Nonplanar Nanographene with a Large Conjugated π-Surface.

Conjugated π-surfaces are ubiquitous in molecules and materials. However, large π-surfaces up to a few nanometers in size are difficult to construct in an atomically precise manner. They tend to aggregate because of strong π-π interactions, resulting in notorious problems for both purification and spectroscopic investigations. Here, by contrast, we report the design, synthesis, and full characterizations of a nonplanar nanographene 1, which has a large, precise, and nonstacked π-surface. It is soluble in common organic solvents and allows for thorough investigations. The structure of 1, comprising 85 fused rings with an extended π-surface of 3 nm in size, is unambiguously confirmed by single-crystal X-ray diffraction. Unusual electronic structures, record-high near-infrared absorption, pronounced magnetic shielding, and ultrastrong heteromolecular van der Waals complexations are demonstrated, enabling us to establish a clear structure-property relationship, which has been elusive for decades. These results have broad implications for studying and understanding various phenomena and processes relevant to both discrete and interacting π-surfaces.

Steerable Interfacial Assembly of 1D Amyloid-Like Protein Nanocomposites for Enhanced Nanoherbicide Utilization.

Conventional herbicide formulations suffer from serious problems such as easy drift, run-off and scouring into the environment, which pose enormous threats to human health and environmental safety. Herein, an innovative strategy is proposed to prepare oil-in-water nanoemulsions with long-term stability, enhanced droplet deposition, and improved nanoherbicide adhesion via steerable interfacial assembly of 1D amyloid-like protein nanocomposites. Bovine serum albumin (BSA) undergoes rapid amyloid-like aggregation upon reduction of its disulfide bond. The resulting phase-transitioned BSA (PTB) oligomers instantly self-assemble on the surface of cellulose nanofibers (CNF) to form the 1D PTB/CNF nanocomposites, which greatly expands the parameter space for interfacial assembly of amyloid-like proteins. The PTB/CNF nanocomposites exhibit excellent interfacial activity, enabling spontaneous adsorption at the oil-water interface to stabilize nanoemulsion. The excess PTB/CNF nanocomposites would also self-assemble at the air-aqueous interface upon spraying, resulting in efficient droplet deposition on (super)hydrophobic leaves. The deposited nanoherbicides show excellent resistance to wind/rain corrosion due to the robust amyloid-mediated adhesion, with a retention rate of more than 80% after severe scouring. Consequently, herbicide applications can be reduced by at least 30% compared to commercial emulsifiable concentrates, showing greater herbicidal efficiency. This study provides novel insights and approaches to promote sustainable agricultural development.

Adipose lipolysis is important for ethanol to induce fatty liver in the National Institute on Alcohol Abuse and Alcoholism murine model of chronic and binge ethanol feeding.

BACKGROUND AND AIMS: Alcohol-associated liver disease (ALD) pathologies include steatosis, inflammation, and injury, which may progress to fibrosis, cirrhosis, and cancer. The liver receives ~60% of fatty acids from adipose tissue triglyceride hydrolysis, but the role of this lipolytic pathway in ALD development has not been directly examined in any genetic animal models with selective inactivation of adipose lipolysis. APPROACH AND RESULTS: Using adipose-specific comparative gene identification-58 (CGI-58) knockout (FAT-KO) mice, a model of impaired adipose lipolysis, we show that mice deficient in adipose lipolysis are almost completely protected against ethanol-induced hepatic steatosis and lipid peroxidation when subjected to the National Institute on Alcohol Abuse and Alcoholism chronic and binge ethanol feeding model. This is unlikely due to reduced lipid synthesis because this regimen of ethanol feeding down-regulated hepatic expression of lipogenic genes similarly in both genotypes. In the pair-fed group, FAT-KO relative to control mice displayed increased hepatocyte injury, neutrophil infiltration, and activation of the transcription factor signal transducer and activator of transcription 3 (STAT3) in the liver; and none of these were exacerbated by ethanol feeding. Activation of STAT3 is associated with a marked increase in hepatic leptin receptor mRNA expression and adipose inflammatory cell infiltration. CONCLUSIONS: Our findings establish a critical role of adipose lipolysis in driving hepatic steatosis and oxidative stress during ALD development.

Robotic Versus Thoracoscopic Sub-lobar Resection for Octogenarians with Clinical Stage IA Non-small Cell Lung Cancer: A Propensity Score-Matched Real-World Study.

BACKGROUND: Minimally invasive sub-lobectomy is sufficient in treating small early-stage non-small cell lung cancer (NSCLC). However, comparison of the feasibility and oncologic efficacy between robot-assisted thoracoscopic surgery (RATS) and video-assisted thoracoscopic surgery (VATS) in performing sub-lobectomy for early-stage NSCLC patients age 80 years or older is scarce. METHODS: Octogenarians with clinical stage IA NSCLC (tumor size, ≤ 2 cm) undergoing minimally invasive wedge resection or segmentectomy at Shanghai Chest Hospital from 2011 to 2020 were retrospectively reviewed from a prospectively maintained database. Propensity score-matching (PSM) with a RATS versus VATS ratio of 1:4 was performed. Perioperative and long-term outcomes were analyzed. RESULTS: The study identified 594 patients (48 RATS and 546 VATS patients), and PSM resulted in 45 cases in the RATS group and 180 cases in the VATS group. The RATS patients experienced less intraoperative bleeding (60 mL [interquartile range (IQR), 50-100 mL] vs. 80 mL [IQR, 50-100 mL]; P = 0.027) and a shorter postoperative hospital stay (4 days [IQR, 3-5 days] vs. 5 days [IQR, 4-6 days]; P = 0.041) than the VATS patients. The two surgical approaches were comparable concerning other perioperative outcomes and postoperative complications (20.00% vs. 26.11%; P = 0.396). Additionally, during a median follow-up period of 66 months, RATS and VATS achieved comparable 5-year overall survival (90.48% vs. 87.93%; P = 0.891), recurrence-free survival (83.37% vs. 83.18%; P = 0.782), and cumulative incidence of death. Further subgroup comparison also demonstrated comparable long-term outcomes between the two approaches. Finally, multivariate Cox analysis indicated that the surgical approach was not independently correlated with long-term outcomes. CONCLUSIONS: The RATS approach shortened the postoperative hospital stay, reduced intraoperative bleeding by a statistically notable but clinically insignificant amount, and achieved long-term outcomes comparable with VATS in performing sub-lobectomy for octogenarians with early-stage small NSCLC.

Realizing Stable Luminescence in Antimony Doped Hybrid Tin(IV) Chloride toward Full Spectrum WLED and Anticounterfeiting Applications.

The outstanding optical properties empower Sb3+-doped zero-dimensional hybrid metal halides as cutting-edge luminescent materials. In this research, we present an efficient hybrid tin chloride, TEA2SnCl6:Sb3+ (TEA = tetraethylammonium), with broad dual emission bands peaking in the blue and orange regions that arise from the singlet and triplet state emissions of [SbCl5]2-, respectively. TEA2SnCl6:Sb3+ demonstrates a high photoluminescence quantum yield (PLQY) of 83.5% under 328 nm excitation, while 358 nm light induces an orange emission with a PLQY of 92.5% and a low thermal quenching behavior (73.9% at 423 K). Benefiting from the appealing luminescence properties of TEA2SnCl6:Sb3+, a full spectrum white light-emitting diode (WLED) device and an anticounterfeiting model were constructed, affirming the potential use of Sb3+-doped TEA2SnCl6 hybrid metal halide in versatile application fields.

Causal association between Helicobacter pylori infection and Sjogren's syndrome: a bidirectional Mendelian randomization analysis.

BACKGROUND: The results of observational studies indicate a potential link between Helicobacter pylori infection and Sjogren's syndrome (SS), but the causal relationship between them remains unknown. This study applied Mendelian randomization (MR) to evaluate this relationship. METHOD: Genome-wide association study (GWAS) summary statistics on H. pylori infection [sample size=8735 (EBI, https://gwas.mrcieu.ac.uk/ )] and SS [sample size=368,028 (cases=2495, controls=365533) (FinnGen, https://r9.finngen.fi/ )] were analyzed. We used bidirectional MR to evaluate the association between H. pylori infection and SS and identify causation. The major MR analysis method was inverse-variance weighted (IVW) MR, supplemented by MR‒Egger and weighted median approaches. In addition, the stability and reliability of the results were tested using the retention method, heterogeneity test, and horizontal gene pleiotropy test. RESULTS: Evidence of the impact of H. pylori infection on SS risk was found in the IVW results [odds ratio (OR)=1.6705; 95% confidence interval (CI)=1.0966 to 2.5446; P=0.0168]. Evidence of the impact of SS on H. pylori infection risk was also found (OR=1.0158; 95% CI=1.0033 to 1.0285; P=0.0128). CONCLUSION: The results of MR analysis support a causal association between H. pylori infection and SS and indicate that SS can lead to a greater risk of H. pylori infection. Our research will support the development of novel approaches for continued H. pylori and SS-related research and therapy that consider the genetic relationship between H. pylori infection and SS.

Multimedia Mercury Recovery from Coal-Fired Power Plants Utilizing N-Containing Conjugated Polymer Functionalized Fly Ash.

To recover multimedia mercury from coal-fired power plants, a novel N-containing conjugated polymer (polyaniline and polypyrrole) functionalized fly ash was prepared, which could continuously adsorb 99.2% of gaseous Hg0 at a high space velocity of 368,500 h-1 and nearly 100% of aqueous Hg2+ in the solution pH range of 2-12. The adsorption capacities of Hg0 and Hg2+ reach 1.62 and 101.36 mg/g, respectively. Such a kind of adsorbent has good environmental applicability, i.e. good resistance to coexisting O2/NO/SO2 and coexisting Na+/K+/Ca2+/Mg2+/SO42-. This adsorbent has very low specific resistances (6 × 106-5 × 109 Ω·cm) and thus can be easily collected by an electrostatic precipitator under low-voltage (0.1-0.8 kV). The Hg-saturated adsorbent can desorb almost 100% Hg under relatively low temperature (<250 °C). Characterization and theoretical calculations reveal that conjugated-N is the critical site for adsorbing both Hg0 and Hg2+ as well as activating chlorine. Gaseous Hg0 is oxidized and adsorbed in the form of HgXClX(ad), while aqueous Hg2+ is adsorbed to form a complex with conjugated-N, and parts of Hg2+ are reduced to Hg+ by conjugated-N. This adsorbent can be easily large-scale manufactured; thus, this novel solid waste functionalization method is promising to be applied in coal-fired power plants and other Hg-involving industrial scenes.

Photocatalytic Reduction of Perrhenate and Pertechnetate in a Strongly Acidic Aqueous Solution.

Pertechnetate (99TcO4-), a physiologically toxic radioactive anion, is of great concern due to its high mobility in environmental contamination remediation. Although the soluble oxyanion can be photoreduced to sparingly soluble TcO2·nH2O, its effective removal from a strongly acidic aqueous solution remains a challenge. Here, we found that low-crystalline nitrogen-doped titanium oxide (N-TiO2, 0.6 g L-1) could effectively uptake perrhenate (ReO4-, 10 mg L-1, a nonradioactive surrogate for TcO4-) with 50.8% during 360 min under simulated sunlight irradiation at pH 1.0, but P25 and anatase could not. The nitrogen active center formed by trace nitrogen doping in N-TiO2 can promote the separation and transfer of photogenerated carriers. The positive valence band value of N-TiO2 is slightly higher than those of P25 and anatase, which means that the photogenerated holes have a stronger oxidizability. These holes are involved in the formation of strong reducing •CO2- radicals from formic acid oxidation. The active radicals convert ReO4- to Re(VI), which is subsequently disproportionated to Re(IV) and Re(VII). Effective photocatalytic reduction/removal of Re(VII)/Tc(VII) is performed on the material, which may be considered a potential and convenient strategy for technetium decontamination and extraction in a strongly acidic aqueous solution.

Rational design of a two-dimensional high-temperature ferromagnet from HCP cobalt.

Cobalt has the highest Curie temperature (Tc) among the elemental ferromagnetic metals and has a hexagonal close-packed (HCP) structure at room temperature. In this study, HCP Co was thinned to the thickness of several (n) unit cells along the c-axis and then passivated by halogen atoms, thus being named Co2nX2 (X = F, Cl, Br and I). For Co2X2 and Co3X2, all of them are not only kinetically but also thermodynamically stable from the viewpoint of the phonon spectra and molecular dynamics. Similar to HCP Co, two-dimensional (2D) Co2F2, Co2Cl2 and Co3X2 (X = Cl, Br and I) are still ferromagnetic metals within the Stoner model but Co2X2 (X = Br and I) is a ferromagnetic half-metal with the coexistence of the metallic behavior for one spin and the insulating behavior for the other spin. Taking into account the spin-orbital coupling (SOC), the easy-magnetization axis is within the plane where the magnetization is isotropic, making it look like a 2D XY magnet. Applying a critical biaxial strain could lead to an easy-magnetization axis changing from the in-plane to the out-of-plane direction. Finally, we use classical Monte Carlo simulations to estimate the Curie temperature (Tc) which is as high as 957 and 510 K for Co2F2 and Co2Cl2, respectively, because of the strong direct exchange interaction. Different from being obtained by mechanical or liquid exfoliation from van der Waals layered structures, our study opens up new possibilities to search for novel 2D ferromagnets from the elemental ferromagnets and provides opportunities for realizing realistic ultra-thin spintronic devices.

Association of PM2.5 exposure in early pregnancy and maternal liver function: A retrospective cohort study in Shenzhen, China.

OBJECTIVE: Studies have shown that fine particulate matter (PM2.5) has adverse effects on the liver function, but epidemiological evidence is limited, especially regarding pregnant women. This study aims to investigate the association between PM2.5 exposure in early pregnancy and maternal liver function during pregnancy. METHODS: This retrospective cohort study included 13,342 pregnant participants. PM2.5 and Ozone (O3) exposure level, mean temperature, and relative humidity for each participant were assessed according to their residential address. The levels of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (TBIL) were measured during the second and third trimesters. Data on PM2.5 and O3 exposure level were sourced from Tracking Air Pollution in China (TAP), while the mean temperature and relative humidity were obtained from the ERA5 dataset. The Generalized Additive Model (GAM) was used to analyze the associations between PM2.5 exposure and maternal liver function during pregnancy, adjusting for potential confounding factors. RESULTS: According to the results, each 10 µg/m3 increase in PM2.5 was associated with an increase of 3.57% (95% CI: 0.29%, 6.96%) in ALT and 4.25% (95% CI: 2.33%, 6.21%) in TBIL during the second trimester and 4.51% (95% CI: 2.59%, 6.47%) in TBIL during the third trimester, respectively. After adjusting for O3, these associations remained significant, and the effect of PM2.5 on ALT during the second trimester was further strengthened. No significant association observed between PM2.5 and AST. CONCLUSIONS: PM2.5 exposure in early pregnancy is associated with increasement of maternal ALT and TBIL, suggesting that PM2.5 exposure may have an adverse effect on maternal liver function. Although this finding indicates an association between PM2.5 exposure and maternal liver function, more research is needed to confirm our findings and explore the underlying biological mechanisms.

High lipoprotein(a) concentration is associated with moyamoya disease.

BACKGROUND: Moyamoya disease (MMD) has attracted the attention of scholars because of its rarity and unknown etiology. METHODS: Data for this study were sourced from the Second Affiliated Hospital of Nanchang University. Regression analyses were conducted to examine the association in Lipoprotein [Lp(a)] and MMD. R and IBM SPSS were conducted. RESULTS: A cohort comprising 1012 MMD patients and 2024 controls was established through the propensity score matching method. Compared with controls, MMD patients showed higher median Lp(a) concentrations [18.5 (9.6-37.8) mg/dL vs. 14.9 (7.8-30.5) mg/dL, P < 0.001]. The odds ratios and 95% confidence intervals for Lp(a) were calculated in three models: unadjusted model, model 1 (adjusted for body mass index and systolic blood pressure), and model 2 (adjusted for model 1 plus triglyceride, C-reactive protein, homocysteine, and low-density lipoprotein cholesterol). Results were [1.613 (1.299-2.002), P < 0.001], [1.598 (1.286-1.986), P < 0.001], and [1.661 (1.330-2.074), P < 0.001], respectively. Furthermore, age, sex, or hypertension status had nothing to do with this relationship. CONCLUSIONS: Positive relationship exists between Lp(a) and MMD.

Decoupling the effects of air temperature change on soil erosion in Northeast China.

Changes in the air temperature tend to indirectly affect soil erosion by influencing rainfall, vegetation growth, economic development, and agricultural activities. In this study, the partial least squares-structural equation model (PLS-SEM) was used to decouple the impacts of temperature change on soil erosion in Northeast China from 2001 to 2019, and the indirect effect of temperature change on the pathways of natural and socioeconomic factors was analyzed. The results showed that temperature increase in Northeast China caused an increase in soil erosion by increasing rainfall and promoting economic development. Under the pathway of natural factors, in spring, the promoting effect on soil erosion under the influence of temperature change on rainfall was greater than the inhibiting effect on soil erosion under by the influence of temperature change on vegetation. In summer, the opposite effect was observed. Under the pathway of natural factors, over time, the promoting effect of temperature increase on soil erosion increased by 22.7%. Under the pathway of socioeconomic factors, temperature change not only aggravated soil erosion by promoting economic development, but also indirectly increased investments in agriculture and water conservation by improving the economy, thus inhibiting soil erosion to a certain extent. Over time, the contribution of temperature change to soil erosion through socioeconomic pathway was reduced by 44.4%. When the pathway of natural factors is compared with that of socioeconomics factors, temperature change imposed a more notable effect on the change in soil erosion through the socioeconomic pathway, indicating that human activities are the driving factors with a greater effect on soil erosion. Based on this, reasonable human intervention is an important means to alleviate soil erosion aggravation caused by rising temperatures.

Goal-directed fluid therapy during post-resection phase in low central venous pressure assisted laparoscopic hepatectomy: a randomized controlled superiority trial.

PURPOSE: The purpose of this prospective single blinded randomized controlled trial was to find out whether goal-directed fluid therapy (GDFT) strategy in post-transection period in low central venous pressure (CVP) assisted laparoscopic hepatectomy (LH) has more benefit than traditional fluid strategy. METHODS: Between April 2020 and Dec 2021, patients who were scheduled for laparoscopic liver resection surgery were eligible to participate in the study. Patients were randomly divided into two groups: control group that received traditional fluid strategy in post-transection period in low CVP assisted laparoscopic hepatectomy and GDFT strategy group that received GDFT strategy in post-transection period. The primary outcome parameter is the incidence of postoperative complications. Secondary outcome parameters include perioperative clinical outcomes, postoperative clinical outcomes, length of hospital stay after surgery, postoperative lactic acid, fluids and vasoactive medications during the operation. RESULTS: A total of 159 patients in the control group and 160 patients in the GDFT were included. Two groups had no significant difference in the incidence of postoperative complications including pneumonia (P = 0.34), acute kidney injury (P = 0.72), hepatic insufficiency (P = 0.25), pleural effusion (P = 0.08) and seroperitoneum (P = 1.00), respectively. The amount of perioperative urine output is fewer in GDFT group than in the control group (P = 0.0354), while other perioperative variables and postoperative variables were comparable between two groups. CONCLUSIONS: The results show the implementation of GDFT strategy is not associated with fewer postoperative complications. GDFT strategy did not result in improved outcomes in low CVP-assisted laparoscopic hepatectomy.

Surface Molecular Engineering for Fully Textured Perovskite/Silicon Tandem Solar Cells.

Developing large-scale monolithic perovskite/silicon tandem devices based on industrial Czochralski silicon wafers will likely have to adopt double-side textured architecture, given their optical benefits and low manufacturing costs. However, the surface engineering strategies that are widely used in solution-processed perovskites to regulate the interface properties are not directly applicable to micrometric textures. Here, we devise a surface passivation strategy by dynamic spray coating (DSC) fluorinated thiophenethylammonium ligands, combining the advantages of providing conformal coverage and suppressing phase conversion on textured surfaces. From the viewpoint of molecular engineering, theoretical calculation and experimental results demonstrate that introducing trifluoromethyl group provide more effective surface passivation through strong interaction and energy alignment by forming a dipole layer. Consequently, the DSC treatment of this bifunctional molecule enables the tandem cells based on industrial silicon wafers to achieve a certified stabilized power conversion efficiency of 30.89 %. In addition, encapsulated devices display excellent operational stability by retaining over 97 % of their initial performance after 600 h continuous illumination.

Achieving Record External Quantum Efficiency of 11.5 % in Solution-Processable Deep-Blue Organic Light-Emitting Diodes Utilizing Hot Exciton Mechanism.

High performance solution-processable deep-blue emitters with a Commission International de l'Eclairage (CIE) coordinate of CIEy≤0.08 are highly desired in ultrahigh-definition display. Although, deep-blue materials with hybridized local and charge-transfer (HLCT) excited-state feature are promising candidates, their rigidity and planar molecular structures limit their application in solution-processing technique. Herein, four novel deep-blue solution-processable HLCT emitters were first proposed by attaching rigid imide aliphatic rings as functional units onto the HLCT emitting core. The functional units not only improve solubility, enhance thermal properties and morphological stability of the emitting core, but also promote photoluminescence efficiency, balance charge carrier transport, and inhibit aggregation-caused quenching effect due to the weak electron-withdrawing property as well as steric hindrance. The corresponding solution-processable organic light-emitting diodes (OLEDs) substantiate an unprecedented maximum external quantum efficiency (EQEmax) of 11.5 % with an emission peak at 456 nm and excellent colour purity (full width at half maximum=56 nm and CIEy=0.09). These efficiencies represent the state-of-the-art device performance among the solution-processable blue OLEDs based on the "hot exciton" mechanism. This simple strategy opens up a new avenue for designing highly efficient solution-processable deep-blue organic luminescent materials.

Homoleptic Al(III) Photosensitizers for Durable CO2 Photoreduction.

Exploiting noble-metal-free systems for high-performance photocatalytic CO2 reduction still presents a key challenge, partially due to the long-standing difficulties in developing potent and durable earth-abundant photosensitizers. Therefore, based on the very cheap aluminum metal, we have deployed a systematic series of homoleptic Al(III) photosensitizers featuring 2-pyridylpyrrolide ligands for CO2 photoreduction. The combined studies of steady-state and time-resolved spectroscopy as well as quantum chemical calculations demonstrate that in anerobic CH3CN solutions at room temperature, visible-light excitation of the Al(III) photosensitizers leads to an efficient population of singlet excited states with nanosecond-scale lifetimes and notable emission quantum yields (10-40%). The results of transient absorption spectroscopy further identified the presence of emissive singlet and unexpectedly nonemissive triplet excited states. More importantly, the introduction of methyl groups at the pyrrolide rings can greatly improve the visible-light absorption, reducing power, and durability of the Al(III) photosensitizers. With triethanolamine, BIH (1,3-dimethyl-2-phenyl-2,3-dihydro-1H-benzo[d]imidazole), and an Fe(II)-quaterpyridine catalyst, the most methylated Al(III) photosensitizer achieves an apparent quantum efficiency of 2.8% at 450 nm for selective (>99%) CO2-to-CO conversion, which is nearly 28 times that of the unmethylated one (0.1%) under identical conditions. The optimal system realizes a maximum turnover number of 10250 and higher robustness than the systems with Ru(II) and Cu(I) benchmark photosensitizers. Quenching experiments using fluorescence spectroscopy elucidate that the photoinduced electron transfer in the Al(III)-sensitized system follows a reductive quenching pathway. The remarkable tunability and cost efficiency of these Al(III) photosensitizers should allow them as promising components in noble-metal-free systems for solar fuel conversion.

The predictive value of inflammatory biomarkers for major pathological response in non-small cell lung cancer patients receiving neoadjuvant chemoimmunotherapy and its association with the immune-related tumor microenvironment: a multi-center study.

BACKGROUND: Inflammatory biomarkers in the peripheral blood have been established as predictors for immunotherapeutic efficacy in advanced non-small cell lung cancer (NSCLC). Whether they can also predict major pathological response (MPR) in neoadjuvant setting remains unclear. METHODS: In this multi-center retrospective study, 122 and 92 stage I-IIIB NSCLC patients from six hospitals who received neoadjuvant chemoimmunotherapy followed by surgery were included in the discovery and external validation cohort, respectively. Baseline and on-treatment neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR) and systemic immune-inflammation index (SII) were calculated and associated with MPR. Furthermore, resected tumor samples from 37 patients were collected for RNA-sequencing to investigate the immune-related tumor microenvironment. RESULTS: In both the discovery and validation cohorts, the on-treatment NLR, dNLR, PLR, and SII levels were significantly lower in the patients with MPR versus non-MPR. On-treatment SII remained an independent predictor of MPR in multivariate logistic regression analysis. The area under the curve (AUC) of on-treatment SII for predicting MPR was 0.75 (95%CI, 0.67-0.84) in the discovery cohort. Moreover, the predictive value was further improved by combining the on-treatment SII and radiological tumor regression data, demonstrating an AUC of 0.82 (95%CI, 0.74-0.90). The predictive accuracy was validated in the external cohort. Compared with the SII-high group, patients with SII-Low were associated with the activated B cell receptor signaling pathway and a higher intratumoral immune cell infiltration level. CONCLUSIONS: On-treatment SII was independently associated with MPR in NSCLC patients receiving neoadjuvant chemoimmunotherapy. Further prospective studies are warranted.

Metabolic systems approaches update molecular insights of clinical phenotypes and cardiovascular risk in patients with homozygous familial hypercholesterolemia.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is an orphan metabolic disease characterized by extremely elevated low-density lipoprotein cholesterol (LDL-C), xanthomas, aortic stenosis, and premature atherosclerotic cardiovascular disease (ASCVD). In addition to LDL-C, studies in experimental models and small clinical populations have suggested that other types of metabolic molecules might also be risk factors responsible for cardiovascular complications in HoFH, but definitive evidence from large-scale human studies is still lacking. Herein, we aimed to comprehensively characterize the metabolic features and risk factors of human HoFH by using metabolic systems strategies. METHODS: Two independent multi-center cohorts with a total of 868 individuals were included in the cross-sectional study. First, comprehensive serum metabolome/lipidome-wide analyses were employed to identify the metabolomic patterns for differentiating HoFH patients (n = 184) from heterozygous FH (HeFH, n = 376) and non-FH (n = 100) subjects in the discovery cohort. Then, the metabolomic patterns were verified in the validation cohort with 48 HoFH patients, 110 HeFH patients, and 50 non-FH individuals. Subsequently, correlation/regression analyses were performed to investigate the associations of clinical/metabolic alterations with typical phenotypes of HoFH. In the prospective study, a total of 84 HoFH patients with available follow-up were enrolled from the discovery cohort. Targeted metabolomics, deep proteomics, and random forest approaches were performed to investigate the ASCVD-associated biomarkers in HoFH patients. RESULTS: Beyond LDL-C, various bioactive metabolites in multiple pathways were discovered and validated for differentiating HoFH from HoFH and non-FH. Our results demonstrated that the inflammation and oxidative stress-related metabolites in the pathways of arachidonic acid and lipoprotein(a) metabolism were independently associated with the prevalence of corneal arcus, xanthomas, and supravalvular/valvular aortic stenosis in HoFH patients. Our results also identified a small marker panel consisting of high-density lipoprotein cholesterol, lipoprotein(a), apolipoprotein A1, and eight proinflammatory and proatherogenic metabolites in the pathways of arachidonic acid, phospholipid, carnitine, and sphingolipid metabolism that exhibited significant performances on predicting first ASCVD events in HoFH patients. CONCLUSIONS: Our findings demonstrate that human HoFH is associated with a variety of metabolic abnormalities and is more complex than previously known. Furthermore, this study provides additional metabolic alterations that hold promise as residual risk factors in HoFH population.

Neoadjuvant Chemoimmunotherapy Increases Tumor Immune Lymphocytes Infiltration in Resectable Non-small Cell Lung Cancer.

BACKGROUND: Neoadjuvant chemoimmunotherapy treatment (NCIT) has achieved great success for non-small cell lung cancer (NSCLC); however, the intrinsic mechanism underlying this treatment remains unclear. METHODS: Thirty-two patients with stage IIA-IIIC NSCLC who underwent surgery after NCIT were included in this retrospective study. Multiplex immunofluorescence (mIF) staining and image analysis assays were performed on the samples collected before and after NCIT for each patient. RNA analyses was applied to confirm the mIF results. RESULTS: Among the enrolled patients, 14 achieved major pathological response or pathological complete response (pCR) and were defined as the 'response' group, whereas 18 patients did not respond well to NCIT and were defined as the 'nonresponse' group. The results of the mIF assays revealed an overall increase in tumor immune lymphocytes (TILs) after NCIT in the stroma area (p = 0.03) rather than the tumor area (p = 0.86). The percentage of CD8+ T cells and tertiary lymphoid structure counts in both the response and nonresponse groups increased significantly after NCIT compared with before NCIT. CD3+ T cells and FOXP3+ cells decreased significantly in the response group but remained unchanged or increased in the nonresponse group. A comparison of the response and nonresponse groups showed that CD3, FOXP3+ and CD8+/PD-1+ cells before NCIT may serve as predictors of the response to neoadjuvant immunotherapy. The RNA analyses confirmed the mIF results that TILs were elevated after NCIT. CONCLUSIONS: The infiltration of immune cells before NCIT was correlated with pathologic complete response, which enhanced the TILs as a promising predictor for selecting patients who were more likely to benefit from NCIT.

Non-linear modifications enhance prediction of pathological response to pre-operative PD-1 blockade in lung cancer: A longitudinal hybrid radiological model.

Major pathologic remission (MPR, residual tumor <10%) is a promising clinical endpoint for prognosis analysis in patients with lung cancer receiving pre-operative PD-1 blockade therapy. Most of the current biomarkers for predicting MPR such as PD-L1 and tumor mutation burden (TMB) need to be obtained invasively. They cannot overcome the spatiotemporal heterogeneity or provide dynamic monitoring solutions. Radiomics and artificial intelligence (AI) models provide a practical tool enabling non-invasive follow-up observation of tumor structural information through high-throughput data analysis. Currently, AI-based models mainly focus on the single baseline scan or pipeline, namely sole radiomics or deep learning (DL). This work merged the delta-radiomics based on the slope of classic radiomics indexes within a time interval and the features extracted by deep networks from the subtraction between the baseline and follow-up images. The subtracted images describing the tumor changes were based on the transformation generated by registration. Stepwise optimization of components was performed by repeating experiments among various combinations of DL networks, registration methods, feature selection algorithms, and classifiers. The optimized model could predict MPR with a cross-validation AUC of 0.91 and an external validation AUC of 0.85. A core set of 27 features (eight classic radiomics, 15 delta-radiomics, one classic DL features, and three delta-DL features) was identified. The changes in delta-radiomics indexes during the treatment were fitted with mathematic models. The fitting results revealed that over half of the features were of non-linear dynamics. Therefore, non-linear modifications were made on eight features by replacing the original features with non-linear fitting parameters, and the modified model achieved an improved power. The dynamic hybrid model serves as a novel and promising tool to predict the response of lesions to PD-1 blockade, which implies the importance of introducing the non-linear dynamic effects and DL approaches to the original delta-radiomics in the future.