Great advances in immune checkpoint blockade have resulted in a paradigm shift in patients with lung cancer. Immune-checkpoint inhibitor (ICI) treatment, either as monotherapy or combination therapy, ...has been established as the standard of care for patients with locally advanced/metastatic non-small cell lung cancer without EGFR/ALK alterations or extensive-stage small cell lung cancer. An increasing number of clinical trials are also ongoing to further investigate the role of ICIs in patients with early-stage lung cancer as neoadjuvant or adjuvant therapy. Although PD-L1 expression and tumor mutational burden have been widely studied for patient selection, both of these biomarkers are imperfect. Due to the complex cancer-immune interactions among tumor cells, the tumor microenvironment and host immunity, collaborative efforts are needed to establish a multidimensional immunogram to integrate complementary predictive biomarkers for personalized immunotherapy. Furthermore, as a result of the wide use of ICIs, managing acquired resistance to ICI treatment remains an inevitable challenge. A deeper understanding of the underlying biological mechanisms of acquired resistance to ICIs is helpful to overcome these obstacles. In this review, we describe the cutting-edge progress made in patients with lung cancer, the optimal duration of ICI treatment, ICIs in some special populations, the unique response patterns during ICI treatment, the emerging predictive biomarkers, and our understanding of primary and acquired resistance mechanisms to ICI treatment.
Carbon–fluorine bond activation of the trifluoromethyl group represents an important approach to fluorine‐containing molecules. While selective defluorinative functionalization reactions of ...CF3‐containing substrates have been achieved by invoking difluorocarbocation, difluorocarboradical, or difluoroorganometallic species as the key intermediates, the transformations via fluorocarbanion mechanism only achieved limited success. Furthermore, the enantioselective defluorinative transformation of the CF3 group remained a formidable challenge. Here we report a defluorinative functionalization reaction of 4‐trifluoromethylpyridines involving difluoro(pyrid‐4‐yl)methyl anion as the key intermediate, which was developed based upon our previous studies on the N‐boryl pyridyl anion chemistry. In particular, asymmetric defluoroallylation of 4‐trifluoromethylpyridines and ‐pyrimidines could be achieved by using Ir‐catalysis to forge a difluoroalkyl‐substituted chiral center.
Enantioselective defluorinative transformation of the trifluoromethyl group represents a formidable challenge. An asymmetric defluoroallylation reaction of 4‐trifluoromethylpyridines and ‐pyrimidines is reported, which features an umpolung C−F bond activation, a broad substrate scope and excellent enantioselectivities.
Approximately one third of all lung cancer patients in East Asia are never-smokers. Furthermore, the proportion of lung cancer in never smokers (LCINS) has been increasing over time. Never-smokers ...are more often diagnosed with adenocarcinoma in East Asia, a subtype largely defined by oncogenic drivers. In this subgroup of patients, as high as 90% of patients have been found to harbor well-known oncogenic mutations and can be successfully managed with targeted therapies inhibiting specific oncogenic mutant kinases. EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment has been the most important targeted therapy in lung adenocarcinoma from East Asian never-smokers as approximately 70% of these patients have the opportunity to receive EGFR-TKI treatment. Lung squamous cell carcinoma (SQCC) and small cell lung cancer (SCLC) are two common histologic types of smoking-related non-small cell lung cancer (NSCLC). The proportion of never-smokers with SQCC and SCLC in East Asian patients seems to be higher than that in Caucasian patients. Recent studies also suggest that lung SQCC and SCLC in never-smokers may be distinct subtypes. Therefore, better understanding of the biologic characteristics of these subtypes of patients may provide new insights for the treatment. In this review, we will provide an overview of East Asian experience in the treatment of advanced, never-smoking lung cancer, focusing on etiologic factors in the development of LCINS, targeted therapy for never-smokers with adenocarcinoma, distinct characteristics of never-smokers with lung SQCC and SCLC, and the role of immunotherapy in never-smokers with NSCLC.
Cancer-secreted exosomal miRNAs are emerging mediators of cancer-stromal cross-talk in the tumor environment. Our previous miRNAs array of cervical squamous cell carcinoma (CSCC) clinical specimens ...identified upregulation of miR-221-3p. Here, we show that miR-221-3p is closely correlated with peritumoral lymphangiogenesis and lymph node (LN) metastasis in CSCC. More importantly, miR-221-3p is characteristically enriched in and transferred by CSCC-secreted exosomes into human lymphatic endothelial cells (HLECs) to promote HLECs migration and tube formation in vitro, and facilitate lymphangiogenesis and LN metastasis in vivo according to both gain-of-function and loss-of-function experiments. Furthermore, we identify vasohibin-1 (VASH1) as a novel direct target of miR-221-3p through bioinformatic target prediction and luciferase reporter assay. Re-expression and knockdown of VASH1 could respectively rescue and simulate the effects induced by exosomal miR-221-3p. Importantly, the miR-221-3p-VASH1 axis activates the ERK/AKT pathway in HLECs independent of VEGF-C. Finally, circulating exosomal miR-221-3p levels also have biological function in promoting HLECs sprouting in vitro and are closely associated with tumor miR-221-3p expression, lymphatic VASH1 expression, lymphangiogenesis, and LN metastasis in CSCC patients. In conclusion, CSCC-secreted exosomal miR-221-3p transfers into HLECs to promote lymphangiogenesis and lymphatic metastasis via downregulation of VASH1 and may represent a novel diagnostic biomarker and therapeutic target for metastatic CSCC patients in early stages.
The state of charge (SOC) estimation and battery equalization method are essential in battery management system (BMS). In this paper, an improved H infinity filter algorithm based on the reverse ...recursion of historical data which could update the inner parameters of algorithm online is proposed. The battery life decay experiment result shows that open circuit voltage (OCV)–SOC relationship and the actual capacity of battery have a great impact on the SOC estimation accuracy based on H infinity, and the max SOC estimation error can exceed 15%. The improved H infinity algorithm proposed in this paper can keep the SOC error within 3% and its convergence to the true SOC is faster than the sliding mode observer algorithm. On this basis, a novel equalization strategy based on shunting is proposed. The equalization strategy model is simulated in SIMULINK, and as compared with the general cell bypass methods, the proposed method utilizes a redundant cell to achieve a high efficiency beyond 99%. The analysis results show that the 6Ah redundant cell could decrease the inconsistence of SOCs to 2%.
•The SOC estimation based on H infinity filter algorithm is introduced for equalization strategy.•An improved H infinity filter algorithm based on reverse recursion of historical data is proposed.•The equilibrium efficiency higher than 99% is achieved using the proposed balancing method.•A 6Ah redundant cell could improve the in consistence of SOCs to 1.5%.
Lithium-ion batteries are a key technology for multiple clean energy applications. Their energy and power density is largely determined by the cathode materials, which store Li by incorporation into ...their crystal structure. Most commercialized cathode materials, such as LiCoO(2) (ref. 1), LiMn(2)O(4) (ref. 2), Li(Ni,Co,Al)O(2) or Li(Ni,Co,Mn)O(2) (ref. 3), form solid solutions over a large concentration range, with occasional weak first-order transitions as a result of ordering of Li or electronic effects. An exception is LiFePO(4), which stores Li through a two-phase transformation between FePO(4) and LiFePO(4) (refs 5-8). Notwithstanding having to overcome extra kinetic barriers, such as nucleation of the second phase and growth through interface motion, the observed rate capability of LiFePO(4) has become remarkably high. In particular, once transport limitations at the electrode level are removed through carbon addition and particle size reduction, the innate rate capability of LiFePO(4) is revealed to be very high. We demonstrate that the reason LiFePO(4) functions as a cathode at reasonable rate is the availability of a single-phase transformation path at very low overpotential, allowing the system to bypass nucleation and growth of a second phase. The Li(x)FePO(4) system is an example where the kinetic transformation path between LiFePO(4) and FePO(4) is fundamentally different from the path deduced from its equilibrium phase diagram.
Immune escape frequently occurs and restricts the durability of the antitumor immune response to radiotherapy. Programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) are important immune ...checkpoint molecules that could cause tumor cells to escape the host immune response. The aim of the study was to explore the role of PD-L1 in radioresistance and the antitumor effect of combined radiotherapy and anti–PD-L1 therapy in NSCLC.
The role of the phosphoinositide 3-kinase/protein kinase B signal transducer and activator of transcription 3, epithelial-mesenchymal transition, and tripartite motif containing 21 in regulating PD-L1 expression after radiotherapy was investigated by small interfering-PD-L1-RNA transfection, immunohistochemistry, Western blot, and immunoprecipitation. The synergistic effect of radiotherapy and anti–PD-L1 antibody was evaluated in a mouse model. PD-L1 expression on tumor specimens was examined in a retrospective cohort of patients who received concurrent chemoradiotherapy.
PD-L1 expression was increased in vivo and in vitro after conventionally fractionated radiation. Radiotherapy in combination with anti–PD-L1 antibody synergistically enhanced antitumor immunity by promoting CD8-positive T-cell infiltration and reducing the accumulation of myeloid-derived suppressor cells and tumor-infiltrating regulatory T cells in a mouse model. Radiotherapy may up-regulate PD-L1 expression through the phosphoinositide 3-kinase/AKT and signal transducer and activator of transcription 3 pathways. PD-L1 may also stimulate cell migration and facilitate the epithelial-mesenchymal transition process to induce radioresistance. Moreover, down-regulating PD-L1 could alleviate radioresistance by promoting apoptosis. Intriguingly, patients with negative PD-L1 expression had a significantly higher objective response rate (88% versus 43.1% p < 0.001) and disease control rate (100% versus 86.2% p = 0.026) than those with positive PD-L1 expression after delivery of radiotherapy.
Conventionally fractionated radiotherapy in combination with anti–PD-L1 antibody shows a synergistic antitumor immunity in NSCLC. Furthermore, PD-L1 expression may be a significant clinical predictive factor for treatment response to radiotherapy in NSCLC.
Background and aimsLiver fibrosis is a wound-healing response that disrupts the liver architecture and function by replacing functional parenchyma with scar tissue. Recent progress has advanced our ...knowledge of this scarring process, but the detailed mechanism of liver fibrosis is far from clear.MethodsThe fibrotic specimens of patients and HLF (hepatic leukemia factor)PB/PB mice were used to assess the expression and role of HLF in liver fibrosis. Primary murine hepatic stellate cells (HSCs) and human HSC line Lx2 were used to investigate the impact of HLF on HSC activation and the underlying mechanism.ResultsExpression of HLF was detected in fibrotic livers of patients, but it was absent in the livers of healthy individuals. Intriguingly, HLF expression was confined to activated HSCs rather than other cell types in the liver. The loss of HLF impaired primary HSC activation and attenuated liver fibrosis in HLFPB/PB mice. Consistently, ectopic HLF expression significantly facilitated the activation of human HSCs. Mechanistic studies revealed that upregulated HLF transcriptionally enhanced interleukin 6 (IL-6) expression and intensified signal transducer and activator of transcription 3 (STAT3) phosphorylation, thus promoting HSC activation. Coincidentally, IL-6/STAT3 signalling in turn activated HLF expression in HSCs, thus completing a feedforward regulatory circuit in HSC activation. Moreover, correlation between HLF expression and alpha-smooth muscle actin, IL-6 and p-STAT3 levels was observed in patient fibrotic livers, supporting the role of HLF/IL-6/STAT3 cascade in liver fibrosis.ConclusionsIn aggregate, we delineate a paradigm of HLF/IL-6/STAT3 regulatory circuit in liver fibrosis and propose that HLF is a novel biomarker for activated HSCs and a potential target for antifibrotic therapy.
N6-Methyladenosine (m6A) RNA methylation plays important roles during development in different species. However, knowledge of m6A RNA methylation in monocots remains limited. In this study, we ...reported that OsFIP and OsMTA2 are the components of m6A RNA methyltransferase complex in rice and uncovered a previously unknown function of m6A RNA methylation in regulation of plant sporogenesis. Importantly, OsFIP is essential for rice male gametogenesis. Knocking out of OsFIP results in early degeneration of microspores at the vacuolated pollen stage and simultaneously causes abnormal meiosis in prophase I. We further analyzed the profile of rice m6A modification during sporogenesis in both WT and OsFIP loss-of-function plants, and identified a rice panicle specific m6A modification motif "UGWAMH". Interestingly, we found that OsFIP directly mediates the m6A methylation of a set of threonine protease and NTPase mRNAs and is essential for their expression and/or splicing, which in turn regulates the progress of sporogenesis. Our findings revealed for the first time that OsFIP plays an indispensable role in plant early sporogenesis. This study also provides evidence for the different functions of the m6A RNA methyltransferase complex between rice and Arabidopsis.
Image super-resolution (SR) has been an active research problem which has recently received renewed interest due to the introduction of new technologies such as deep learning. However, the lack of ...suitable criteria to evaluate the SR performance has hindered technology development. In this paper, we fill a gap in the literature by providing the first publicly available database as well as a new image quality assessment (IQA) method specifically designed for assessing the visual quality of super-resolved images (SRIs). In constructing the quality assessment database for SRIs (QADS), we carefully selected 20 reference images and created 980 SRIs using 21 image SR methods. Mean opinion score (MOS) for these SRIs is collected through 100 individuals participating in a suitably designed psychovisual experiment. Extensive numerical and statistical analysis is performed to show that the MOS of QADS has excellent suitability and reliability. The psychovisual experiment has led to the discovery that, unlike distortions encountered in other IQA databases, artifacts of the SRIs degenerate the image structure as well as the image texture. Moreover, the structural and textural degenerations have distinctive perceptual properties. Based on these insights, we propose a novel method to assess the visual quality of SRIs by separately considering the structural and textural components of images. Observing that textural degenerations are mainly attributed to dissimilar texture or checkerboard artifacts, we propose to measure the changes of textural distributions. We also observe that structural degenerations appear as blurring and jaggies artifacts in SRIs and develop separate similarity measures for different types of structural degenerations. A new pooling mechanism is then used to fuse the different similarities together to give the final quality score for an SRI. The experiments conducted on the QADS demonstrate that our method significantly outperforms the classical as well as current state-of-the-art IQA methods.
PDF
