Anlotinib may enhance the efficacy of anti-PD1 therapy by inhibiting the AKT pathway and promoting the apoptosis of CAFs in lung adenocarcinoma.

Although PD-1 inhibitors have revolutionized the treatment paradigm of non-small cell lung cancer (NSCLC), their efficacy in treating NSCLC has remained unsatisfactory. Targeting cancer-associated fibroblasts (CAFs) is a potential approach for improving the immunotherapy response. Multitarget antiangiogenic tyrosine kinase receptor inhibitors (TKIs) can enhance the efficacy of PD-1 inhibitors in NSCLC patients. However, the effects and mechanisms of antiangiogenic TKIs on CAFs have not been elucidated. In this study, we first compared anlotinib with other antiangiogenic TKIs and confirmed the superior efficacy of anlotinib. Furthermore, we established NSCLC-associated CAF models and found that anlotinib impaired CAF viability and migration capacity and contributed to CAF apoptosis and cell cycle arrest in the G2/M phase. Moreover, anlotinib treatment attenuated the capacity of CAFs to recruit lung cancer cells and macrophages. Experiments in animal models suggested that anlotinib could enhance the efficacy of anti-PD1 therapy in NSCLC and affect CAF proliferation and apoptosis. Anlotinib increased the abundance of tumor-infiltrating CD8 + T cells, and PD-1 inhibitor-induced cytotoxicity to tumor cells was achieved through the transformation of the tumor microenvironment (TME) caused by anlotinib, which may partly explain the synergistic antitumor effect of anlotinib and PD-1 inhibitors. Mechanistically, anlotinib affects CAF apoptosis and cell viability at least in part by inhibiting the AKT pathway. In conclusion, our study suggested that anlotinib could regulate the TME, inhibit the AKT pathway and promote CAF apoptosis, providing new insights into the antitumor effect of anlotinib and improving the efficacy of immunotherapy.

Efficacy and immunogenicity of AS04-HPV-16/18 vaccine in females with existing cervical HR-HPV infection at first vaccination: A pooled analysis of four large clinical trials worldwide.

Females with existing high-risk HPV (HR-HPV) infections remain at risk of subsequent multiple or recurrent infections, on which benefit from HPV vaccines was under-reported. We pooled individual-level data from four large-scale, RCTs of AS04-HPV-16/18 vaccine to evaluate efficacy and immunogenicity in females DNA-positive to any HR-HPV types at first vaccination. Females receiving the AS04-HPV-16/18 vaccine in the original RCTs constituted the vaccine group in the present study, while those unvaccinated served as the control group. Vaccine efficacy (VE) against new infections and associated cervical intraepithelial neoplasia (CIN) 2+ in females DNA-negative to the considered HR-HPV type but positive to any other HR-HPV types, VE against reinfections in females DNA-positive to the considered HR-HPV type but cleared naturally during later follow-up, and levels of anti-HPV-16/18 IgG were assessed. Our final analyses included 5137 females (vaccine group = 2532, control group = 2605). The median follow-up time was 47.88 months (IQR: 45.72-50.04). For the prevention of precancerous lesions related to the non-infected HR-HPV types at baseline, VE against HPV-16/18 related CIN 2+ was 82.70% (95% CI: 63.70-93.00%). For the prevention of reinfections related to the infected HR-HPV types following natural clearance, VE against HPV-16/18 12MPI was non-significant (p > .05), albeit robust immunity persisted for at least 48 months. Females with existing HR-HPV infections at first vaccination still benefit from vaccination in preventing precancers related to the non-infected types at baseline. VE against reinfections related to the infected types following natural clearance remains to be further investigated.

Iodide and sulfite synergistically accelerate the photo-reduction and recovery of As(V) and As(III) in sulfite/iodide/UV process: Efficiency and mechanism.

Photo-reduction of arsenic (As) by hydrated electron (eaq-) and recovery of elemental arsenic (As(0)) is a promising pathway to treat As-bearing wastewater. However, previously reported sulfite/UV system needs large amounts of sulfite as the source of eaq-. This work suggests a sulfite/iodide/UV approach that is more efficient and consumes much less chemical reagents to remove As(III) and As(V) and recover valuable As(0) from wastewater, hence preventing the production of large amounts of As-containing hazardous wastes. Our results showed that more than 99.9% of As in the aqueous phase was reduced to highly pure solid As(0) (>99.5 wt%) by sulfite/iodide/UV process under alkaline conditions. Sulfite and iodide worked synergistically to enhance reductive removal of As. Compared with sulfite/UV, the addition of iodide had a substantially greater effect on As(III) (over 200 times) and As(V) (approximately 30 times) removals because of its higher absorptivity and quantum yield of eaq-. Furthermore, more than 90% of the sulfite consumption was decreased by adding a small amount of iodide while maintaining similar reduction efficiency. Hydrated electron (eaq-) was mainly responsible for As(III) and As(V) reductions and removals under alkaline conditions, while both SO3•- and reactive iodine species (e.g., I•, I2, I2•-, and I3-) may oxidize As(0) to As(III) or As(V). Acidic circumstances caused sulfite protonation and the scavenging of eaq- by competing processes. Dissolved oxygen (O2) and CO32- prevented As reduction by light blocking or eaq- scavenging actions, but Cl-, Ca2+, and Mg2+ showed negligible impacts. This study presented an efficient method for removing and recovering As from wastewater.

Early-stage neutralizing antibody level associated with the re-positive risk of Omicron SARS-CoV-2 RNA in patients recovered from COVID-19.

Post-discharge re-positivity of Omicron SARS-CoV-2 is challenging for the sufficient control of this pandemic. However, there are few studies about the risk of re-positivity. We aimed to explore the association of neutralizing antibodies (nAbs, AU/mL) with the incidence of re-positivity among patients recovered from COVID-19. A retrospective cohort study selected 318 Omicron-infected patients was conducted in China between December 2021 and April 2022. The peak value of nAb levels (nAb-peak) within 14 days of disease onset was defined as the baseline and was mainly used for the subsequent analyses. In the unadjusted, minimally adjusted, fully adjusted, and additionally adjusted for IgG models, a per-standard deviation (SD) increase in the nAb-peak values was significantly associated with a 59 %, 59 %, 50 %, and 75 % decreased risk of Omicron SARS-CoV-2 re-positivity during post-discharge surveillance, respectively. Stratified analyses showed no significant changes in the relationship between nAbs and re-positivity. Our study suggested that the increase in baseline nAb levels independently associated with a low risk of re-positivity in patients recovered from COVID-19.

Exploring the surface plasmon catalytic reactions mechanism by three-phase interface modification combining with in-situ EC-SERS methods.

Local surface plasmon resonance (LSPR) is a novel catalytic technique that has emerged in recent years, especially in the catalysis of aromatic amine compounds. However, the response process and mechanism are still unclear in current study. In the current field of study, the response process and mechanism are still unclear. In this work, the gas-liquid-solid three-phase interface (GLSTI) was innovatively utilized in this study to validate the reaction mechanism by surface-enhanced Raman spectroscopy. P-Aminothiophenol (PATP) and P-Phenylenediamine (PDA) underwent a surface plasmon-catalyzed reaction by using a silver nano-dendrites substrate with strong SERS activity. The GLSTI significantly facilitates the occurrence of surface plasmon catalytic reactions, which can supply enough oxygen by providing three-phase points. In situ SERS and EC-SERS technologies were combined in this study for the explorations. Therefore, this work is dedicated to deepening the exploration and expanding into new directions in plasmon-induced catalytic reactions.

Mitigating cadmium accumulation in dicotyledonous vegetables by iron fertilizer through inhibiting Fe transporter IRT1-mediated Cd uptake.

The solubility of cadmium (Cd) in soil and its transfer to plants are influenced by soil pH. While increasing soil pH reduces Cd solubility and accumulation in rice plants grown in acidic soils, its effect on Cd accumulation in vegetables remains inconclusive. Here, we investigated the impact of soil pH on Cd accumulation in dicotyledonous vegetables and elucidated the underlying molecular mechanisms. Soils collected from various locations were supplemented with varying quantities of lime to achieve soil pH values of around 5.0, 6.0, 7.0, and 8.0. Raising soil pH from around 5.0 to 8.0 markedly decreased extractable Cd. However, increasing soil pH tended to promote shoot Cd accumulation in dicotyledonous vegetable species including lettuce, pakchoi, and Chinese cabbage, and the model dicotyledonous plant Arabidopsis thaliana. Conversely, soil pH increase resulted in a monotonic decrease in rice Cd accumulation. In our hydroponic experiments, we discovered that iron (Fe) deficiency substantially increased Cd uptake and accumulation in dicotyledonous plants but not in rice. Increasing soil pH reduced soil Fe availability and induced the Fe transporter gene IRT1 expression in dicotyledonous vegetables roots, which led to an increase in IRT1-mediated Cd uptake and subsequently increased Cd accumulation as soil pH increases. A comprehensive model incorporating extractable Cd and root IRT1 expression better explained Cd accumulation in vegetable shoots. The application of 50 mg/kg of Fe fertilizer in neutral or alkaline soils resulted in a significant reduction in Cd accumulation by 34-58% in dicotyledonous vegetables. These findings reveal that increasing soil pH has two opposite effects, decreasing soil Cd availability while promoting Cd uptake through IRT1 upregulation, reconciling the inconsistency in its effect on Cd accumulation in dicotyledonous plants. Our findings provide important insights for understanding the factors affecting Cd uptake in plants and offer a practical solution to mitigate Cd contamination in vegetables.

Laser-Activatable In Situ Vaccine Enhances Cancer-Immunity Cycle.

The immune response in cancer reflects a series of carefully regulated events; however, current tumor immunotherapies typically address a single key aspect to enhance anti-tumor immunity. In the present study, a nanoplatform (Fe3 O4 @IR820@CpG)-based immunotherapy strategy that targets the multiple key steps in cancer-immunity cycle is developed: 1) promotes the release of tumor-derived proteins (TDPs), including tumor-associated antigens and pro-immunostimulatory factors), in addition to the direct killing effect, by photothermal (PTT) and photodynamic therapy (PDT); 2) captures the released TDPs and delivers them, together with CpG (a Toll-like receptor 9 agonist) to antigen-presenting cells (APCs) to promote antigen presentation and T cell activation; 3) enhances the tumor-killing ability of T cells by combining with anti-programmed death ligand 1 antibody (α-PD-L1), which collectively advances the outstanding of the anti-tumor effects on colorectal, liver and breast cancers. The broad-spectrum anti-tumor activity of Fe3 O4 @IR820@CpG with α-PD-L1 demonstrates that optimally manipulating anti-cancer immunity not singly but as a group provides promising clinical strategies.

Deciphering the Potential of Multidimensional Carbon Materials for Surface-Enhanced Raman Spectroscopy through Density Functional Theory.

Surface-enhanced Raman spectroscopy (SERS) is a potent analytical tool, particularly for molecular identification and structural analysis. Conventional metallic SERS substrates, however, suffer from low reproducibility and compatibility with biological molecules. Recently, metal-free SERS substrates based on chemical enhancement have emerged as a promising alternative with carbon-based materials offering excellent reproducibility and compatibility. Nevertheless, our understanding of carbon materials in SERS remains limited, which hinders their rational design. Here we systematically explore multidimensional carbon materials, including zero-dimensional fullerenes (C60), one-dimensional carbon nanotubes, two-dimensional graphene, and their B-, N-, and O-doped derivatives, for SERS applications. Using density functional theory, we elucidate the nonresonant polarizability-enhanced and resonant charge-transfer-based chemical enhancement mechanisms of these materials by evaluating their static/dynamic polarizability and electron excitation properties. This work provides a critical reference for the future design of carbon-based SERS substrates, opening a new avenue in this field.

A real-world analysis of trametinib in combination with hydroxychloroquine or CDK4/6 inhibitor as third- or later-line therapy in metastatic pancreatic adenocarcinoma.

BACKGROUND: There are no standard third-line treatment options for metastatic pancreatic ductal adenocarcinoma (mPDAC). Trametinib in combination with hydroxychloroquine (HCQ) or CDK4/6 inhibitors for pancreatic adenocarcinoma showed promising efficacy in preclinical studies. However, the regimens have not been well examined in patients with mPDAC. METHODS: Patients with mPDAC who received the combination of trametinib and HCQ or CDK4/6 inhibitors as third- or later-line therapy were reviewed. The efficacy and prognosis were further analyzed. RESULTS: A total of 13 mPDAC patients were enrolled, of whom 8 and 5 patients were treated with trametinib plus HCQ or a CDK4/6 inhibitor (palbociclib or abemaciclib), respectively. All enrolled patients had either KRAS G12D or G12V mutations and had received a median of 3 prior lines of therapy (range, 2-6). The median trametinib treatment duration was 1.4 months. Of the 10 patients with measurable disease, only 1 patient achieved stable disease, and the remaining patients had progressive disease. Moreover, in patients treated with trametinib plus HCQ and a CDK4/6 inhibitor, the median progression-free survival was 2.0 and 2.8 months, respectively, and the median overall survival was 4.2 and 4.7 months, respectively. Moreover, 5 (50%) patients experienced grade 3-4 adverse events in 10 patients with available safety data. CONCLUSIONS: The combination of trametinib and HCQ or CDK4/6 inhibitors may not be an effective later-line treatment for mPDAC, and the current preliminary findings need to be confirmed by other studies with larger sample sizes.

Health and economic impact of delaying large-scale HPV vaccination and screening implementation on cervical cancer in China: a modelling study.

Background: Current uptake of HPV vaccination and screening in China is far below World Health Organization 2030 targets for cervical cancer elimination. We quantified health and economic losses of delaying large-scale HPV vaccination and screening implementation in China. Methods: We used a previously validated transmission model to project lifetime health benefits, costs, effectiveness, and timeline for cervical cancer elimination of alternative scenarios, including combining HPV vaccination initiated from 2022 to 2030 with screening in different modalities and coverage increase rates, as well as screening alone. All women living or projected to be born in China during 2022-2100 were considered. We employed a societal perspective. Findings: Regardless of vaccine type, immediate large-scale vaccination initiated in 2022 and achieving 70% coverage of HPV-based screening in 2030 (no-delay scenario) would be the least costly and most effective. Compared with the no-delay scenario, delaying vaccination by eight years would result in 434,000-543,000 additional cervical cancer cases, 138,000-178,000 deaths, and $2863-4437 million costs, and delay elimination by 9-10 years. Even with immediate vaccination, the gradual scale-up of LBC-based screening to 70% coverage in 2070 would result in 2,530,000-3,060,000 additional cases, 909,000-1,040,000 deaths, and $5098-5714 million costs compared with no-delay scenario, and could not achieve elimination if domestic 2vHPV or 4vHPV vaccines are used (4.09-4.21 cases per 100,000 woman in 2100). Interpretation: Delaying large-scale HPV vaccination and/or high-performance screening implementation has detrimental consequences for cervical cancer morbidity, mortality, and expenditure. These findings should spur health authorities to expedite large-scale vaccine rollout and improve screening. Funding: Bill & Melinda Gates Foundation (INV-031449 and INV-003174) and CAMS Innovation Fund for Medical Sciences (CIFMS) (2021-I2M-1-004).

A novel SERS sensor array based on AuNRs and AuNSs inverse-etching for the discrimination of five antioxidants.

Antioxidants play an important role in life health and food safety. Herein, an inverse-etching platform based on gold nanorods (AuNRs) and gold nanostars (AuNSs) for high-throughput discrimination of antioxidants was constructed. Under the action of hydrogen peroxide (H2O2) and horseradish peroxidase (HRP), 3,3',5,5'-tetramethylbenzidine (TMB) would be oxidized to TMB+ or TMB2+. HRP reacts with H2O2 to release oxygen free radicals, which then react with TMB. Au nanomaterials can react with TMB2+, at the same time, Au was oxidized into Au (I), leading to the etching of the shape. Antioxidants, with good reduction ability, would prevent the further oxidation of TMB+ to TMB2+. So the presence of antioxidants will prevent further oxidation while avoiding the etching of Au in the catalytic oxidation process, thereby achieved inverse etching. Distinctive surface enhanced Raman scattering (SERS) fingerprint of five antioxidants were obtained based on the differential ability to scavenge free radicals. Five antioxidants, including ascorbic acid (AA), melatonin (Mel), glutathione (GSH), tea polyphenols (TPP), and uric acid (UA) were successfully distinguished by using linear discriminant analysis (LDA), heat map analysis and hierarchical cluster analysis (HCA). The study exhibits an effective inverse-etching based SERS sensor array for the response of antioxidants, which has great reference value in the field of human disease and food detection.

Enhancement of arsenic uptake and accumulation in green microalga Chlamydomonas reinhardtii through heterologous expression of the phosphate transporter DsPht1.

Arsenate (AsV) is a predominant arsenic contaminant in aerobic water. Microalgae have been recently used in the phytoremediation of arsenic-contaminated water. However, the amount of AsV uptake in microalgae is limited, which hinders the application of microalgae in arsenic-contaminated water treatment. Here, we found that the expression of a novel phosphate transporter DsPht1 in Dunaliella salina was highly upregulated after AsV exposure. Fluorescent protein-tagging analysis showed the plasma membrane location of DsPht1. Furthermore, DsPht1 was overexpressed in a model microalga Chlamydomonas reinhardtii. The DsPht1 transgenetic lines accumulated up to 6.4-fold higher total arsenic than the untransformed line, and the AsV amount in total arsenic increased by 8.3-fold. Moreover, the organoarsenic content was also higher in the transgenetic lines. Overall, the DsPht1 transformants generated in this study increased arsenate uptake and transformation, which are promising for the effective phytoremediation of arsenic-contaminated water.

3D-Printed Polylactic Acid/Lignin Films with Great Mechanical Properties and Tunable Functionalities towards Superior UV-Shielding, Haze, and Antioxidant Properties.

Three-dimensional (3D) printing is regarded as a novel technique to realize the customized production of films. However, the relative lack of printable materials with excellent mechanical properties and tailored functionalities seriously restricts its wide application. Herein, a promising multifunctional 3D printing filament was fabricated by incorporating lignin into the polylactic acid (PLA) matrix and firstly applied to film production. The results indicate that lignin was an excellent mechanical reinforcement of the PLA matrix, especially for toughening. Only 0.5% lignin doping improved the toughness by 81.8%. Additionally, 3D-printed films with 0.5-5% lignin exhibited excellent ultraviolet (UV)-blocking capability of 87.4-99.9% for UVB and 65.6-99.8% for UVA, as well as remarkable antioxidant properties, ranging from 24.0% to 79.0%, and high levels of haze, ranging from 63.5% to 92.5%. Moreover, the prepared PLA/lignin (P/L) films based on 3D printing achieved the customization of film production and have potential applications in the fields of packaging, electronic products, medical care, and so forth. Overall, this work not only enriches the 3D printing composites with tailored multifunctionality but also brings the promising potential for the production of customized films.

The prognostic role of WeChat-based instant doctor-patient communication in patients with advanced pancreatic cancer.

BACKGROUND: Patients with advanced pancreatic ductal adenocarcinoma (PDAC) need timely medical assistance since the emergence of complications due to the disease and antitumor treatment. Studies have confirmed that instant messaging can improve the quality of life and compliance of cancer patients. However, the prognostic role of instant doctor-patient communication based on instant messaging applications in PDAC has not been studied. METHODS: Patients with PDAC who received first-line chemotherapy at Peking Union Medical College Hospital between January 2015 and October 2022 were reviewed. We categorized patients into two groups according to whether they received WeChat-based instant doctor-patient communication, and the prognosis and toxicity data between the two groups were compared. RESULTS: A total of 431 PDAC patients were enrolled, of whom 163 had long-term instant communication with their doctors based on WeChat, and 268 did not receive WeChat-based instant communication. There was no significant correlation between WeChat-based communication and first-line chemotherapy overall response rate (14.1% vs. 8.6%, p = 0.074), incidence of grade ≥ 3 adverse events (66.9% vs. 65.7%, p = 0.814) or overall survival (14.7 vs. 13.9 months, p = 0.170) in all enrolled patients. However, patients who received WeChat-based instant communication had a higher completion rate of first-line chemotherapy (42.0% vs. 30.7%, p = 0.023). Consistently, in the patients who developed grade ≥ 3 adverse events (n = 231), those who received WeChat-based instant communication had significantly longer overall survival (17.3 vs. 15.3 months, p = 0.018), even after adjustment for biases. CONCLUSIONS: WeChat-based instant doctor-patient communication demonstrated no superiority in improving the efficacy of chemotherapy or preventing chemotherapy toxicity in PDAC patients, but it may contribute to improving the completion rate of chemotherapy and the prognosis in patients who experienced severe adverse events. IMPLICATIONS FOR CANCER SURVIVORS: Instant doctor‒patient communication may help to timely and appropriately deal with adverse events and prolong the survival time of patients with PDAC, supporting the promotion of mobile technology in clinical practice.

POSTN Secretion by Extracellular Matrix Cancer-Associated Fibroblasts (eCAFs) Correlates with Poor ICB Response via Macrophage Chemotaxis Activation of Akt Signaling Pathway in Gastric Cancer.

Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment, but its clinical benefit is limited in advanced gastric cancer (GC). Cancer-associated fibroblasts (CAFs) have been reported to be associated with ICB resistance, but the underlying mechanism has not been fully elucidated. Our previous single-cell RNA-seq analysis of GC revealed that POSTN+FAP+ extracellular matrix CAFs (eCAFs) communicate with macrophages. Here, we evaluated the correlation between eCAFs and ICB response in TCGA-STAD and real-world cohorts. Immune infiltration analysis and correlation analysis were performed to assess the relationship between eCAFs and macrophages. We first confirmed a negative correlation between the abundance of eCAFs and the overall response rate (ORR) to anti-PD-1 treatment in TCGA-STAD and real-world GC cohorts. Overexpression of POSTN in CAFs enhanced macrophage chemotaxis, while POSTN interference showed the opposite effect in vitro and in vivo. Furthermore, the cell density of POSTN+ CAFs was positively correlated with the infiltration level of CD163+ macrophages in GC patient tissues. The results demonstrated that POSTN secreted by CAFs enhances macrophage chemotaxis by activating the Akt signaling pathway in macrophages. Additionally, we found that POSTN+FAP+ eCAFs may exist in multiple solid tumors and are associated with ICB resistance. eCAFs promote macrophage chemotaxis through the secretion of POSTN, thereby leading to ICB resistance. High expression of POSTN is likely to predict a poor response to ICB. POSTN downregulation may be considered as a candidate therapeutic strategy to improve ICB efficacy.

Cost-effectiveness of the screen-and-treat strategies using HPV test linked to thermal ablation for cervical cancer prevention in China: a modeling study.

BACKGROUND: Self-sampling HPV test and thermal ablation are effective tools to increase screening coverage and treatment compliance for accelerating cervical cancer elimination. We assessed the cost-effectiveness of their combined strategies to inform accessible, affordable, and acceptable cervical cancer prevention strategies. METHODS: We developed a hybrid model to evaluate costs, health outcomes, and incremental cost-effectiveness ratios (ICER) of six screen-and-treat strategies combining HPV testing (self-sampling or physician-sampling), triage modalities (HPV genotyping, colposcopy or none) and thermal ablation, from a societal perspective. A designated initial cohort of 100,000 females born in 2015 was considered. Strategies with an ICER less than the Chinese gross domestic product (GDP) per capita ($10,350) were considered highly cost-effective. RESULTS: Compared with current strategies in China (physician-HPV with genotype or cytology triage), all screen-and-treat strategies are cost-effective and self-HPV without triage is optimal with the most incremental quality-adjusted life-years (QALYs) gained (220 to 440) in rural and urban China. Each screen-and-treat strategy based on self-collected samples is cost-saving compared with current strategies (-$818,430 to -$3540) whereas more costs are incurred using physician-collected samples compared with current physician-HPV with genotype triage (+$20,840 to +$182,840). For screen-and-treat strategies without triage, more costs (+$9404 to +$380,217) would be invested in the screening and treatment of precancerous lesions rather than the cancer treatment compared with the current screening strategies. Notably, however, more than 81.6% of HPV-positive women would be overtreated. If triaged with HPV 7 types or HPV16/18 genotypes, 79.1% or 67.2% (respectively) of HPV-positive women would be overtreated with fewer cancer cases avoided (19 cases or 69 cases). CONCLUSIONS: Screen-and-treat strategy using self-sampling HPV test linked to thermal ablation could be the most cost-effective for cervical cancer prevention in China. Additional triage with quality-assured performance could reduce overtreatment and remains highly cost-effective compared with current strategies.

Synchronous Modulation of Energy Level Gradient and Defects for High-Efficiency HTL-Free Carbon-Based All-Inorganic Perovskite Solar Cells.

In order to improve the thermal stability of perovskite solar cells (PSCs) and reduce production costs, hole transport layer (HTL)-free carbon-based CsPbI3 PSCs (C-PSCs) have attracted the attention of researchers. However, the power conversion efficiency (PCE) of HTL-free CsPbI3 C-PSCs is still lower than that of PSCs with HTL/ metal electrodes. This is because the direct contact between the carbon electrode and the perovskite layer has a higher requirement on the crystal quality of perovskite layer and matched energy level at perovskite/carbon interface. Herein, the acyl chloride group and its derivative trichloroacetyl chloride are used to passivate CsPbI3 C-PSCs for the first time. The results show that the carbonyl group of trichloroacetyl chloride can effectively passivate the uncoordinated Pb2+ ions in perovskite. At the same time, leaving group Cl- ions can increase the grain size of perovskite and improve the crystallization quality of perovskite layer. In addition, the trichloroacetyl chloride tends to generate cesium chloride acetate, which acts as an electron blocking layer, reduces charge recombination, promotes gradient energy level arrangement, and effectively improves the separation and extraction ability of carriers. The PCE of CsPbI3 HTL-free C-PSCs is successfully increased from 13.40% to 14.82%.

Establishment and validation of a nomogram model for predicting distant metastasis in medullary thyroid carcinoma: An analysis of the SEER database based on the AJCC 8th TNM staging system.

Objective: Medullary thyroid carcinoma (MTC) patients with distant metastases frequently present a relatively poor survival prognosis. Our main purpose was developing a nomogram model to predict distant metastases in MTC patients. Methods: This was a retrospective study based on the Surveillance, Epidemiology, and End Results (SEER) database. Data of 807 MTC patients diagnosed from 2004 to 2015 who undergone total thyroidectomy and neck lymph nodes dissection was included in our study. Independent risk factors were screened by univariate and multivariate logistic regression analysis successively, which were used to develop a nomogram model predicting for distant metastasis risk. Further, the log-rank test was used to compare the differences of Kaplan-Meier curves of cancer-specific survival (CSS) in different M stage and each independent risk factor groups. Results: Four clinical parameters including age > 55 years, higher T stage (T3/T4), higher N stage (N1b) and lymph node ratio (LNR) > 0.4 were significant for distant metastases at the time of diagnosis in MTC patients, and were selected to develop a nomogram model. This model had satisfied discrimination with the AUC and C-index of 0.894, and C-index was confirmed to be 0.878 through bootstrapping validation. A decision curve analysis (DCA) was subsequently made to evaluate the feasibility of this nomogram for predicting distant metastasis. In addition, CSS differed by different M stage, T stage, N stage, age and LNR groups. Conclusions: Age, T stage, N stage and LNR were extracted to develop a nomogram model for predicting the risk of distant metastases in MTC patients. The model is of great significance for clinicians to timely identify patients with high risk of distant metastases and make further clinical decisions.

Mechanistic insights into spontaneous transition from cellular alternans to ventricular fibrillation.

T-wave alternans (TWA) has been used for predicting the risk of malignant cardiac arrhythmias and sudden cardiac death (SCD) in multiple clinical settings; however, possible mechanism(s) underlying the spontaneous transition from cellular alternans reflected by TWA to arrhythmias in impaired repolarization remains unclear. The healthy guinea pig ventricular myocytes under E-4031 blocking IKr (0.1 µM, N = 12; 0.3 µM, N = 10; 1 µM, N = 10) were evaluated using whole-cell patch-clamp. The electrophysiological properties of isolated perfused guinea pig hearts under E-4031 (0.1 µM, N = 5; 0.3 µM, N = 5; 1 µM, N = 5) were evaluated using dual- optical mapping. The amplitude/threshold/restitution curves of action potential duration (APD) alternans and potential mechanism(s) underlying the spontaneous transition of cellular alternans to ventricular fibrillation (VF) were examined. There were longer APD80 and increased amplitude and threshold of APD alternans in E-4031 group compared with baseline group, which was reflected by more pronounced arrhythmogenesis at the tissue level, and were associated with steep restitution curves of the APD and the conduction velocity (CV). Conduction of AP alternans augmented tissue's functional spatiotemporal heterogeneity of regional AP/Ca alternans, as well as the AP/Ca dispersion, leading to localized uni-directional conduction block that spontaneous facilitated the formation of reentrant excitation waves without the need for additional premature stimulus. Our results provide a possible mechanism for the spontaneous transition from cardiac electrical alternans in cellular action potentials and intercellular conduction without the involvement of premature excitations, and explain the increased susceptibility to ventricular arrhythmias in impaired repolarization. In this study, we implemented voltage-clamp and dual-optical mapping approaches to investigate the underlying mechanism(s) for the arrhythmogenesis of cardiac alternans in the guinea pig heart at cellular and tissue levels. Our results demonstrated a spontaneous development of reentry from cellular alternans, arising from a combined actions of restitution properties of action potential duration, conduction velocity of excitation wave and interplay between alternants of action potential and the intracellular Ca handling. We believe this study provides new insights into underlying the mechanism, by which cellular cardiac alternans spontaneously evolves into cardiac arrhythmias.

Rapid identification of high and low cadmium (Cd) accumulating rice cultivars using machine learning models with molecular markers and soil Cd levels as input data.

Excessive accumulation of cadmium (Cd) in rice grains threatens food safety and human health. Growing low Cd accumulating rice cultivars is an effective approach to produce low-Cd rice. However, field screening of low-Cd rice cultivars is laborious, time-consuming, and subjected to the influence of environment × genotype interactions. In the present study, we investigated whether machine learning-based methods incorporating genotype and soil Cd concentration can identify high and low-Cd accumulating rice cultivars. One hundred and sixty-seven locally adapted high-yielding rice cultivars were grown in three fields with different soil Cd levels and genotyped using four molecular markers related to grain Cd accumulation. We identified sixteen cultivars as stable low-Cd accumulators with grain Cd concentrations below the 0.2 mg kg-1 food safety limit in all three paddy fields. In addition, we developed eight machine learning-based models to predict low- and high-Cd accumulating rice cultivars with genotypes and soil Cd levels as input data. The optimized model classifies low- or high-Cd cultivars (i.e., the grain Cd concentration below or above 0.2 mg kg-1) with an overall accuracy of 76%. These results indicate that machine learning-based classification models constructed with molecular markers and soil Cd levels can quickly and accurately identify the high- and low-Cd accumulating rice cultivars.