YTHDF2 regulates MSS51 expression contributing to mitochondria dysfunction of granulosa cells in polycystic ovarian syndrome patients.

RESEARCH QUESTION: Granulosa cells (GCs) dysfunction plays a crucial role in the pathogenesis of polycystic ovary syndrome (PCOS). It is reported that YTH domain-containing family protein 2 (YTHDF2) is upregulated in mural GCs of PCOS patients. What effect does the differential expression of YTHDF2 have in PCOS patients? DESIGN: Mural GCs and cumulus GCs from 15 patients with PCOS and 15 ovulatory controls and 4 cases of pathological sections in each group were collected. Real-time PCR, Western Blot, immunohistochemistry, and immunofluorescence experiments were conducted to detect gene and protein expression. RNA immunoprecipitation assay was performed to evaluate the binding relationship between YTHDF2 and MSS51. Mitochondrial morphology, cellular ATP and ROS levels and glycolysis-related gene expression were detected after YTHDF2 overexpression or MSS51 inhibition. RESULTS: In the present study, we found that YTHDF2 was upregulated in GCs of PCOS patients while MSS51 was downregulated. YTHDF2 protein can bind to MSS51 mRNA and affect MSS51 expression. The reduction of MSS51 expression or the increase in YTHDF2 expression can lead to mitochondrial damage, reduced ATP levels, increased ROS levels and reduced expression of LDHA, PFKP and PKM. CONCLUSIONS: YTHDF2 may regulate the expression of MSS51, affecting the structure and function of mitochondria in GCs and interfering with cellular glycolysis, which may disturb the normal biological processes of GCs and follicle development in PCOS patients.

In vitro and in vivo antiproliferative activity on lung cancer of two acylhydrazone based zinc(II) complexes.

Two acylhydrazone based zinc(II) complexes [Zn(HL)2Cl2(CH3OH)2] (Zn1) and [ZnL(AC)]2 (Zn2) were synthesized from 3-(1-(salicyloylhydrazono)ethyl) pyridine (HL). Single crystal X-ray structure analyses showed that complexes Zn1 and Zn2 have a zero-dimensional monomer or dimer structure. Antiproliferative activity studies revealed that Zn1 and Zn2 are both more effective against A549 cells than cisplatin. The results of the reactive oxygen species (ROS) generation assay on A549 cells showed that both Zn1 and Zn2 induced apoptosis through ROS accumulation. The apoptosis-inducing and cell cycle arrest effects of Zn1 and Zn2 on A549 cells indicated that the antitumor effect was achieved through apoptosis induction and inhibition of DNA synthesis by blocking the G0/G1 phase of the cell cycle. What's more, the results of wound-healing assay showed that Zn1 and Zn2 could inhibit the migration of A549 cells. Western blot analysis further demonstrated that Zn1 and Zn2 induced cell apoptosis through the mitochondrial pathway, in which process, the expression level of cytochrome C, cleaved-PARP, cleaved-caspase 3 and cleaved-caspase 9 proteins increased while pro-caspase 3 and pro-caspase 9 expression decreased. In vivo anticancer evaluation demonstrated that both Zn1 and Zn2 complexes effectively inhibited tumor growth without causing significant toxicity in systemic organs.

Differential Analysis of Various Moisture Phases on N2 Displacement of CH4 in Coal.

The aim of the study was to elucidate the impact of different moisture phases during gas injection on coalbed methane displacement. The coal samples were treated with two methods: water vapor adsorption and liquid water stirring. The differences in the coal samples treated with various moisture phases during gas injection for coalbed methane displacement were investigated by using the isothermal adsorption curves of CH4, N2, and H2O in coal and N2 displacement of CH4 in coal. The results indicate that variations in the gas adsorption capacity of coal are treated with different moisture phases. The gas adsorption capacities and displacement capacities of the coal samples treated with the water vapor adsorption methods are better than those treated with the stirring methods. In the isothermal adsorption experiment, for the coal samples treated with different moisture phases, at a moisture content of 2.75%, the saturated adsorption capacities of CH4/N2 are 0.204/0.189 (cm3/g), and at a moisture content of 5.63%, the saturated adsorption capacities of CH4/N2 are 0.151/0.139 (cm3/g). In addition, in the displacement experiment, for the coal samples treated with different moisture phases, at a moisture content of 2.75%, the difference in the total gas adsorption capacities is 0.62 cm3/g and the difference in the CH4 adsorption capacities is 0.473 cm3/g, and at a moisture content of 5.63%, the difference in the total gas adsorption capacities is 0.3 cm3/g and the difference in CH4 adsorption capacities is 0.22 cm3/g. For the coal samples treated with various moisture phases, the differences in the CH4/N2 adsorption and displacement capacities are greater at a moisture content of 2.75% than at 5.63%. Notably, the moisture phase has only a marginal influence on the CH4 desorption capacity and desorption rate. The study is important to understand the interactions between coal and moisture.

Pore Structure and Deformation Correlation of an Aluminum Foam Sandwich Subject to Three-Point Bending.

An Al-Si matrix foam sandwich (AFS) with 6063 Al alloy cover sheets was fabricated by hot rolling combined with melt foaming. A foamable AlSiMg1/SiCp matrix precursor was prepared by the melting route. Hot rolling at 480 °C was carried out to obtain a mechanical bonding interface between the cover sheet and the foamable precursor. Meanwhile, the pore structure of the AFS was deeply affected by the foaming temperature and foaming time during the foaming process. Different pore growth mechanics of the crack-like pore disappearance mechanism (CDM) and pore active expansion mechanism (AEM) were concluded based on the pressure difference in pores inside and outside. Three bending tests were applied to three types of AFSs with different pore structures to evaluate the relation between pore structures and AFS mechanical properties. The bending property of the AFS with fewer layers of pores is like that of a dense material. The bending property of the AFS with a pore size in the range of 0~1 mm presents a typical sandwich shear failure mode. The AFS with a uniform pore structure, in which the shapes of the pores are predominately polygons and the pore diameter is concentrated in the range of 0.5~3 mm, processes a good energy absorption capacity, and the bending stress-strain curve fluctuates greatly after the first stress drop.

Synergizing the interaction of single nucleotide polymorphisms with dosiomics features to build a dual-omics model for the prediction of radiation pneumonitis.

OBJECTIVE: Radiation pneumonitis (RP) is the major dose-limiting toxicity of thoracic radiotherapy. This study aimed to developed a dual-omics (single nucleotide polymorphisms, SNP and dosiomics) prediction model for symptomatic RP. MATERIALS AND METHODS: The potential SNPs, which are of significant difference between the RP grade ≥ 3 group and the RP grade ≤ 1 group, were selected from the whole exome sequencing SNPs using the Fisher's exact test. Patients with lung cancer who received thoracic radiotherapy at our institution from 2009 to 2016 were enrolled for SNP selection and model construction. The factorization machine (FM) method was used to model the SNP epistasis effect, and to construct the RP prediction model (SNP-FM). The dosiomics features were extracted, and further selected using the minimum redundancy maximum relevance (mRMR) method. The selected dosiomics features were added to the SNP-FM model to construct the dual-omics model. RESULTS: For SNP screening, peripheral blood samples of 28 patients with RP grade ≥ 3 and the matched 28 patients with RP grade ≤ 1 were sequenced. 81 SNPs were of significant difference (P < 0.015) and considered as potential SNPs. In addition, 21 radiation toxicity related SNPs were also included. For model construction, 400 eligible patients (including 108 RP grade ≥ 2) were enrolled. Single SNP showed no strong correlation with RP. On the other hand, the SNP-SNP interaction (epistasis effect) of 19 SNPs were modeled by the FM method, and achieved an area under the curve (AUC) of 0.76 in the testing group. In addition, 4 dosiomics features were selected and added to the model, and increased the AUC to 0.81. CONCLUSIONS: A novel dual-omics model by synergizing the SNP epistasis effect with dosiomics features was developed. The enhanced the RP prediction suggested its promising clinical utility in identifying the patients with severe RP during thoracic radiotherapy.

High-speed AFM imaging reveals DNA capture and loop extrusion dynamics by cohesin-NIPBL.

3D chromatin organization plays a critical role in regulating gene expression, DNA replication, recombination, and repair. While initially discovered for its role in sister chromatid cohesion, emerging evidence suggests that the cohesin complex (SMC1, SMC3, RAD21, and SA1/SA2), facilitated by NIPBL, mediates topologically associating domains and chromatin loops through DNA loop extrusion. However, information on how conformational changes of cohesin-NIPBL drive its loading onto DNA, initiation, and growth of DNA loops is still lacking. In this study, high-speed atomic force microscopy imaging reveals that cohesin-NIPBL captures DNA through arm extension, assisted by feet (shorter protrusions), and followed by transfer of DNA to its lower compartment (SMC heads, RAD21, SA1, and NIPBL). While binding at the lower compartment, arm extension leads to the capture of a second DNA segment and the initiation of a DNA loop that is independent of ATP hydrolysis. The feet are likely contributed by the C-terminal domains of SA1 and NIPBL and can transiently bind to DNA to facilitate the loading of the cohesin complex onto DNA. Furthermore, high-speed atomic force microscopy imaging reveals distinct forward and reverse DNA loop extrusion steps by cohesin-NIPBL. These results advance our understanding of cohesin by establishing direct experimental evidence for a multistep DNA-binding mechanism mediated by dynamic protein conformational changes.

Taekwondo motion image recognition model based on hybrid neural network algorithm for wearable sensor of Internet of Things.

Conventional IoT wearable sensor Taekwondo motion image recognition model mainly uses Anchor fixed proportion whole body target anchor frame to extract recognition features, which is vulnerable to dynamic noise, resulting in low displacement recognition rate of motion image. Therefore, a new IoT wearable sensor Taekwondo motion image recognition model needs to be designed based on hybrid neural network algorithm. That is, the wearable sensor Taekwondo motion image features are extracted, and the hybrid neural network algorithm is used to generate the optimization model of the wearable sensor Taekwondo motion image recognition of the Internet of Things, so as to achieve effective recognition of Taekwondo motion images. The experimental results show that the designed wearable sensor of the Internet of Things based on the hybrid neural network algorithm has a high recognition rate of the motion image displacement of the Taekwondo motion image recognition model, which proves that the designed Taekwondo motion image recognition model has good recognition effect, reliability, and certain application value, and has made certain contributions to optimizing the Taekwondo movement.

Preparation of Gd-doped AuNBP@mSiO2 nanocomposites for the MR imaging, drug delivery and chemo-photothermal synergistic killing of breast cancer cells.

Under near-infrared (NIR) light, gold nanobipyramids (AuNBPs) exhibit a high photothermal conversion rate and photothermal stability, making them ideal mediators for photothermal therapy (PTT). In this study, highly purified AuNBPs are prepared, followed by coating their surfaces with mesoporous silica (mSiO2). The obtained AuNBP@mSiO2 nanocomplex exhibits an ellipsoidal shape with a relatively large specific surface, pore diameter and pore volume. To achieve MRI guided chemo-photothermal therapy of breast cancer cells, the nanocomplex is further coupled with the MRI contrast agent Gd-DTTA and the chemotherapeutic drug doxorubicin (DOX). The results indicated that under NIR light irradiation, AuNBPs exhibited promising PTT effects, while the cumulative release rate of DOX was significantly enhanced to 81.40%. Moreover, the chemo-photothermal therapy approach effectively eradicated 4T1 breast cancer cells. This work successfully confirms that chemo-photothermal synergistic therapy is an effective tumor treatment strategy and demonstrates the potential application of AuNBP@mSiO2 as a nano-drug delivery platform. Additionally, it introduces new ideas for the integrated study of breast cancer diagnosis and treatment.

Adaptive Search-and-Training for Robust and Efficient Network Pruning.

Both network pruning and neural architecture search (NAS) can be interpreted as techniques to automate the design and optimization of artificial neural networks. In this paper, we challenge the conventional wisdom of training before pruning by proposing a joint search-and-training approach to learn a compact network directly from scratch. Using pruning as a search strategy, we advocate three new insights for network engineering: 1) to formulate adaptive search as a cold start strategy to find a compact subnetwork on the coarse scale; and 2) to automatically learn the threshold for network pruning; 3) to offer flexibility to choose between efficiency and robustness. More specifically, we propose an adaptive search algorithm in the cold start by exploiting the randomness and flexibility of filter pruning. The weights associated with the network filters will be updated by ThreshNet, a flexible coarse-to-fine pruning method inspired by reinforcement learning. In addition, we introduce a robust pruning strategy leveraging the technique of knowledge distillation through a teacher-student network. Extensive experiments on ResNet and VGGNet have shown that our proposed method can achieve a better balance in terms of efficiency and accuracy and notable advantages over current state-of-the-art pruning methods in several popular datasets, including CIFAR10, CIFAR100, and ImageNet. The code associate with this paper is available at: https://see.xidian.edu.cn/faculty/wsdong/Projects/AST-NP.htm.

Corrigendum: Toxicity profile of combined immune checkpoint inhibitors and thoracic radiotherapy in esophageal cancer: A meta-analysis and systematic review.

[This corrects the article DOI: 10.3389/fimmu.2022.1039020.].

The effect of ozone short-term exposure on flow-mediated dilation: Using data before and after COVID-19 lockdown in Shanghai.

BACKGROUND: Short-term ambient ozone exposure has been shown to have an adverse impact on endothelial function, contributing to major cardiovascular diseases and premature death. However, only limited studies have focused on the impact of short-term ozone exposure on Flow-mediated Dilation (FMD), and their results have been inconsistent. The current study aims to explore the relationship between short-term ambient ozone exposure and FMD. In addition, the study aims to investigate how lockdown measures for COVID-19 may influence ozone concentration in the atmosphere. METHODS: Participants were recruited from a hospital in Shanghai from December 2020 to August 2022. Individuals' ozone exposure was determined using residential addresses. A distributed lag nonlinear model was adopted to assess the exposure-response relationship between short-term ozone exposure and FMD. A comparison was made between ambient ozone concentration and FMD data collected before and after Shanghai's lockdown in 2022. RESULTS: When ozone concentration was between 150 and 200 µg/m3, there was a significant reduction in FMD with a 2-day lag. Elderly individuals (age ≥ 65), females, non-drinkers, and non-smokers were found to be more susceptible to high concentrations of ozone exposure. The lockdown did elevate ambient ozone concentration compared to the same period previously. INTERPRETATION: This study proposes that an ambient ozone concentration of 150-200 µg/m3 is harmful to endothelial function, and that a reduction in human activity during lockdown increased the concentration, which in turn reduced FMD. However, the underlying mechanism requires further research.

Quantitation of Ten Urinary Nicotine Metabolites, Including 4-Hydroxy-4-(3-pyridyl) Butanoic Acid, a Product of Nicotine 2'-Oxidation, and CYP2A6 Activity in Japanese Americans, Native Hawaiians, and Whites.

Smoking intensity varies across smokers and is influenced by individual variability in the metabolism of nicotine, the major addictive agent in tobacco. Therefore, lung cancer risk, which varies by racial ethnic group, is influenced by the primary catalyst of nicotine metabolism, cytochrome P450 2A6 (CYP2A6). In smokers, CYP2A6 catalyzes nicotine 5'-oxidation. In vitro, CYP2A6 also catalyzes, to a much lower extent, 2'-oxidation, which leads to the formation of 4-hydroxy-4-(3-pyridyl) butanoic acid (hydroxy acid). The urinary concentration of hydroxy acid has been quantified in only a few small studies of White smokers. To quantitatively assess the importance of nicotine 2'-oxidation in smokers, an LC-MS/MS-based method was developed for the analysis of nicotine and ten metabolites in urine. The concentrations of nicotine and these metabolites were measured in 303 smokers (99 Whites, 99 Native Hawaiians, and 105 Japanese Americans), and the relative metabolism of nicotine by four pathways was determined. Metabolism by these pathways was also compared across quartiles of CYP2A6 activity (measured as the plasma ratio of 3-hydroxycotinine to cotinine). As reported previously and consistent with their average CYP2A6 activity, nicotine 5'-oxidation was highest in Whites and lowest in Japanese Americans. Nicotine N-glucuronidation and N-oxidation increased with decreasing CYP2A6 activity. However, the relative urinary concentration of hydroxy acid (mean, 2.3%; 95% CI, 2.2-2.4%) did not vary by ethnic group or by CYP2A6 activity. In summary, CYP2A6 is not an important catalyst of nicotine 2'-oxidation in smokers, nor does nicotine 2'-oxidation compensate for decreased CYP2A6 activity.

Enhancing bioactivity and stability of polymer-based material-tissue interface through coupling multiscale interfacial interactions with atomic-thin TiO2 nanosheets.

Stable and bioactive material-tissue interface (MTF) basically determines the clinical applications of biomaterials in wound healing, sustained drug release, and tissue engineering. Although many inorganic nanomaterials have been widely explored to enhance the stability and bioactivity of polymer-based biomaterials, most are still restricted by their stability and biocompatibility. Here we demonstrate the enhanced bioactivity and stability of polymer-matrix bio-composite through coupling multiscale material-tissue interfacial interactions with atomically thin TiO2 nanosheets. Resin modified with TiO2 nanosheets displays improved mechanical properties, hydrophilicity, and stability. Also, we confirm that this resin can effectively stimulate the adhesion, proliferation, and differentiation into osteogenic and odontogenic lineages of human dental pulp stem cells using in vitro cell-resin interface model. TiO2 nanosheets can also enhance the interaction between demineralized dentinal collagen and resin. Our results suggest an approach to effectively up-regulate the stability and bioactivity of MTFs by designing biocompatible materials at the sub-nanoscale. Electronic Supplementary Material: Supplementary material (further details of fabrication and characterization of TiO2 NSs and TiO2-ARCs, the bioactivity evaluation of TiO2-ARCs on hDPSCs, and the measurement of interaction with demineralized dentin collagen) is available in the online version of this article at 10.1007/s12274-022-5153-1.

Toxicity profile of combined immune checkpoint inhibitors and thoracic radiotherapy in esophageal cancer: A meta-analysis and systematic review.

Background: Therapies based on the combination of immune checkpoint inhibitors (ICIs) and thoracic radiotherapy (TRT) are transforming the treatment landscape of esophageal cancer. Nevertheless, the available data on adverse events (AEs) mainly stemmed from several prospective clinical trials and retrospective studies, in which, AE data are often handled and reported with less rigor than the primary beneficial outcomes of the study. Thus, we conducted a systematic review to investigate the toxicity spectrum of these novel regimens. Method: We searched for all prospective clinical trials investigating the role of ICIs combined with TRT published between January 2010 and August 2022. Study articles and conference proceedings involving esophageal cancers and reporting the overall incidence or details of treatment-related AEs (trAEs) were synthesized to determine the toxicity profile of combination treatment. We compared trAEs between cancer type, programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors, and between sequential and concurrent administration of ICIs and TRT to identify potentially high-risk patients. Results: We obtained toxicity data from 14 clinical trials involving 863 patients. The pooled overall incidence was 88.97% for any-grade trAEs and 18.48% for high-grade trAEs. The three most frequent non-hematologic any-grade trAEs were reactive cutaneous capillary endothelial proliferation (RCCEP, 63.80%), esophagitis (51.54%), and fatigue (33.63%). Meanwhile, RCCEP (15.69%) was the most common non-hematologic high-grade trAE, followed by nausea (4.91%) and anorexia (3.81%). The occurrence rates of any-grade and high-grade pneumonitis were 10.82% and 0.66%, respectively. In subgroup analysis, the toxicity profiles of PD-1 and PD-L1 inhibitors were mostly similar, except for any-grade pneumonitis (15.20% vs 4.88%, p=0.03) and high-grade leukopenia (6.25% vs 59.09%, p=0.00). In addition, concurrent treatment seemed to have a higher incidence of any-grade trAEs (95.20% vs 70.85%, p=0.03) compared with sequential treatment. ESCC seems to have higher incidence of any-grade hypothyroidism (22.55% vs 8.96%, p=0.049) compared to EAC. Conclusion: Our study is the first systematic review to provide a toxicity profile of trAEs in esophageal cancer patients who received ICIs combined with TRT. Most AEs of this combination treatment are tolerable, although the incidence of any-grade trAEs was higher in the concurrent group. The difference in any-grade pneumonitis between PD-1 and PD-L1 inhibitor groups needs further validation in a large clinical trial.

Fabrication of core-shell-like structured polymeric ionic liquid hybrid catalysts for aqueous reactions.

Core-shell-like structured polymeric ionic liquid hybrid nanoreactors with "internal hydrophobic-external hydrophilic" characteristics were successfully synthesized through the Stöber method and reversible addition-fragmentation chain transfer (RAFT) polymerization. Firstly, we introduced hydrophobic organosilicon as an inner core and fixed Pd nanoparticles (∼0.69 mmol g-1) in the pore and finally constructed a hydrophilic shell, which not only ensured the dispersity of the catalyst in water but also effectively prevented the leaching of Pd species. The structure and properties of nMIE@Pd/SiNP-CPDB were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), N2 adsorption-desorption, ICP-OES, thermogravimetric analysis (TGA) and ultraviolet and visible spectrophotometry (UV-vis) characterization methods. The adsorption enthalpy of the best catalyst for styrene was calculated using the Clausius-Clapeyron equation and the value was -12.765 kJ mol-1, which strongly verified that the prepared catalyst could effectively promote mass transfer and the adsorption of reactants or products. Furthermore, the as-prepared nanoreactors exhibit distinguished catalytic activity for aqueous hydrogenation reactions and even after 7 cycles, the catalysts still maintain their superior catalytic activity, showing almost no leaching of palladium species.

The Sialyl Lewis X Glycan Receptor Facilitates Infection of Subtype H7 Avian Influenza A Viruses.

Subtype H7 avian influenza A viruses (IAVs) are enzootic in wild aquatic birds and have caused sporadic spillovers into domestic poultry and humans. Here, we determined the distribution of fucosylated α2,3 sialoglycan (i.e., sialyl Lewis X [SLeX]) in chickens and five common dabbling duck species and the association between SLeX and cell/tissue/host tropisms of H7 IAVs. Receptor binding analyses showed that H7 IAVs bind to both α2,3-linked (SA2,3Gal) and α2,6-linked sialic acids (SA2,6Gal), but with a higher preference for SLeX; H7 IAVs replicated more efficiently in SLeX-overexpressed than SLeX-deficient MDCK cells. While chickens and all tested dabbling ducks expressed abundant SA2,3Gal and SA2,6Gal, SLeX was detected in both respiratory and gastrointestinal tissues of chickens and mallard ducks and in only the respiratory tissues of gadwall, green-wing teal, and northern shoveler but not in wood ducks. Viral-tissue binding assays showed that H7 IAVs bind to chicken colon crypt cells that express SLeX but fewer bind to mallard colon crypt cells, which do not express SLeX; H7 IAVs bind efficiently to epithelial cells of all tissues expressing SA2,3Gal. High viral replication was identified in both chickens and mallards infected with an H7 virus, regardless of SLeX expression, and viruses were detected in all cells to the same degree as viruses detected in the viral-tissue binding assays. In summary, this study suggests that SLeX facilitates infection of H7 viruses, but other types of SA2,3Gal glycan receptors shape the tissue/host tropisms of H7 IAVs. IMPORTANCE In addition to causing outbreaks in domestic poultry, subtype H7 IAVs can cause sporadic spillover infections in lower mammals and humans. In this study, we showed that SLeX expression varies among wild dabbling ducks. Although it facilitated virus binding and affected infection of H7 IAV in cells, SLeX expression is not the only determinant of viral replication at either the tissue or host level. This study suggested that access to heterologous SA2,3Gal glycan receptors, including fucosylated α2,3-linked sialoglycans, shape tissue and host tropism of H7 IAVs in aquatic wild birds.

Comprehensive Pneumonitis Profile of Thoracic Radiotherapy Followed by Immune Checkpoint Inhibitor and Risk Factors for Radiation Recall Pneumonitis in Lung Cancer.

Purpose: Whilst survival benefits of thoracic radiotherapy (TRT) followed by immune checkpoint inhibitor (ICI) have been reported in patients with lung cancer, the potential high risk of treatment-related pneumonitis remains a concern. Asians may be more sensitive to lung toxicity than other races. This retrospective study intended to provide a comprehensive pneumonitis profile of TRT followed by ICI and investigate the risk factors from a Chinese cohort of lung cancer. Methods and Materials: From January 2016 to July 2021, 196 patients with lung cancer who received TRT prior to ICI were retrospectively analyzed. Treatment-related pneumonitis, including checkpoint inhibitor pneumonitis (CIP), radiation pneumonitis (RP), and radiation recall pneumonitis (RRP), were recorded and graded through medical records and chest computed tomography. Characteristics predictive of pneumonitis were assessed using logistic regression models, and the receiver operating characteristic analyses were performed to identify optimal cut points for quantitative variables. Results: With a median follow-up of 18 months, a total of 108 patients (55.1%) developed treatment-related pneumonitis during ICI therapy, with an incidence of 25.5% for grade 2 or higher (G2+) and 4.1% for G3+. The overall rates of CIP, RP and RRP were 8.2% (n=16), 46.9% (n=92) and 7.1% (n=14), respectively. With a total mortality rate of 1.5%, vast majority of the patients recovered from pneumonitis or remained stable. No patients died of RRP. Half of the patients with G2+ RP who withheld ICI therapy restarted ICI safely after resolution of RP. The history of chronic pulmonary diseases (P=0.05), mean lung dose (MLD, P=0.038), percent volume of lung receiving ≥5 Gy (V5, P=0.012) and percent volume of lung receiving ≥20 Gy (V20, P=0.030) predicted the occurrence of RRP in univariate analyses. Interval between TRT and ICI less than 3 months was an independent predictor for G2+ treatment-related pneumonitis in a multivariate model (Odds ratio OR=2.787, P=0.004). Conclusions: Treatment-related pneumonitis, especially RRP, is acceptable and manageable in the setting of TRT followed by ICI in this Asian population. Dosimetric parameters MLD, V5 and V20 may improve the predictions of RRP in clinical practice.

Floquet Engineering Hz-Level Rabi Spectra in Shallow Optical Lattice Clock.

Quantum metrology with ultrahigh precision usually requires atoms prepared in an ultrastable environment with well-defined quantum states. Thus, in optical lattice clock systems deep lattice potentials are used to trap ultracold atoms. However, decoherence, induced by Raman scattering and higher order light shifts, can significantly be reduced if atomic clocks are realized in shallow optical lattices. On the other hand, in such lattices, tunneling among different sites can cause additional dephasing and strongly broadening of the Rabi spectrum. Here, in our experiment, we periodically drive a shallow ^{87}Sr optical lattice clock. Counterintuitively, shaking the system can deform the wide broad spectral line into a sharp peak with 5.4 Hz linewidth. With careful comparison between the theory and experiment, we demonstrate that the Rabi frequency and the Bloch bands can be tuned, simultaneously and independently. Our work not only provides a different idea for quantum metrology, such as building shallow optical lattice clock in outer space, but also paves the way for quantum simulation of new phases of matter by engineering exotic spin orbit couplings.

Local Therapy Combined With First-Line EGFR Tyrosine Kinase Inhibitor Achieves Favorable Survival in Patients With EGFR-Mutant Metastatic Non-Small Cell Lung Cancer.

BACKGROUND: EGFR tyrosine kinase inhibitor (TKI) is recommended as the first-line therapy for patients with EGFR-mutant metastatic non-small cell lung cancer (NSCLC). Yet, resistance often occurs in 1 year after therapy and most progressions occur at the initial sites of disease. Addition of local therapy to the first-line TKI therapy may delay the progression and provide survival benefit to the patients. METHODS: From 2010 to 2017, metastatic NSCLC patients with EGFR activating mutations who received first-line TKI and relatively radical local therapy (RRLT) were reviewed. RRLT was defined as local curative therapy to the main site or any intensity of local therapy to all sites of disease. The Kaplan-Meier method and log-rank test were used for survival estimation and comparison. RESULTS: A total of 45 patients were included in this retrospective study with a median follow-up of 48.0 months. The median progression-free survival (PFS) and overall survival (OS) was 17.0 months (95% confidence interval [CI]: 14.6-19.3) and 55.0 months (95% CI: 49.3-60.6), respectively. Univariate analysis indicated that age ⩽ 60 years (P = .019), first-line TKI duration ⩾ 10 months (P = .028), and accumulated TKI duration ⩾ 20 months (P = .016) were significantly associated with favorable OS. Among the 36 patients who progressed during the follow-up, 55.8% of the progressions occurred at the new sites. RRLT combined with TKI did not show any severe toxicity to the patients. CONCLUSIONS: Combined application of RRLT and first-line TKI may improve the survival and alter the pattern of failure for metastatic NSCLC patients with EGFR activating mutations.