation for IHD, arrhythmia, and HF, with HRs (95% CIs) of 1.48 (1.13-1.93), 2.69 (1.70-4.25), and 4.36 (2.86-6.64), respectively. The risk of stroke associated with pneumonia hospitalisation remained elevated until the seventh year for IS (HR = 1.30; 95% CI: 1.04-1.63), and until the second year for HS (1.39; 1.07-1.80). The above associations were consistently observed across various characteristics of the participants. Interpretation: In middle-aged and older Chinese adults, pneumonia hospitalisation was associated with short- and long-term CVD risk, with the elevated risk of certain CVD outcomes persisting for up to 8 years. Funding: National Natural Science Foundation of China, the National Key R&D Program of China, the Chinese Ministry of Science and Technology, the Kadoorie Charitable Foundation in Hong Kong, the UK Wellcome Trust.

Xiao-Chai-Hu Decoction Ameliorates Poly (I:C)-Induced Viral Pneumonia through Inhibiting Inflammatory Response and Modulating Serum Metabolism.

Viral pneumonia is widespread, progresses rapidly, and has a high mortality rate. Developing safe and effective therapies to treat viral pneumonia can minimize risks to public health and alleviate pressures on the associated health systems. Xiao-Chai-Hu (XCH) decoction can be used in the treatment of viral pneumonia. However, the mechanisms of XCH on viral pneumonia remain unclear. In this study, poly (I:C) was used to establish a mouse model of viral pneumonia, and the therapeutic effects of XCH on viral pneumonia were assessed. Furthermore, we evaluated the effects of XCH on inflammatory response. Lastly, untargeted metabolomics were used to study the metabolic regulatory mechanisms of XCH on viral pneumonia model mice. Our results showed that XCH treatment decreased the wet/dry ratio in lung tissue, total protein concentration, and total cell count in bronchoalveolar lavage fluid (BALF). H&E staining indicated that XCH treatment alleviated the pathological changes in lung. Moreover, XCH treatment decreased the levels of proinflammatory cytokines (IL-1ß, IL-6, and TNF-α) and lowered the ratio of CD86+/CD206+ macrophages and CD11b+LY6G+ neutrophils in BALF. XCH treatment also decreased the myeloperoxidase (MPO) and reduced the phosphorylations of PI3K, AKT, and NF-κB p65 in lung. Serum untargeted metabolomics analysis showed that XCH treatment could affect 18 metabolites in serum such as creatine, hydroxyproline, cortisone, hydrocortisone, corticosterone, hypotaurine, and taurine. These metabolites were associated with arginine and proline metabolism, steroid hormone biosynthesis, and taurine and hypotaurine metabolism processes. In conclusion, our study demonstrated that treatment with XCH can ameliorate viral pneumonia and reduce inflammatory response in viral pneumonia. The mechanism of action of XCH in the treatment of viral pneumonia may be associated with inhibiting the activation of PI3K/AKT/NF-κB signaling pathway in lung and regulating arginine and proline metabolism, steroid hormone biosynthesis, and taurine and hypotaurine metabolism in serum.

Knockdown of LMNB1 Inhibits the Proliferation of Lung Adenocarcinoma Cells by Inducing DNA Damage and Cell Senescence.

Background: Lung cancer has considerably high mortality and morbidity rate. Lung adenocarcinoma (LUAD) tissues highly express lamin B1 (LMNB1), compared with normal tissues. In this study, we knocked down LMNB1 in LUAD cells A549 and NCI-1299 to explore the effect of its inhibition on the proliferation of cells and the potential mechanism. Methods: Using bioinformatics methods, we analyzed the specificity of LMNB1 mRNA expression level in LUAD and its effect on prognosis from TCGA data. SiRNAs were used to knock down LMNB1 in the A549 cell line, and the knockdown effect was identified by western blotting and qRT-PCR. Through CCK8 cell proliferation assay, wound healing assay, TRAP, cloning formation Assay, DNase I-TUNEL assay, ATAC-seq, immunofluorescence, FISH, in vivo mouse xenograft studies, etc, we evaluated the influence and mechanism of LMNB1 on LUAD cell line proliferation in vitro and in vivo. Results: According to bioinformatics analysis, LMNB1 is substantially abundant in LUAD tissues and is associated with tumor stage and patient survival (P < 0.05). After silencing LMNB1, the rate of cell growth, wound healing, the number of transwells, and the number of cell colonies all decreased significantly (P < 0.01). With the decreased LMNB1 expression, H3K9me3 protein expression decreases, chromosome accessibility increases, P53, P21, P16 and γ-H2AX protein expression increases, and the number of senescence staining positive cells increases. At the same time, in vivo mouse xenograft experiments showed that the tumor volume of the LMNB1-silenced group was significantly reduced, compared to that of the control group (P < 0.01), and the proliferation biomarker Ki-67 level (P < 0.01) was considerably reduced. Conclusions: Overexpression of LMNB1 in LUAD cells is significant, which has excellent potential to be an indicator for evaluating the clinical prognosis of LUAD patients and a target for precise treatment.

Low-risk Lifestyle and Health Factors and Risk of Mortality and Vascular Complications in Chinese Patients With Diabetes.

BACKGROUND: There is an evidence gap about whether a low-risk lifestyle is as important as achieving blood pressure (BP) and random blood glucose (RBG) control. OBJECTIVES: To explore the long-term impacts and relative importance of low-risk lifestyle and health factors on the risk of all-cause and cancer mortality and macrovascular and microvascular complications among patients with diabetes. METHODS: This study included 26,004 diabetes patients in the China Kadoorie Biobank. We defined 5 lifestyle factors (smoking, alcohol drinking, physical activity, fruit and vegetable intake, and waist-to-hip ratio) and 2 health factors (BP and RBG). Cox regression was used to yield adjusted hazard ratios (HRs) and CIs for individual and combined lifestyle and health factors with the risks of diabetes-related outcomes. RESULTS: There were 5063 deaths, 6848 macrovascular complications, and 2055 microvascular complications that occurred during a median follow-up of 10.2 years. Combined low-risk lifestyle factors were associated with lower risk of all main outcomes, with HRs (95% CIs) for participants having 4 to 5 low-risk factors vs 0 to 1 of 0.50 (0.44-0.57) for all-cause mortality, 0.55 (0.43-0.71) for cancer mortality, 0.60 (0.54-0.67) for macrovascular complications, and 0.75 (0.62-0.91) for microvascular complications. The combined 4 to 5 low-risk lifestyle factors showed relative importance in predicting all-cause and cancer mortality and macrovascular complications. CONCLUSIONS: Assuming causality exists, our findings suggest that adopting a low-risk lifestyle should be regarded as important as achieving ideal BP and glycemic goals in the prevention and management of diabetes-related adverse outcomes.

Study of a position-sensitive scintillator neutron detector prototype based on 6LiF/ZnS scintillator and silicon photomultiplier arrays readout.

Due to the shortage of the 3He gas and its rapidly increasing price, scintillator detectors, the advantages of which are high spatial resolution and capability of detection in real time, become widely used in many neutron instruments. In this work, a position-sensitive neutron detector consisting of a 6LiF/ZnS scintillation screen and a silicon photomultiplier array linked to a capacitive network to detect the positions of incident neutrons, is constructed and tested. To evaluate the detector performance, a series of neutron beam experiments with the detector prototype were performed in the BL20 at the China Spallation Neutron Source. The spatial resolution was measured, and the energy-selective neutron imaging and Bragg edge measurements of a 316L stainless steel sample were performed. A sub-millimeter spatial resolution could be obtained for the detector prototype under study. The detector with such a high spatial resolution is promising for applications in neutron scattering experimental installations, especially for neutron single-crystal diffractometers.

LINC00244 suppresses cell growth and metastasis in hepatocellular carcinoma by downregulating programmed cell death ligand 1.

The role of programmed cell death ligand 1 (PD-L1) in suppressing antitumor immune responses has been widely reported, and recent studies showed that PD-L1 also plays an important role in epithelial-mesenchymal transition (EMT), determination of tumor cell phenotypes, metastasis, and drug resistance. Long non-coding RNAs (lncRNAs) are involved in a variety of epigenetic regulatory processes. The tumorigenesis and development of most cancers cannot be studied separately from their regulation by lncRNAs. To explore the epigenetic regulation of PD-L1, we identified an lncRNA, LINC00244, which reduced PD-L1 expression and predicted good clinical outcomes in hepatocellular carcinoma (HCC). LINC00244 inhibited the proliferation, invasion, and metastasis of HCC by downregulating PD-L1 expression. In addition, low LINC00244 expression activated epithelial-mesenchymal transition (EMT) pathways and facilitated the rapid growth and metastasis of HCC cells. Thus, LINC00244 is a potential therapeutic target for HCC.

Chemical coupling of manganese-cobalt oxide and oxidized multi-walled carbon nanotubes for enhanced lithium storage.

Carbonaceous materials are extensively utilized to optimize the electrochemical performance of the transition metal oxides as anode for lithium-ion batteries. However, the in-depth mechanism of the synergistic effect and the interfacial interaction between transition metal oxides and conductive carbon material has not been elucidated clearly. Herein, by using the oxidized multi-walled carbon nanotubes (oMWCNTs), an advanced MnO2/(Co, Mn)(Co, Mn)2O4/oMWCNTs (MO/CMO/oMWCNTs) nanocomposite with abundant metal-oxygen-carbon (Me-OC) bonds as linkage bridge is fabricated for the first time. The strong covalent bonds interactions can simultaneously enhance the intrinsic sluggish kinetics and structural stability of MO/CMO/oMWCNTs nanocomposite. Meanwhile, the mixed transition metal oxides featuring mix valence state can significantly promote the electrode material activity. Consequently, the newly prepared MO/CMO/oMWCNTs electrode displays superior long-term durability with the capacity of 897 mAh g-1 over 1000 cycles at 2 A g-1 and ultrafast charging/discharging capability of 673 mAh g-1 at 5 A g-1. Detailed electrochemical kinetic analysis reveals that over 70% of the energy storage of MO/CMO/oMWCNTs electrode is dominated by the pseudocapacitive behavior. This work demonstrates an easily scalable approach for constructing high-performance transition metal oxides/carbon electrode materials through interfacial regulation.

Multimorbidity patterns and association with mortality in 0.5 million Chinese adults.

BACKGROUND: Few studies have assessed the relationship between multimorbidity patterns and mortality risk in the Chinese population. We aimed to identify multimorbidity patterns and examined the associations of multimorbidity patterns and the number of chronic diseases with the risk of mortality among Chinese middle-aged and older adults. METHODS: We used data from the China Kadoorie Biobank and included 512,723 participants aged 30 to 79 years. Multimorbidity was defined as the presence of two or more of the 15 chronic diseases collected by self-report or physical examination at baseline. Multimorbidity patterns were identified using hierarchical cluster analysis. Cox regression was used to estimate the associations of multimorbidity patterns and the number of chronic diseases with all-cause and cause-specific mortality. RESULTS: Overall, 15.8% of participants had multimorbidity. The prevalence of multimorbidity increased with age and was higher in urban than rural participants. Four multimorbidity patterns were identified, including cardiometabolic multimorbidity (diabetes, coronary heart disease, stroke, and hypertension), respiratory multimorbidity (tuberculosis, asthma, and chronic obstructive pulmonary disease), gastrointestinal and hepatorenal multimorbidity (gallstone disease, chronic kidney disease, cirrhosis, peptic ulcer, and cancer), and mental and arthritis multimorbidity (neurasthenia, psychiatric disorder, and rheumatoid arthritis). During a median of 10.8 years of follow-up, 49,371 deaths occurred. Compared with participants without multimorbidity, cardiometabolic multimorbidity (hazard ratios [HR] = 2.20, 95% confidence intervals [CI]: 2.14 - 2.26) and respiratory multimorbidity (HR = 2.13, 95% CI:1.97 - 2.31) demonstrated relatively higher risks of mortality, followed by gastrointestinal and hepatorenal multimorbidity (HR = 1.33, 95% CI:1.22 - 1.46). The mortality risk increased by 36% (HR = 1.36, 95% CI: 1.35 - 1.37) with every additional disease. CONCLUSION: Cardiometabolic multimorbidity and respiratory multimorbidity posed the highest threat on mortality risk and deserved particular attention in Chinese adults.

Place of death and phenomenon of going home to die in Chinese adults: A prospective cohort study.

BACKGROUND: China is embracing an ageing population without sustainable end-of-life care services. However, changes in place of death and trends of going home to die (GHTD) from the hospital remains unknown. METHODS: A total of 42,956 participants from the China Kadoorie Biobank, a large Chinese cohort, who died between 2009 and 2017 was included into analysis. GHTD was defined as death at home within 7 days after discharge from the hospital. A modified Poisson regression was used to investigate temporal trends of the place of death and GHTD, and estimate prevalence ratios (PRs) and 95% confidence intervals (CIs) for the association of GHTD with health insurance (HI) schemes. FINDINGS: From 2009 to 2017, home remained the most common place of death (71·5%), followed by the hospital (21·6%). The proportion of GHTD for Urban and Rural Residents' Basic Medical Insurance (URRBMI) beneficiaries was around six times higher than that for Urban Employee Basic Medical Insurance (UEBMI) beneficiaries (66·0% vs 11·6%). Besides, a substantial increase in the proportion of GHTD throughout the study period was observed regardless of HI schemes (4·4% annually for URRBMI, and 5·4% for UEBMI). Compared with UEBMI beneficiaries, URRBMI beneficiaries were more likely to experience GHTD, with an adjusted PR (95% CI) of 1·19 (95% CI: 1·12, 1·27) (P<0·001). INTERPRETATION: In China, most of deaths occurred at home, with a large proportion of decedents GHTD from the hospital, especially for URRBMI beneficiaries. Substantial variation in the phenomenon of GHTD across HI schemes indicates inequalities in end-of-life care utilization. FUNDING: The National Natural Science Foundation of China, the Kadoorie Charitable Foundation, the National Key R&D Program of China, the Chinese Ministry of Science and Technology.

STAT3/LINC00671 axis regulates papillary thyroid tumor growth and metastasis via LDHA-mediated glycolysis.

Lactate dehydrogenase A (LDHA), a critical component of the glycolytic pathway, relates to the development of various cancers, including thyroid cancer. However, the regulatory mechanism of LDHA inhibition and the physiological significance of the LDHA inhibitors in papillary thyroid cancer (PTC) are unknown. Long non-coding RNA (lncRNA) plays a vital role in tumor growth and progression. Here, we identified a novel lncRNA LINC00671 negatively correlated with LDHA, downregulating LDHA expression and predicting good clinical outcome in thyroid cancer. Moreover, hypoxia inhibits LINC00671 expression and activates LDHA expression largely through transcriptional factor STAT3. STAT3/LINC00671/LDHA axis regulates thyroid cancer glycolysis, growth, and lung metastasis both in vitro and in vivo. In thyroid cancer patients, LINC00671 expression is negatively correlated with LDHA and STAT3 expression. Our work established STAT3/LINC00671/LDHA as a critical axis to regulate PTC growth and progression. Inhibition of LDHA or STAT3 or supplement of LINC00671 could be potential therapeutic strategies in thyroid cancer.

LSD1-Demethylated LINC01134 Confers Oxaliplatin Resistance Through SP1-Induced p62 Transcription in HCC.

BACKGROUND AND AIMS: Oxaliplatin (OXA) is one of the most common chemotherapeutics in advanced hepatocellular carcinoma (HCC), the resistance of which poses a big challenge. Long noncoding RNAs (lncRNAs) play vital roles in chemoresistance. Therefore, elucidating the underlying mechanisms and identifying predictive lncRNAs for OXA resistance is needed urgently. METHODS: RNA sequencing (RNA-seq) and fluorescence in situ hybridization (FISH) were used to investigate the OXA-resistant (OXA-R) lncRNAs. Survival analysis was performed to determine the clinical significance of homo sapiens long intergenic non-protein-coding RNA 1134 (LINC01134) and p62 expression. Luciferase, RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), and chromatin isolation by RNA purification (ChIRP) assays were used to explore the mechanisms by which LINC01134 regulates p62 expression. The effects of LINC01134/SP1/p62 axis on OXA resistance were evaluated using cell viability, apoptosis, and mitochondrial function and morphology analysis. Xenografts were used to estimate the in vivo regulation of OXA resistance by LINC01134/SP1/p62 axis. ChIP, cell viability, and xenograft assays were used to identify the demethylase for LINC01134 up-regulation in OXA resistance. RESULTS: LINC01134 was identified as one of the most up-regulated lncRNAs in OXA-R cells. Higher LINC01134 expression predicted poorer OXA therapeutic efficacy. LINC01134 activates anti-oxidative pathway through p62 by recruiting transcription factor SP1 to the p62 promoter. The LINC01134/SP1/p62 axis regulates OXA resistance by altering cell viability, apoptosis, and mitochondrial homeostasis both in vitro and in vivo. Furthermore, the demethylase, lysine specific demethylase 1 (LSD1) was responsible for LINC01134 up-regulation in OXA-R cells. In patients with HCC, LINC01134 expression was positively correlated with p62 and LSD1 expressions, whereas SP1 expression positively correlated with p62 expression. CONCLUSIONS: LSD1/LINC01134/SP1/p62 axis is critical for OXA resistance in HCC. Evaluating LINC01134 expression in HCC will be effective in predicting OXA efficacy. In treatment-naive patients, targeting the LINC01134/SP1/p62 axis may be a promising strategy to overcome OXA chemoresistance.

Adherence to Healthy Lifestyle and Attenuation of Biological Aging in Middle-Aged and Older Chinese Adults.

BACKGROUND: Little is known about the effects of lifestyle modification on biological aging in population-based studies of middle-aged and older adults. METHOD: We examined the individual and joint associations of multiple lifestyle factors with accelerated biological aging measured by change in frailty index (FI) over 8 years in a prospective study of Chinese adults. Data were obtained on 24 813 participants in the China Kadoorie Biobank on lifestyle factors and frailty status at baseline and at 8 years after baseline. Adherence to healthy lifestyle factors included nonsmoking or quitting smoking for reasons other than illness, avoidance of heavy alcohol consumption, daily intake of fruit and vegetables, being physically active, body mass index of 18.5-23.9 kg/m2, and waist-to-hip ratio of <0.90 (men)/0.85 (women). FI was constructed separately at baseline and resurvey using 25 age- and health-related items. RESULTS: Overall, 8 760 (35.3%) individuals had a worsening frailty status. In multivariable-adjusted logistic regression analyses, adherence to healthy lifestyle was associated with a lower risk of worsening frailty status. Compared with robust participants maintaining 0-1 healthy lifestyle factors, the corresponding odds ratios (95% CIs) were 0.93 (0.83-1.03), 0.75 (0.67-0.84), 0.68 (0.60-0.77), and 0.55 (0.46-0.65) for robust participants with 2, 3, 4, and 5-6 healthy lifestyle factors. The decreased risk of frailty status worsening by adherence to healthy lifestyle factors was similar in both middle-aged and older adults, and in both robust and prefrail participants at baseline. CONCLUSIONS: Adherence to a healthy lifestyle may attenuate the rate of change in biological aging in middle-aged and older Chinese adults.