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Skeletal muscle consists of different muscle fiber types whose heterogeneity is characterized by different metabolic patterns and expression of MyHC isomers. The transformation of muscle fiber types is regulated by a complex molecular network in which long noncoding (lnc) RNAs play an important role. In this study, we found that lnc-H19 is more enriched in slow muscle fibers. In vitro, interference of lnc-H19 by siRNA significantly promoted the expression of fast muscle fiber gene MyHC IIB and inhibited the expression of the slow muscle fiber gene MyHC I, thereby leading to a fast muscle fiber phenotype. In addition, interference of lnc-H19 significantly inhibited mRNA expression of the mitochondrial genes, such as COX5A, COX-2, UQCRFSL, FABP3, and CD36. Overexpression of lnc-H19 resulted in an opposite result. In vivo, knockdown of lnc-H19 by AAV-shRNA-H19 suppressed the mRNA expression of the slow muscle fiber gene MyHC I and the protein expression of slow-MyHC. Simultaneously, mitochondria were reduced in number, swollen, and vacuolated. The activities of succinate dehydrogenase, lactic dehydrogenase, and superoxide dismutase were significantly inhibited, and malondialdehyde content was significantly increased, indicating that deficiency of lnc-H19 leads to decreased oxidative metabolism and antioxidant capacity in muscle. Furthermore, inhibition of lnc-H19 decreased the weight-bearing swimming time and limb suspension time of mice. In conclusion, our results revealed the role of lnc-H19 in maintaining slow muscle fiber types and maintaining exercise endurance, which may help to further improve the regulatory network of lnc-H19 in muscle function.
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RNA Longo não Codificante , Animais , Camundongos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Cadeias Pesadas de Miosina/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Masculino , Linhagem Celular , Camundongos Endogâmicos C57BLRESUMO
In the emerging Sb2S3-based solar energy conversion devices, a CdS buffer layer prepared by chemical bath deposition is commonly used to improve the separation of photogenerated electron-hole pairs. However, the cation diffusion at the Sb2S3/CdS interface induces detrimental defects but is often overlooked. Designing a stable interface in the Sb2S3/CdS heterojunction is essential to achieve high solar energy conversion efficiency. As a proof of concept, this study reports that the modification of the Sb2S3/CdS heterojunction with an ultrathin Al2O3 interlayer effectively suppresses the interfacial defects by preventing the diffusion of Cd2+ cations into the Sb2S3 layer. As a result, a water-splitting photocathode based on Ag:Sb2S3/Al2O3/CdS heterojunction achieves a significantly improved half-cell solar-to-hydrogen efficiency of 2.78% in a neutral electrolyte, as compared to 1.66% for the control Ag:Sb2S3/CdS device. This work demonstrates the importance of designing atomic interfaces and may provide a guideline for the fabrication of high-performance stibnite-type semiconductor-based solar energy conversion devices.
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Platelet-derived extracellular vesicles (PEVs) showing great potential in wound healing have attracted increasing attention recently. Nondestructive isolation and effective utilization strategies are highly conducive for PEVs developing into recognized therapeutic entities. Here, we present an efficient strategy for PEV isolation and bacterial infected wound healing based on self-assembled DNA microflowers. First, DNA microflowers are prepared using rolling circle amplification. Then, the hydrophobic interaction between cholesteryl modified on DNA microflowers and the phospholipid bilayer membrane of PEVs leads to the formation of a network structure with improved mechanical strength and the separation of PEVs from biological samples. Finally, controlled release of PEVs is achieved through bacterial-induced hydrogel degradation. In vitro experiments demonstrate the obtained DNA hydrogel with good cytocompatibility and therapeutic potential. Taken together, the DNA microflower-based hydrogels with bioadhesive, self-healing, tunable mechanical properties and bacteria-responsive behavior offer substantial potential for EV isolation and wound healing.
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Plaquetas , DNA , Vesículas Extracelulares , Hidrogéis , Cicatrização , Vesículas Extracelulares/química , Cicatrização/efeitos dos fármacos , DNA/química , Plaquetas/metabolismo , Humanos , Hidrogéis/química , Hidrogéis/farmacologia , Animais , CamundongosRESUMO
Kainoid synthases are key enzymes in the biosynthesis of kainoids. Kainoids, as represented by DA and KA, are a class of naturally occurring non-protein amino acids with strong neurotransmitter activity in the mammalian central nervous system. Marine algae kainoid synthases include PnDabC from diatoms, which synthesizes domoic acid (DA), and DsKabC and GfKabC from red algae, which synthesize kainic acid (KA). Elucidation of the catalytic mechanism of kainoid synthases is of great significance for the rational design of better biocatalysts to promote the industrial production of kainoids for use in new drugs. Through modeling, molecular docking, and molecular dynamics simulations, we investigated the conformational dynamics of kainoid synthases. We found that the kainoid synthase complexes showed different stability in the simulation, and the binding and catalytic processes showed significant conformational transformations of kainoid synthase. The residues involved in specific interactions with the substrate contributed to the binding energy throughout the simulation process. Binding energy, the relaxed active pocket, electrostatic potential energy of the active pocket, the number and rotation of aromatic residues interacting with substrates during catalysis, and the number and frequency of hydrogen bonds between the individual functional groups revealed the structure-activity relationships and affected the degree of promiscuity of kainoid synthases. Our research enriches the understanding of the conformational dynamics of kainoid synthases and has potential guiding significance for their rational design.
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Diatomáceas , Ácido Caínico , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Relação Estrutura-Atividade , Ácido Caínico/análogos & derivados , Diatomáceas/enzimologia , Rodófitas/enzimologia , Oxo-Ácido-Liases/química , Oxo-Ácido-Liases/metabolismo , Ligação de HidrogênioRESUMO
Moso bamboo (Phyllostachys edulis) is a valuable nontimber forestry product with a biennial cycle, producing abundant bamboo shoots within one year (on-year) and few shoots within the following year (off-year). Moso bamboo plants undergo clonal reproduction, resulting in similar genetic backgrounds. However, the number of moso bamboo shoots produced each year varies. Despite this variation, the impact of soil nutrients and the root microbiome on the biennial bearing of moso bamboo is poorly understood. We collected 139 soil samples and determined 14 major physicochemical properties of the rhizosphere, rhizoplane, and bulk soil in different seasons (i.e., the growing and deciduous seasons) and different years (i.e., on- and off-years). Based on 16S rRNA and metagenomic sequencing, major variations were found in the rhizospheric microbial composition during different seasons and years in the moso bamboo forest. Environmental driver analysis revealed that essential nutrients (i.e., SOC, TOC, TN, P, and NH4+) were the main drivers of the soil microbial community composition and were correlated with the on- and off-year cycles. Moreover, 19 MAGs were identified as important biomarkers that could distinguish on- and off-years. We found that both season and year influenced both the microbial community structure and functional pathways through the biosynthesis of nutrients that potentially interact with the moso bamboo growth rhythm, especially the on-year root-associated microbiome, which had a greater abundance of specific nutrients such as gibberellins and vitamin B6. This work provides a dynamic perspective of the differential responses of various on- and off-year microbial communities and enhances our understanding of bamboo soil microbiome biodiversity and stability.
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Poaceae , Rizosfera , RNA Ribossômico 16S/genética , Florestas , Solo/químicaRESUMO
We investigated a mechanism of crystal melting and crystallization behavior of a two-dimensional coordination polymer [Ag2(L1)(CF3SO3)2] (1, L1 = 4,4'-biphenyldicarbonitrile) upon heating-cooling processes. The crystal showed melting at 282 °C, and the following gentle cooling induced the abrupt crystallization at 242 °C confirmed by DSC. A temperature-dependent structural change has been discussed through calorimetric, spectroscopic, and mechanical measurements. They indicated that the coordination-bond networks are partially retained in the melt state, but the melt showed a significantly low viscosity of 9.8 × 10-2 Pa·s at Tm which is six orders lower than that of ZIF-62 at Tm (435 °C). Rheological studies provided an understanding of the fast relaxation dynamics for the recrystallization process, along with that the high Tm provides enough thermal energy to crossover the activation energy barrier for the nucleation. The isothermal crystallization kinetics through calorimetric measurements with applying the Avrami equation identified the nature of the nuclei and its crystal growth mechanism.
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Polímeros , Cristalização , Cinética , Polímeros/química , Varredura Diferencial de Calorimetria , Transição de FaseRESUMO
Tantalum nitride (Ta3 N5 ) has emerged as a promising photoanode material for photoelectrochemical (PEC) water splitting. However, the inefficient electron-hole separation remains a bottleneck that impedes its solar-to-hydrogen conversion efficiency. Herein, we demonstrate that a core-shell nanoarray photoanode of NbNx -nanorod@Ta3 N5 ultrathin layer enhances light harvesting and forms a spatial charge-transfer channel, which leads to the efficient generation and extraction of charge carriers. Consequently, an impressive photocurrent density of 7â mA cm-2 at 1.23â VRHE is obtained with an ultrathin Ta3 N5 shell thickness of less than 30â nm, accompanied by excellent stability and a low onset potential (0.46â VRHE ). Mechanistic studies reveal the enhanced performance is attributed to the high-conductivity NbNx core, high-crystalline Ta3 N5 mono-grain shell, and the intimate Ta-N-Nb interface bonds, which accelerate the charge-separation capability of the core-shell photoanode. This study demonstrates the key roles of nanostructure design in improving the efficiency of PEC devices.
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Crystalline triazine-based covalent organic frameworks (COFs) are aromatic nitrogen-rich porous materials. COFs typically show high thermal/chemical stability, and are promising for energy applications, but often require harsh synthesis conditions and suffer from low crystallinity. In this work, we propose an environmentally friendly route for the synthesis of crystalline COFs from CO2 molecules as a precursor. The mass ratio of CO2 conversion into COFs formula unit reaches 46.3 %. The synthesis consists of two steps; preparation of 1,4-piperazinedicarboxaldehyde from CO2 and piperazine, and condensation of the dicarboxaldehyde and melamine to construct the framework. The CO2 -derived COF has a 3-fold interpenetrated structure of 2D layers determined by powder X-ray diffraction, high-resolution transmission electron microscopy, and select-area electron diffraction. The structure shows a high Brunauer-Emmett-Teller surface area of 945â m2 g-1 and high stability against strong acid (6â M HCl), base (6â M NaOH), and boiling water over 24â hours. Post-modification of the framework with oxone has been demonstrated to modulate hydrophilicity, and it exhibits proton conductivity of 2.5×10-2 â S cm-1 at 85 °C, 95 % of relative humidity.
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Exploring new porous coordination polymers (PCPs) that have tunable structure and conductivity is attractive but remains challenging. Herein, fine pore structure engineering by ligand conformation control of naphthalene diimide (NDI)-based semiconducting PCPs with π stacking-dependent conductivity tunability is achieved. The π stacking distances and ligand conformation in these isoreticular PCPs were modulated by employing metal centers with different coordination geometries. As a result, three conjugated PCPs (Co-pyNDI, Ni-pyNDI, and Zn-pyNDI) with varying pore structure and conductivity were obtained. Their crystal structures were determined by three-dimensional electron diffraction. The through-space charge transfer and tunable pore structure in these PCPs result in modulated selectivity and sensitivity in gas sensing. Zn-pyNDI can serve as a room-temperature operable chemiresistive sensor selective to acetone.
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Melt and glassy states of coordination polymers (CPs)/metal-organic frameworks (MOFs) have gained attention as a new class of amorphous materials. Many bridging ligands such as azolate, nitrile, thiocyanide, thiolate, pyridine, sulfonate, and amide are available to construct crystals with melting temperatures in the range of 60-593 °C. Here, we discuss the mechanism of crystal melting, glass structures, and mechanical properties by considering both experimental and theoretical studies. High and exclusive H+ or Li+ conductivities in moldable CP glasses have been proven in the all-solid-state devices such as fuel cells or secondary batteries. Transparent glasses with wide composition and available dopants are also attractive for nonlinear optics, photoconductivity, emission, and light-harvesting. The ongoing challenge in the field is to develop the design principles of CP/MOF melts and glasses, corresponding functions of mass (ion, electron, photon, phonon, and so forth). transport and conversion, and the integration of devices with the use of their tunable mechanical properties.
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Industrial hydrogen production based on methane steam reforming (MSR) remains challenges in intensive carbon emissions, retarded hydrogen generation owing to coke deposition over catalysts and huge consumption of water. We herein report an electrochemical splitting of methane (ESM) in molten salts at 500 °C to produce hydrogen in an energy saving, emission-free and water-free manner. Following the most energy-saving route on methane-to-hydrogen conversion, methane is electrochemically oxidized at anode to generate carbon dioxide and hydrogen. The generated anodic carbon dioxide is in situ captured by the melts and reduced to solid carbon at cathode, enabling a spatial separation of anodic hydrogen generation from cathodic carbon deposition. Life-cycle assessment on hydrogen-generation technologies shows that the ESM experiences an equivalent carbon emission much lower than MSR, and a lower equivalent energy input than alkaline water electrolysis.
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Magnesium potassium phosphate cement (MKPC) is increasingly used in the solidification/stabilization (SS) of heavy metal (HM) pollutants. However, research on composite HM pollutants remains limited. In this study, four heavy metals (Pb/Zn/Cu/Cd) were individually and simultaneously introduced into MKPC systems with different magnesium/phosphorus (M/P) molar ratios. The introduction of HMs altered the extent of hydration and morphology of MgKPO4·6H2O. Among the MKPC pastes, those with M/P = 2 and 3 had the highest HM solidification efficiency and strength, respectively. The HM solidification efficiency of all specimens exceeded 99 %. In samples with M/P = 3, the codoping of four HMs slightly increased the M/P ratio, thereby increasing MgKPO4·6H2O content and enhancing strength. Pb could generate additional low-solubility precipitates, such as PbHPO4, Pb3 (PO4)2, Pb5 (OH) (PO4)3, and Pb (OH)2, which easily accumulated in pores and were encapsulated by MgKPO4·6H2O, leading to the highest solidification efficiency of Pb by MKPC. Pb and Cu could also form the composite phosphate products Pb2Cu (PO4)3 (OH)·4H2O, thus promoting the S/S effect of Cu. Therefore, the use of MKPC with M/P ratio of 2-3 for the S/S of complex pollutants containing Pb and Cu is a promising approach.
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Poluentes Ambientais , Compostos de Magnésio , Metais Pesados , Compostos de Potássio , Magnésio , Potássio , Chumbo , FosfatosRESUMO
Obesity has emerged as a worldwide epidemic. Both butyrate and glutamine counteract obesity-related metabolic disorders; however, whether and how they synergistically cooperate with each other remains a mystery. In the study, a high-fat diet (HFD, 60% calories from fat) was used to develop a model of obesity-related metabolic disorder and compared with administrated saline and sodium butyrate (SB, 300 mg/kg body weight) daily by gavage. Compared with HFD counterparts, oral administration of SB in mice exhibited significantly reduced body weight and fat mass and decreased hepatic triglyceride content. The targeted mass spectrum revealed that SB restored serum contents of glutamine, which were significantly decreased by HFD. Furthermore, SB significantly elevated the expression of glutamine synthetase (GS, encoded by GLUL) in the liver, accompanied by more enrichment of H3K27ac modifications within its promoter. In summary, the study verified the contribution of elevated glutamine to the beneficial effects of butyrate on metabolic disorders induced by a high-fat diet, providing a novel pathway for understanding how butyrate benefits metabolic homeostasis.
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Glutamina , Doenças Metabólicas , Animais , Camundongos , Glutamina/metabolismo , Obesidade/tratamento farmacológico , Obesidade/genética , Obesidade/metabolismo , Ácido Butírico/metabolismo , Fígado/metabolismo , Peso Corporal , Dieta Hiperlipídica/efeitos adversos , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Camundongos Endogâmicos C57BLRESUMO
Sewage sludge (SS) pyrolysis to produce biochar is a vital approach for treating and utilizing SS, while reducing the carbon footprint of SS disposal. However, the high inorganic content in SS results in low carbon content and underdeveloped pore structure of biochar prepared under inert atmospheres. There is a significant risk of secondary pollutant emissions, including CO2, SO2, and NOx. In this study, we propose an innovative approach that utilizes excess molten salts, specifically a Li-Na-K molten carbonate (MC) and a Li-Na-K molten chloride (MCH), to create a medium-temperature liquid phase reaction environment (500 °C) for SS pyrolysis. This environment promotes the functional enhancement of biochar (SSB-MC and SSB-MCH) and in-situ absorption of secondary pollutants. The pore structure of SSB-MC and SSB-MCH are greatly optimized. Thanks to the dissolution of calcium-silicon-aluminum-based minerals by molten salt, the carbon content is also significantly increased. The increased specific surface area and surface-enriched functional groups (O, N, P, etc.) of SSB-MC result in greatly enhanced adsorption performance for Rhodamine B (27.9 to 89.1 mg g-1). SSB-MCH, due to the increased iron and phosphorus doping, also exhibits enhanced Fenton oxidation capability. Life cycle assessments demonstrate that the molten salt processes effectively reduce the carbon footprint, energy consumption, and environmental impact.
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Poluentes Ambientais , Esgotos , Esgotos/química , Águas Residuárias , Pegada de Carbono , Carvão Vegetal/química , Carbono , Cloreto de Sódio , CarbonatosRESUMO
Background: Although screening is widely used to reduce cancer burden, untargeted cancers are frequently missed after single cancer screening. Joint cancer screening is presumed as a more effective strategy to reduce overall cancer burden. Methods: Gender-specific screening effects on PLCO cancer incidence, PLCO cancer mortality, all-neoplasms mortality and all-cause mortality were evaluated, and meta-analyses based on gender-specific screening effects were conducted to achieve the pooled effects. The cut-off value of time-dependent receiver-operating-characteristic curve of 10-year combined PLCO cancer risk was used to reclassify participants into low- and high-risk subgroups. Further analyses were conducted to investigate screening effects stratified by risk groups and screening compliance. Results: After a median follow-up of 10.48 years for incidence and 16.85 years for mortality, a total of 5,506 PLCO cancer cases, 1,845 PLCO cancer deaths, 3,970 all-neoplasms deaths, and 14,221 all-cause deaths were documented in the screening arm, while 6,261, 2,417, 5,091, and 18,516 outcome-specific events in the control arm. Joint cancer screening did not significantly reduce PLCO cancer incidence, but significantly reduced male-specific PLCO cancer mortality (hazard ratio and 95% confidence intervals [HR(95%CIs)]: 0.88(0.82, 0.95)) and pooled mortality [0.89(0.84, 0.95)]. More importantly, joint cancer screening significantly reduced both gender-specific all-neoplasm mortality [0.91(0.86, 0.96) for males, 0.91(0.85, 0.98) for females, and 0.91(0.87, 0.95) for meta-analyses] and all-cause mortality [0.90(0.88, 0.93) for male, 0.88(0.85, 0.92) for female, and 0.89(0.87, 0.91) for meta-analyses]. Further analyses showed decreased risks of all-neoplasm mortality was observed with good compliance [0.72(0.67, 0.77) for male and 0.72(0.65, 0.80) for female] and increased risks with poor compliance [1.61(1.40, 1.85) for male and 1.30(1.13, 1.40) for female]. Conclusion: Joint cancer screening could be recommended as a potentially strategy to reduce the overall cancer burden. More compliance, more benefits. However, organizing a joint cancer screening not only requires more ingenious design, but also needs more attentions to the potential harms. Trial registration: NCT00002540 (Prostate), NCT01696968 (Lung), NCT01696981 (Colorectal), NCT01696994 (Ovarian).
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Background: Previous studies focused more on the short-term risk of cardiovascular (CV) death due to traumatic psychological stress after a cancer diagnosis and the acute cardiotoxicity of anticancer treatments than on the long-term risk of CV death. Methods: Time trends in the proportions of CV death (PCV), cancer death (PCA), and other causes in deaths from all causes were used to show preliminary relationships among the three causes of death in 4,806,064 patients with cancer from the Surveillance, Epidemiology, and End Results (SEER) program. Competing mortality risk curves were used to investigate when the cumulative CV mortality rate (CMRCV) began to outweigh the cumulative cancer mortality rate (CMRCA) for patients with cancer who survived for more than 10 years. Multivariable competing risk models were further used to investigate the potential factors associated with CV death. Results: For patients with cancer at all sites, the PCV increased from 22.8% in the 5th year after diagnosis to 31.0% in the 10th year and 35.7% in the 20th year, while the PCA decreased from 57.7% in the 5th year after diagnosis to 41.2 and 29.9% in the 10th year and 20th year, respectively. The PCV outweighed the PCA (34.6% vs. 34.1%) since the 15th year for patients with cancer at all sites, as early as the 9th year for patients with colorectal cancer (37.5% vs. 33.2%) and as late as the 22nd year for patients with breast cancer (33.5% vs. 30.6%). The CMRCV outweighed the CMRCA since the 25th year from diagnosis. Multivariate competing risk models showed that an increased risk of CV death was independently associated with older age at diagnosis [hazard ratio and 95% confidence intervals [HR (95%CI)] of 43.39 (21.33, 88.28) for ≥ 80 vs. ≤ 30 years] and local metastasis [1.07 (1.04, 1.10)] and a decreased risk among women [0.82 (0.76, 0.88)], surgery [0.90 (0.87, 0.94)], and chemotherapy [0.85 (0.81, 0.90)] among patients with cancer who survived for more than 10 years. Further analyses of patients with cancer who survived for more than 20 years and sensitivity analyses by cancer at all sites showed similar results. Conclusion: CV death gradually outweighs cancer death as survival time increases for most patients with cancer. Both the cardio-oncologist and cardio-oncology care should be involved to reduce CV deaths in long-term cancer survivors.
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We report the direct formation of dicarboxylate-based coordination polymer glasses through thermal dehydration. The rearrangement of the coordination networks caused by dehydration was monitored by in situ powder X-ray diffraction, infrared spectroscopy, and synchrotron X-ray characterizations. The microporosity and mechanical properties of these glasses were investigated.
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Sewage sludge (SS) is a frequent and challenging issue for countries with big populations, due to its massive output, significant hazard potential, and challenging resource utilization. Pyrolysis can simultaneously realize the reduction, harmlessness and recycling of SS. Co-pyrolysis offers a wide range of potential in terms of increasing product quality and immobilizing heavy metals (HMs), thanks to its capacity to use additives to address the mismatch between SS characteristics and pyrolysis. High-value utilization potential of SS biochar is the key to evaluating the advancement of treatment technology. A further requirement for using biochar resources is the immobilization and bioavailability reduction of HMs. Due to the catalytic and synergistic effects in the co-pyrolysis process, co-pyrolysis SS biochar exhibits enhanced functionality and has been applied in soil improvement, pollutant adsorption and catalytic reactions. This review focuses on the research progress of different additives in improving the functionality of biochar and influencing the behavior of HMs. The key limitation and challenges in SS co-pyrolysis are then discussed. Future research prospects are detailed from seven perspectives, including pyrolysis process optimization, co-pyrolysis additive selection, catalytic mechanism research of process and product, biochar performance improvement and application field expansion, cooperative immobilization of HMs, and life cycle assessment. This review will offer recommendations and direction for future research paths, while also assist pertinent researchers in swiftly understanding the current state of SS pyrolysis research field.
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Metais Pesados , Esgotos , Pirólise , Carvão VegetalRESUMO
Objectives: Despite the increasing use of computed tomography (CT), chest X-ray (CXR) remains the first-line investigation for suspected lung cancer (LC) in primary care. However, the associations of CXR trajectories, smoking and LC risk remain unknown. Methods: A total of 52,486 participants from the PLCO and 22,194 participants from the NLST were included. The associations of CXR trajectories with LC risk were evaluated with multivariable COX regression models and pooled with meta-analyses. Further analyses were conducted to explore the stratified associations by smoking status and the factors associated with progression and regression in CXR. Results: Compared to stable negative CXR (CXRSN), HRs (95%CIs) of LC incidence were 2.88(1.50-5.52), 3.86(2.03-7.35), and 1.08(0.80-1.46) for gain of positive CXR (CXRGP), stable positive CXR (CXRSP), and loss of positive CXR (CXRLP), while the risk of LC mortality were 1.58(1.33-1.87), 2.56(1.53-4.29), and 1.05(0.89-1.25). Similar trends were observed across different smoking status. However, LC risk with CXRGP overweighed that with CXRSP among ever smokers [2.95(2.25-3.88) vs. 2.59(1.33-5.02)] and current smokers [2.33(1.70-3.18) vs. 2.26(1.06-4.83)]. Moreover, compared to CXRSN among never smokers, even no progression in CXR, the HRs(95%CIs) of LC incidence were 7.39(5.60-9.75) and 31.45(23.58-41.95) for ever and current smokers, while risks of LC mortality were 6.30(5.07-7.81) and 27.17(21.65-34.11). If participants gained positive CXR, LC incidence risk significantly climbed to 22.04(15.37-31.60) and 71.97(48.82-106.09) for ever and current smokers, while LC mortality risk climbed to 11.90(8.58-16.50) and 38.92(27.04-56.02). CXRLP was associated with decreased LC risk. However, even smokers lost their positive CXR, and the increased risks of LC incidence and mortality did not decrease to non-significant level. Additionally, smoking was significantly associated with increased risk of CXRGP but not CXRLP. Conclusion: LC risk differed across CXR trajectories and would be modified by smoking status. Comprehensive intervention incorporating CXR trajectories and smoking status should be recommended to reduce LC risk.
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BACKGROUND: Although prostate-specific antigen (PSA) is widely used in prostate cancer (PCa) screening, nearly half of PCa cases are missed and less than one-third of cases are non-lethal. Adopting diagnostic criteria in population-based screening and ignoring PSA progression are presumed leading causes. METHODS: A total of 31,942 participants with multi-round PSA tests from the PLCO trial were included. Time-dependent receiver-operating-characteristic curves and area under curves (tdAUCs) were performed to determine the screening reference level and the optimal subgroup-specific progression indicator. Effects of risk-stratified multi-round PSA screening were evaluated with multivariable Cox regression and measured with hazard ratio [HR (95%CIs)]. RESULTS: After a median follow-up of 11.6 years, a total of 3484 PCa cases and 216 PCa deaths were documented. The tdAUC of 10-year incidence PCa with PSA was 0.816, and the cut-off value was 1.61 ng/ml. Compared to subgroup with stable negative PSA in both first-round (FR) and last-round (LR) tests [FR(-)/LR(-)], HRs (95%CI) of PCa incidence were 1.66 (1.20-2.29), 8.29 (7.25-9.48), and 14.52 (12.95-16.28) for subgroups with loss of positive PSA[FR(+)/LR(-)], gain of positive PSA[FR(-)/LR(+)], and stable positive PSA[FR(+)/LR(+)]; while HRs(95%CI) of PCa mortality were 1.47 (0.52-4.15), 5.71 (3.68-8.86), and 5.01 (3.41-7.37). After excluding regressive PSA [(namely FR(+)/LR(-)], absolute velocity was the shared optimal progression indicator for subgroups with FR(-)/LR(-), FR(-)/LR(+), and FR(+)/LR(+), with tdAUCs of 0.665, 0.681 and 0.741, and cut-off values of 0.07, 0.21, and 0.33 ng/ml/year. After reclassifying participants into groups with positive and negative progression based on subgroup-specific progression indicators, incidence HR (95%CI) were 2.41 (1.87-3.10), 2.91 (2.43-3.48), and 3.16 (2.88-3.46) for positive progression compared to negative progression within subgroups of FR(-)/LR(-), FR(-)/LR(+), and FR(+)/LR(+), while mortality HR (95%CI) were 2.22 (0.91-5.38), 2.37 (1.28-4.38), and 2.98 (1.94-4.59). To improve screening performances by excluding regressive PSA and low-risk positive progression in FR(-)/LR(-), optimized screening strategy not only significantly reduce 32.4% of missed PCa (54.0% [1881/3484] vs. 21.6% [754/3484], P < 0.001), but also detected additional 8.0% of high-grade PCa (Gleason score 7-10: 36.0% [665/1849] vs. 28.0% [206/736], P < 0.001) than traditional screening strategy. CONCLUSIONS: Risk-stratified multi-round PSA screening strategy integrating the screening reference level and the optimal subgroup-specific progression indicator of PSA could be recommended as a fundamental strategy to reduce missed diagnosis and improve the detection of high-grade PCa cases.