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Abstract Recent research highlights that non-exhaust emissions from the abrasion of tires and other organic materials have emerged as a substantial source of airborne particulate matter and marine microplastics. Despite their growing impact, the underlying mechanisms driving these abrasion emissions have remained largely unexplored. In this study, we uncover that abrasion emissions from organic materials are fundamentally governed by a fatigue fracture process, wherein particles are progressively detached from the material surface under cyclic abrasion loads. Our findings demonstrate that these emissions increase significantly only when the applied abrasion loads surpass the material’s toughness threshold. We establish a scaling relationship between the concentration of emitted particulate matter and the measurable crack propagation rate of the organic material, offering a robust quantitative method to estimate abrasion emissions. This work not only introduces a novel mechanistic framework for understanding particulate matter pollution from organic material abrasion but also provides a scientific basis for developing strategies to mitigate emissions of airborne particulates and marine microplastics.

Abstract Background The initial randomized, double‐blinded, actively controlled, phase III ANEAS study (NCT03849768) demonstrated that aumolertinib showed superior efficacy relative to gefitinib as first‐line therapy in epidermal growth factor receptor (EGFR)‐mutated advanced non‐small cell lung cancer (NSCLC). Metastatic disease in the central nervous system (CNS) remains a challenge in the management of NSCLC. This study aimed to compare the efficacy of aumolertinib versus gefitinib among patients with baseline CNS metastases in the ANEAS study. Methods Eligible patients were enrolled and randomly assigned in a 1:1 ratio to orally receive either aumolertinib or gefitinib in a double‐blinded fashion. Patients with asymptomatic, stable CNS metastases were included. Follow‐up imaging of the same modality as the initial CNS imaging was performed every 6 weeks for 15 months, then every 12 weeks. CNS response was assessed by a neuroradiological blinded, independent central review (neuroradiological‐BICR). The primary endpoint for this subgroup analysis was CNS progression‐free survival (PFS). Results Of the 429 patients enrolled and randomized in the ANEAS study, 106 patients were found to have CNS metastases (CNS Full Analysis Set, cFAS) at baseline by neuroradiological‐BICR, and 60 of them had CNS target lesions (CNS Evaluable for Response, cEFR). Treatment with aumolertinib significantly prolonged median CNS PFS compared with gefitinib in both cFAS (29.0 vs. 8.3 months; hazard ratio [HR] = 0.31; 95% confidence interval [CI], 0.17‐0.56; P < 0.001) and cEFR (29.0 vs. 8.3 months; HR = 0.26; 95% CI, 0.11‐0.57; P < 0.001). The confirmed CNS overall response rate in cEFR was 85.7% and 75.0% in patients treated with aumolertinib and gefitinib, respectively. Competing risk analysis showed that the estimated probability of CNS progression without prior non‐CNS progression or death was consistently lower with aumolertinib than with gefitinib in patients with and without CNS metastases at baseline. No new safety findings were observed. Conclusions These results indicate a potential advantage of aumolertinib over gefitinib in terms of CNS PFS and the risk of CNS progression in patients with EGFR‐mutated advanced NSCLC with baseline CNS metastases. Trial registration ClinicalTrials.gov number, NCT03849768

Abstract Background The region-specific importance of carcinogenic HPV genotypes is required for optimizing HPV-based screening and promoting appropriate multivalent HPV prophylactic vaccines. This information is lacking for Ningbo, one of the first cities of China’s Healthy City Innovation Pilot Program for Cervical Cancer Elimination. Here, we investigated high-risk HPV (HR-HPV) genotype-specific distribution and attribution to biopsy-confirmed cervical intraepithelial neoplasia grade 2 or worse (CIN2+) before mass vaccination in Ningbo, China. Methods A total of 1393 eligible CIN2+ archived blocks (including 161 CIN2, 1107 CIN3, and 125 invasive cervical cancers [ICC]) were collected from 2017 to 2020 in Ningbo. HR-HPV DNA was genotyped using the SPF10-DEIA-LiPA25 version 1 detection system and the SureX HPV 25X Genotyping Kit. Genotype-specific attribution to CIN2+ was estimated using a fractional contribution approach. Results Ranking by the attributable proportions, HPV16 remained the most important genotype in both cervical precancers and cancers, accounting for 36.8% of CIN2, 53.2% of CIN3, and 73.3% of ICC cases. Among cervical precancers, HPV52 (17.3% in CIN2, 12.7% in CIN3) and HPV58 (13.9%, 14.9%) ranked second and third, while HPV33 (8.3%, 7.9%) and HPV31 (6.5%, 4.1%) ranked fourth and fifth, respectively. However, among ICCs, HPV18 (5.7%) accounted for the second highest proportion, followed by HPV33 (5.4%), HPV58 (4.0%), and HPV45 (3.2%). HPV18/45 together accounted for 46.8% of adenocarcinomas, which was slightly lower than that of HPV16 (47.7%). The remaining HR-HPV genotypes (HPV35/39/51/56/59/66/68) combined accounted for only 6.7% of CIN2, 2.9% of CIN3, and 4.2% of ICC. Conclusions With Ningbo’s strong medical resources, it will be important to continue HPV16/18 control efforts, and could broaden to HPV31/33/45/52/58 for maximum health benefits. However, different strategies should be proposed for other HR-HPV genotypes based on their lower carcinogenic risks.

Abstract Multiple synchronous lung cancers (MSLCs) constitute a unique subtype of lung cancer. To explore the genomic and immune heterogeneity across different pathological stages of MSLCs, we analyse 16 MSLCs from 8 patients using single-cell RNA-seq, single-cell TCR sequencing, and bulk whole-exome sequencing. Our investigation indicates clonally independent tumours with convergent evolution driven by shared driver mutations. However, tumours from the same individual exhibit few shared mutations, indicating independent origins. During the transition from pre-invasive to invasive adenocarcinoma, we observe a shift in T cell phenotypes characterized by increased Treg cells and exhausted CD8+ T cells, accompanied by diminished cytotoxicity. Additionally, invasive adenocarcinomas exhibit greater neoantigen abundance and a more diverse TCR repertoire, indicating heightened heterogeneity. In summary, despite having a common genetic background and environmental exposure, our study emphasizes the individuality of MSLCs at different stages, highlighting their unique genomic and immune characteristics.

Objective China's oil and gas exploration is advancing towards the field of shale oil and gas. Overpressure is commonly developed in organic shale, and the lack of prediction methods for shale pore pressure restricts the research on shale oil and gas. Methods This article analyses the physical response characteristics of rock to hydrocarbon generation, pressurization and disequilibrium compaction. Based on density and sound velocity data, the differential responses of hydrocarbon generation pressurization and disequilibrium compaction pressurization were analysed. The hydrocarbon generation pressurization amount is calculated using sound velocity and density, and the disequilibrium compaction is calculated using the density data. Finally, the sound velocity rebound method was established. This article selects the Bodong Depression, which has superior hydrocarbon generation conditions, as a case study. First, comprehensive mudstone compaction curves, loading-unloading curves, and sound velocity-density diagrams are used to comprehensively identify the cause of overpressure. Then, the sound velocity rebound method is used to quantitatively calculate the pressure increase and formation pore pressure of a single well under compaction and hydrocarbon generation, and the results are compared with those of numerical simulations and conventional calculation methods. Results Taking the LD21-A well as an example, shale overpressure is caused by a combination of hydrocarbon generation and disequilibrium compaction. The pressure prediction results show that the overpressure of nonsource rock layers is contributed by the disequilibrium compaction. The overpressure of the source rock formation is contributed by hydrocarbon generation and disequilibrium compaction, with hydrocarbon generation pressurization mainly distributed between 5 MPa and 15 MPa (accounting for approximately 35% to 65%), and the measured pressure point hydrocarbon generation pressurization is 11.09 MPa (accounting for 45%). Conclusion This new method is vital of importance for the research of both shale and conventional oil and gas fields.

Abstract Backgrounds A growing number of expression quantitative trait loci (eQTLs) have been found to be linked with tumorigenesis. In this article, we employed integrated Mendelian randomization (MR) analyses to identify novel susceptibility genes in renal cancer (RC) and reveal their potential mechanisms. Methods Two-sample MR analyses were performed to infer causal relationships between eQTLs, metabolites, and RC risks through the “TwoSampleMR” R package. Sensitivity analyses, such as heterogeneity, pleiotropy, and leave-one-out analysis, were used to assess the stability of our outcomes. Summary-data-based MR (SMR) analyses were used to verify the causal relationships among cis-eQTLs and RC risks via the SMR 1.3.1 software. Results Our results provided the first evidence for AFF3 eQTL elevating RC risks, suggesting its oncogenic roles (IVW method; odds ratio (OR) = 1.0005; 95% confidence interval (CI) = 1.0001–1.0010; P = 0.0285; heterogeneity = 0.9588; pleiotropy = 0.8397). Further SMR analysis validated the causal relationships among AFF3 cis-eQTLs and RC risks (P

Abstract In higher plants, mature male gametophytes have distinct apertures. After pollination, pollen grains germinate, and a pollen tube grows from the aperture to deliver sperm cells to the embryo sac, completing fertilization. In rice, the pollen aperture has a single-pore structure with a collar-like annulus and a plug-like operculum. A crucial step in aperture development is the formation of aperture plasma membrane protrusion (APMP) at the distal polar region of the microspore during the late tetrad stage. Previous studies identified OsINP1 and OsDAF1 as essential regulators of APMP and pollen aperture formation in rice, but their precise molecular mechanisms remain unclear. We demonstrate that the Poaceae-specific OsSRF8 gene, encoding a STRUBBELIG-receptor family 8 protein, is essential for pollen aperture formation in Oryza sativa. Mutants lacking functional OsSRF8 exhibit defects in APMP and pollen aperture formation, like loss-of-function OsINP1 mutants. OsSRF8 is specifically expressed during early anther development and initially diffusely distributed in the microsporocytes. At the tetrad stage, OsSRF8 is recruited by OsINP1 to the pre-aperture region through direct protein-protein interaction, promoting APMP formation. The OsSRF8-OsINP1 complex then recruits OsDAF1 to the APMP site to co-regulate annulus formation. Our findings provide insights into the mechanisms controlling pollen aperture formation in cereal species.

Abstract There is an urgent need to fully understand the biology of third generation EGFR‐tyrosine kinase inhibitors (EGFR‐TKIs), particularly osimertinib, and to develop mechanism‐driven strategies to manage their acquired resistance. Transient receptor potential melastatin‐2 (TRPM2) functions as an important regulator of Ca2+ influx, but its role in mediating therapeutic efficacies of EGFR‐TKIs and acquired resistance to EGFR‐TKIs has been rarely studied. This study has demonstrated a previously undiscovered role of suppression of TRPM2 and subsequent inhibition of Ca2+ influx and induction of ROS and DNA damage in mediating apoptosis induction and the therapeutic efficacy of osimertinib against EGFR mutant NSCLC. The rebound elevation represents a key mechanism accounting for the emergence of acquired resistance to osimertinib and other third generation EGFR‐TKIs. Accordingly, targeting TRPM2 is a potentially promising strategy for overcoming and preventing acquired resistance to osimertinib, warranting further study in this direction including the development of cancer therapy‐optimized TRPM2 inhibitors.

IntroductionPerinatal depression (PND) affects approximately 15%–20% of women. This study aimed to determine the incidence of PND and identify risk factors.MethodsA prospective study was conducted at the Affiliated People’s Hospital of Ningbo University. The Edinburgh Postnatal Depression Scale (EPDS) was used to screen for PND. Classification models were constructed using Extreme Gradient Boosting (XGBoost), Logistic Regression (LR), Random Forest (RF), and Support Vector Machine (SVM), and the optimal model was selected.ResultsBetween March 2019 and August 2021, a total of 485 participants completed all valid questionnaires. Depression was observed in 75 (15.5%), 47 (9.7%), 25 (5.2%), 94 (19.4%), 85 (17.5%), and 43 (8.9%) cases during the first trimester, the second trimester, the third trimester, 1 week postpartum, 6 months postpartum, and 12 months postpartum, respectively. During the prenatal period, factors such as monthly income, employment status, marital status, and thyroid function significantly impacted depression. Additionally, factors including monthly income, employment status, marital status, parity, and unintended pregnancy were found to affect the likelihood of developing postpartum depression. XGBoost was chosen for its accuracy (0.9097) and precision (0.9005) in predicting prenatal depression, as well as for its accuracy (0.9253) and precision (0.9523) in predicting postpartum depression.DiscussionIn conclusion, the incidence of depression varies throughout the perinatal period, with different factors influencing prenatal and postpartum depression.

ObjectiveTo assess the effectiveness and tolerability of both PD-1 and PD-L1 inhibitors in advanced cervical cancer (CC), focusing on varying PD-L1 levels.MethodsA comprehensive exploration was carried out on EMBASE, PubMed, Cochrane Library databases as well as Web of Science up to May 25, 2024, for studies involving advanced CC patients receiving PD-1/PD-L1 inhibitors. Inclusion criteria were studies reporting objective response rate (ORR), disease control rate (DCR), median progression-free survival (PFS), as well as median overall survival (OS). Data extraction and quality assessment were performed by two reviewers using the JBI Case Series Critical Appraisal Checklist, followed by a meta-analysis via STATA/MP 16.0.ResultsFive eligible studies comprising 223 patients were chosen. ORR and DCR were 42% (95% CI: 17%-66%, P = 0.00) and 70% (95% CI: 22%-117%, P = 0.00), respectively, in the PD-L1 positive patients and were 36% (95% CI: 17%-54%, P = 0.00) and 47% (95% CI: 30%-63%, P = 0.00), respectively, in patients with PD-L1 negativity. For patients exhibiting PD-L1 positivity, median PFS and median OS were 3.98 months (95% CI: 0.80–7.16, P = 0.01) and 11.26 months (95% CI: 3.01–12.58, P = 0.00), respectively.ConclusionWith PD-1/PD-L1 inhibitors, PD-L1 positive CC patients demonstrate superior ORR, DCR, median PFS, and median OS, underscoring PD-L1 as one biomarker for immunotherapy response.

Abstract Introduction Endometriosis (EM) is a multifactorial disease that affects 10 − 15% of women of reproductive age. Additionally, 30–50% of women with EM suffer from infertility. The mechanism of infertility caused by EM has not yet been consistently explained. In recent years, studies have shown a link between infertility associated with EM and changes in the reproductive tract microbiota. Methods In this study, we involved 26 EM patients (8 cases of stage I-II and 18 cases of stage III-IV) and 31 control subjects who were tubal obstruction-related infertility (TORI). The samples from peritoneal fluid (PF) and uterine fluid (UF) were collected and sequenced by 16 S rRNA amplicon. Results In the comparison of microbial diversity, we found no significant differences in the microbial diversity of PF and UF between patients with stage I-II EM and those with TORI. However, there was a significant difference in microbial diversity among patients with stage III-IV EM compared to the previous two groups. Lactobacillus decreased in PF of EM compared to the control group, while it increased in UF. In PF, the abundance of Pseudomonas, Enterococcus, Dubosiella and Klebsiella was significantly higher in patients with stage III-IV compared to TORI patients. And in UF, the main differences existed between stage I-II EM compared to the other two groups. The abundance of pontibacter, aquabacterium, Rikenellaceae and so on at the genus level was significantly enriched in the EM patients with stage I-II. In the analysis based on KEGG database, EM may affect the receptivity related pathways of the endometrium by influencing changes in the uterine microbiota. Conclusion Our results indicated that as EM progresses, the microorganisms in UF and PF keep changing. These changes in the microbiota, as well as the resulting alternations in gene functional classification, may play an important role in the infertility associated with EM.

Abstract Although immunotherapy has made breakthrough progress, its efficacy in solid tumours remains unsatisfactory. Exosomes are the main type of extracellular vesicles that can deliver various intracellular molecules to adjacent or distant cells and organs, mediating various biological functions. Studies have found that exosomes can both activate the immune system and inhibit the immune system. The antigen and major histocompatibility complex (MHC) carried in exosomes make it possible to develop them as anticancer vaccines. Exosomes derived from blood, urine, saliva and cerebrospinal fluid can be used as ideal biomarkers in cancer diagnosis and prognosis. In recent years, exosome-based therapy has made great progress in the fields of drug transportation and immunotherapy. Here, we review the composition and sources of exosomes in the solid cancer immune microenvironment and further elaborate on the potential mechanisms and pathways by which exosomes influence immunotherapy for solid cancers. Moreover, we summarize the potential clinical application prospects of engineered exosomes and exosome vaccines in immunotherapy for solid cancers. Eventually, these findings may open up avenues for determining the potential of exosomes for diagnosis, treatment, and prognosis in solid cancer immunotherapy.

This paper presents a disturbance observer-based sliding mode control strategy of PMSM to address overcurrent and mismatched disturbances. A time-varying disturbance observer is proposed to reduce the influence of mismatched disturbances and estimated peaks. Then, an integral sliding mode control strategy with nonlinear term is designed in permanent magnet synchronous motor control output. Then, the sliding mode surface is constructed by combining the estimates of the mismatched disturbances and the integral sliding mode control. Furthermore, the stability proof of the proposed control strategy is developed. Experimental results are given to validate effectiveness of the proposed control strategy. The proposed control strategy can improve speed control performance under the mismatched disturbances and overcurrent.

As one lethal malignancy in women’s reproductive systems, ovarian cancer (OC) is frequently detected at an advanced phase during diagnosis. when the disease has spread widely. The absence of obvious symptoms and powerful screening tools in the early stages makes treatment difficult and the prognosis poor. Despite the clinical remission that can be achieved in some patients after initial treatment, the recurrence rate is conspicuous, posing a considerable challenge in treating recurrent OC (ROC). In the retrospective analysis, we compared the effects of two treatment regimens, aqupla combined with paclitaxel liposome (NP group) versus aqupla combined with docetaxel (ND group), on survival and biomarkers in patients with ROC. The study included 121 OC patients, and clinical data were collected through an electronic medical record system, outpatient review records, and a follow-up record system. The results revealed a notably higher overall remission rate in the ND group than the NP group, but revealed no notable inter-group discrepancy in toxicities, implying that the aqupla combined with docetaxel regimen may be more effective in platinum-sensitive ROC patients. Additionally, post-treatment CA125 levels were lower in patients in the ND group, suggesting that the regimen may be more effective in reducing tumour load. Survival analysis further revealed that treatment regimen, FIGO stage, number of recurrent lesions, and pretreatment CA125 level were independent prognostic factors affecting patients’ 5-year OS and PFS. Overall for ROC patients, especially platinum-sensitive patients, the aqupla in combination with docetaxel regimen provided an improved survival benefit with a comparable safety profile, highlighting the importance of individualised treatment strategies.

The development of modern agriculture requires the reduction of water and chemical N fertilizer inputs. Increasing the planting density can maintain higher yields, but also consumes more of these restrictive resources. However, whether an increased maize density can compensate for the negative effects of reduced water and N supply on grain yield and N uptake in the arid irrigated areas remains unknown. This study is part of a long-term positioning trial that started in 2016. A split-split plot field experiment of maize was implemented in the arid irrigated area of northwestern China in 2020 to 2021. The treatments included two irrigation levels: local conventional irrigation reduced by 20% (W1, 3,240 m3 ha–1) and local conventional irrigation (W2, 4,050 m3 ha–1); two N application rates: local conventional N reduced by 25% (N1, 270 kg ha–1) and local conventional N (360 kg ha–1); and three planting densities: local conventional density (D1, 75,000 plants ha–1), density increased by 30% (D2, 97,500 plants ha–1), and density increased by 60% (D3, 120,000 plants ha–1). Our results showed that the grain yield and aboveground N accumulation of maize were lower under the reduced water and N inputs, but increasing the maize density by 30% can compensate for the reductions of grain yield and aboveground N accumulation caused by the reduced water and N supply. When water was reduced while the N application rate remained unchanged, increasing the planting density by 30% enhanced grain yield by 13.9% and aboveground N accumulation by 15.3%. Under reduced water and N inputs, increasing the maize density by 30% enhanced N uptake efficiency and N partial factor productivity, and it also compensated for the N harvest index and N metabolic related enzyme activities. Compared with W2N2D1, the N uptake efficiency and N partial factor productivity increased by 28.6 and 17.6% under W1N1D2. W1N2D2 had 8.4% higher N uptake efficiency and 13.9% higher N partial factor productivity than W2N2D1. W1N2D2 improved urease activity and nitrate reductase activity by 5.4% at the R2 (blister) stage and 19.6% at the V6 (6th leaf) stage, and increased net income and the benefit:cost ratio by 22.1 and 16.7%, respectively. W1N1D2 and W1N2D2 reduced the nitrate nitrogen and ammoniacal nitrogen contents at the R6 stage in the 40–100 cm soil layer, compared with W2N2D1. In summary, increasing the planting density by 30% can compensate for the loss of grain yield and aboveground N accumulation under reduced water and N inputs. Meanwhile, increasing the maize density by 30% improved grain yield and aboveground N accumulation when water was reduced by 20% while the N application rate remained constant in arid irrigation areas.

A pre-metastatic niche (PMN) is a protective microenvironment that facilitates the colonization of disseminating tumor cells in future metastatic organs. Extracellular vesicles (EVs) play a role in intercellular communication by delivering cargoes, such as noncoding RNAs (ncRNAs). The pivotal role of extracellular vesicle-derived noncoding RNAs (EV-ncRNAs) in the PMN has attracted increasing attention. In this review, we summarized the effects of EV-ncRNAs on the PMN in terms of immunosuppression, vascular permeability and angiogenesis, inflammation, metabolic reprogramming, and fibroblast alterations. In particular, we provided a comprehensive overview of the effects of EV-ncRNAs on the PMN in different cancers. Finally, we discussed the promising clinical applications of EV-ncRNAs, including their potential as diagnostic and prognostic markers and therapeutic targets.

This study evaluates petrophysical properties (especially porosity, permeability, tortuosity, and diffusivity) of representative geological rocks in the context of injectivity, storage space, and caprock integrity for effective utilization and long-term storage of carbon dioxide. A total of 10 geological rocks were selected as representative storage media for consideration as saline aquifers & depleted oil and gas reservoirs (sandstones and carbonates), basalts, and cap rocks, as well as utilization in organic-rich shale and coal seams. An integrated suite of laboratory tests, including liquid immersion porosimetry, gas expansion porosimetry, grain size distribution, mercury intrusion porosimetry, and gas diffusion, were performed on these various rock samples. The results exhibit a disparity of petrophysical properties among two broad groups of rocks: rocks selected for possible storage of CO2have porosities of ∼10-25%, permeabilities of ∼10−16-10−13m2, μm-sized pore-throat size distribution, and mostly good pore connectivity; in contrast, the potential caprocks have porosities of ∼0.5-5%, permeabilities of ∼10−20-10−18m2, pore throat sizes of

Abstract Breakdown of reproductive isolation facilitates flow of useful trait genes into crop plants from their wild relatives. Hybrid sterility, a major form of reproductive isolation exists between cultivated rice (Oryza sativa) and wild rice (O. meridionalis, Mer). Here, we report the cloning of qHMS1, a quantitative trait locus controlling hybrid male sterility between these two species. Like qHMS7, another locus we cloned previously, qHMS1 encodes a toxin-antidote system, but differs in the encoded proteins, their evolutionary origin, and action time point during pollen development. In plants heterozygous at qHMS1, ~ 50% of pollens carrying qHMS1-D (an allele from cultivated rice) are selectively killed. In plants heterozygous at both qHMS1 and qHMS7, ~ 75% pollens without co-presence of qHMS1-Mer and qHMS7-D are selectively killed, indicating that the antidotes function in a toxin-dependent manner. Our results indicate that different toxin-antidote systems provide stacked reproductive isolation for maintaining species identity and shed light on breakdown of hybrid male sterility.

Abstract Background Combination of chidamide and anti‐PD‐L1 inhibitor produce synergistic anti‐tumor effect in advanced NSCLC patients resistant to anti‐PD‐1 treatment. However, the effect of chidamide plus envafolimab has not been reported. Aims This study aimed to evaluate the efficacy of chidamide plus envafolimab in advanced NSCLC patients resistant toanti‐PD‐1 treatment. Materials and Methods Eligible advanced NSCLC patients after resistant to anti‐PD‐1 therapy received chidamide and envafolimab. The primary endpoint was objective response rate (ORR). The secondary end points included disease control rate (DCR), progression‐free survival (PFS), and safety. The expression of histone deacetylase 2 (HDAC2), PD‐L1, and blood TMB (bTMB) was also analyzed. Results After a median follow‐up of 8.1 (range: 7.6–9.2) months, only two patients achieved partial response. The ORR was 6.7% (2/30), DCR was 50% (15/30), and median PFS (mPFS) was 3.5 (95% confidence interval: 1.9–5.5) months. Biomarker analysis revealed that patients with high‐level HDAC2 expression had numerically superior ORR (4.3% vs. 0), DCR (52.2% vs. 0) and mPFS (3.7 vs. 1.4m). Patients with negative PD‐L1 had numerically superior DCR (52.2% vs. 33.3%) and mPFS (3.7m vs. 1.8m), so were those with low‐level bTMB (DCR: 59.1% vs. 16.7%, mPFS: 3.8 vs.1.9m). Overall safety was controllable. Discussion High HDAC2patients showed better ORR, DCR, and PFS. In addition, patient with negative PD‐L1 and low‐level bTMB had better DCR and PFS. This may be related to the epigenetic function of chidamide. However, the sample size was not big enough, so it is necessary to increase sample size to confirm the conclusion. Conclusion Combination of chidamide and envafolimab showed efficacy signals in certain NSCLC patients. But further identification of beneficial population is necessary for precision treatment.

Summary: Background: Treatment options remain rather limited for extensive disease small cell lung cancer (ED-SCLC) patients in second or further-line setting. Methods: The phase 2 investigator-initiated non-randomized study enrolled patients who had disease progression on at least one line of platinum-based chemotherapy. Participants received intravenous sintilimab 200 mg on day one and oral daily anlotinib 12 mg on days 1–14 once every three weeks per cycle. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. This study is registered with ClinicalTrials.gov (NCT04055792). Findings: Forty-two patients were enrolled between August 29, 2019 and December 26, 2021 at Henan Cancer Hospital in China. 37 patients were evaluable for efficacy. The median follow-up was 24.8 months (IQR: 16.9–28.2). The median PFS was 6.1 months (95% CI: 5.0–7.3). The OS was 12.7 months (95% CI: 7.1–18.2). The ORR was 56.8% (21/37, 95% CI: 40.0–73.5) and the DCR was 89.2% (33/37, 95% CI: 78.7–99.7). Forty patients (40/42, 95%) had at least one treatment-related adverse event (TRAE). Immune-related adverse events (irAEs) were reported in 39 patients (39/42, 93%), while grade 3 or higher irAEs occurred in 11 patients (11/42, 26%). The most frequent irAEs were hypothyroidism (16/42, 38%), elevated gamma-glutamyl transpeptidase (15/42, 36%) and elevated creatine kinase MB (15/42, 36%). The most frequent grade 3 or higher irAEs were elevated gamma-glutamyl transpeptidase (5/42, 12%) and increased aspartate aminotransferase (3/42, 7%). Interpretation: Sintilimab plus anlotinib demonstrated promising antitumor activities as second or further-line therapy for ED-SCLC and had manageable toxicities. The findings support further randomized controlled trials of this combination regimen for ED-SCLC. Funding: Henan Province Health and Youth Subject Leader Training Project, Henan Health Science and Technology Innovation Talents, ZHONGYUAN QIANREN JIHUA, Henan International Joint Laboratory of drug resistance and reversal of targeted therapy for lung cancer, Tumor Research Fund of Anti-Angiogenesis Targeted Therapy of China Anti-Cancer Association.

Glyptosternum maculatum, predominantly found in the middle and upper reaches of the Yarlung Zangbo River (YR) and its tributaries, is a fish species accorded second-class national protection. In 2021, it was recognized as one of the top ten excellent aquatic germplasm resources in China. However, its living conditions are far from promising. Therefore, in this study, we used the MaxEnt model to simulate potentially suitable habitat for G. maculatum, and then reconstructed the ecologically suitable habitat for G. maculatum using the kernel density algorithm after taking into account the distribution characteristics of hydropower stations. We predicted changes in area of the ecologically suitable habitat for G. maculatum under future climate change scenarios. The results indicate that the primary ecologically suitable areas for G. maculatum are situated in Ngamring County, Saga County, and Mainling County, covering a total area of 553.15 km2. Flow accumulation, NDVI, and the seasonality of temperature change are the main environmental factors affecting the distribution of G. maculatum. In the future, considering the ongoing impacts of factors such as hydropower stations and climate conditions, the projected suitable habitat area for G. maculatum is expected to span between 433.90 and 516.23 km2, marking a forecasted decrease of approximately 6.68 to 21.56 %. To prevent further reduction of suitable habitat, protective measures should be taken as early as possible.

Introduction: In Chinese patients with NSCLC, prevalence of EGFR-mutated (EGFRm) disease is high. In the global phase 3 ADAURA study (NCT02511106), adjuvant osimertinib was found to have a statistically significant and clinically meaningful improvement in disease-free survival (DFS) versus placebo in resected stage IB to IIIA EGFRm NSCLC. We present efficacy and safety data from a subgroup analysis of 159 Chinese patients enrolled in the People’s Republic of China from ADAURA. Methods: In ADAURA, patients with completely resected stage IB to IIIA EGFRm (exon 19 deletion/exon 21 L858R) NSCLC were randomized 1:1 to receive osimertinib (80 mg once daily) or placebo for 3 years or until disease recurrence/discontinuation. Adjuvant chemotherapy was permitted before randomization, per physician/patient choice. Primary end point was investigator-assessed DFS in stage II to IIIA disease; secondary end points included DFS in stage IB to IIIA (overall population), overall survival, health-related quality of life (HRQoL), and safety. Results: Of 682 patients enrolled globally, 159 patients in the People’s Republic of China were included in this subgroup analysis (osimertinib n = 77; placebo n = 82). Baseline characteristics were balanced across the treatment arms. At data cutoff, stage II to IIIA DFS hazard ratio (HR) was 0.23 (95% confidence interval [CI]: 0.13–0.42; maturity 59%); stage IB to IIIA DFS HR was 0.29 (95% CI: 0.17–0.48; maturity 42%). At 13% maturity (21 deaths), HR for overall survival in the stage IB to IIIA population was 0.51 (95% CI: 0.21–1.20). HRQoL was maintained from baseline, and safety was consistent with the global population. Conclusions: In this population of Chinese patients from ADAURA, adjuvant osimertinib was found to have a clinically meaningful improvement in DFS versus placebo, with maintained HRQoL and a safety profile consistent with the global study population.

Abstract Background The oncology-related indices between open and video-assisted thoracoscopic surgery (VATS) procedures for thymic carcinomas (TCs) and thymic neuroendocrine tumors (TNETs) remain unclear. Methods Propensity score matching (PSM) and multivariate Cox proportional risk models were used to evaluate the perioperative outcomes and survival rates of patients undergoing open and VATS for TCs and TNETs at the Second Affiliated Hospital of Air Force Military Medical University Hospital, between 2009 and 2018. Results Of the total 126 cases of TCs and TNETs, VATS treatment was used in 39 (30.9%). Advanced age and Masaoka-Koga staging were found to be independent prognostic factors for both TCs and TNETs, through a multifactorial Cox regression analysis. There was no significant difference in survival between the VATS and open groups before and after PSM; however, the VATS group had better perioperative-related indicators. There were no significant differences between the groups in terms of mortality at 30 days, mortality at 90 days, R0 resection rate, and 5-year survival rate (67.5% vs. 58.5% [P = 0.260] in the VATS group compared to the open group, in a PSM analysis of the 27 VATS and 27 open groups). Compared to the open group, the VATS group had a shorter length of hospital stay (13 days vs. 16 days, P = 0.015), a shorter level I care (0 days vs. 1 day, P = 0.016), and less intraoperative bleeding (50 mL vs. 300 mL, P

Abstract Cancer immunotherapy has transformed traditional treatments, with immune checkpoint blockade being particularly prominent. However, immunotherapy has minimal benefit for patients in most types of cancer and is largely ineffective in some cancers (such as pancreatic cancer and glioma). A synergistic anti-tumor response may be produced through the combined application with traditional tumor treatment methods. Radiotherapy (RT) not only kills tumor cells but also triggers the pro-inflammatory molecules’ release and immune cell infiltration, which remodel the tumor microenvironment (TME). Therefore, the combination of RT and immunotherapy is expected to achieve improved efficacy. In this review, we summarize the effects of RT on cellular components of the TME, including T cell receptor repertoires, different T cell subsets, metabolism, tumor-associated macrophages and other myeloid cells (dendritic cells, myeloid-derived suppressor cells, neutrophils and eosinophils). Meanwhile, non-cellular components such as lactate and extracellular vesicles are also elaborated. In addition, we discuss the impact of different RT modalities on tumor immunity and issues related to the clinical practice of combination therapy.

Abstract Malignant pleural mesothelioma (MPM) is a malignant tumor originating from the pleura, and its incidence has been increasing in recent years. Due to the insidious onset and strong local invasiveness of MPM, most patients are diagnosed in the late stage and early screening and treatment for high‐risk populations are crucial. The treatment of MPM mainly includes surgery, chemotherapy, and radiotherapy. Immunotherapy and electric field therapy have also been applied, leading to further improvements in patient survival. The Mesothelioma Group of the Yangtze River Delta Lung Cancer Cooperation Group (East China LUng caNcer Group, ECLUNG; Youth Committee) developed a national consensus on the clinical diagnosis and treatment of MPM based on existing clinical research evidence and the opinions of national experts. This consensus aims to promote the homogenization and standardization of MPM diagnosis and treatment in China, covering epidemiology, diagnosis, treatment, and follow‐up.

Peptide‒drug conjugates (PDCs) are drug delivery systems consisting of a drug covalently coupled to a multifunctional peptide via a cleavable linker. As an emerging prodrug strategy, PDCs not only preserve the function and bioactivity of the peptides but also release the drugs responsively with the cleavable property of the linkers. Given the ability to significantly improve the circulation stability and targeting of drugs in vivo and reduce the toxic side effects of drugs, PDCs have already been extensively applied in drug delivery. Herein, we review the types and mechanisms of peptides, linkers and drugs used to construct PDCs, and summarize the clinical applications and challenges of PDC drugs.

Abstract MAVS is an adapter protein involved in RIG-I-like receptor (RLR) signaling in mitochondria, peroxisomes, and mitochondria-associated ER membranes (MAMs). However, the role of MAVS in glucose metabolism and RLR signaling cross-regulation and how these signaling pathways are coordinated among these organelles have not been defined. This study reports that RLR action drives a switch from glycolysis to the pentose phosphate pathway (PPP) and the hexosamine biosynthesis pathway (HBP) through MAVS. We show that peroxisomal MAVS is responsible for glucose flux shift into PPP and type III interferon (IFN) expression, whereas MAMs-located MAVS is responsible for glucose flux shift into HBP and type I IFN expression. Mechanistically, peroxisomal MAVS interacts with G6PD and the MAVS signalosome forms at peroxisomes by recruiting TNF receptor-associated factor 6 (TRAF6) and interferon regulatory factor 1 (IRF1). By contrast, MAMs-located MAVS interact with glutamine-fructose-6-phosphate transaminase, and the MAVS signalosome forms at MAMs by recruiting TRAF6 and TRAF2. Our findings suggest that MAVS mediates the interaction of RLR signaling and glucose metabolism.

To enhance the erosion efficiency in traditional abrasive water jet processing, an abrasive water jet processing method based on self-excited fluid oscillation is proposed. Traditional abrasive water jet methods suffer from reduced jet kinetic energy due to the presence of a stagnation layer, which hinders efficient material removal. By integrating a self-oscillation chamber into the conventional abrasive water jet nozzle, the continuous jet is transformed into a pulsed jet, thereby increasing the jet velocity and enhancing the kinetic energy of the process. This modification aims to improve material removal efficiency. Using Ansys Fluent, we simulated the material removal efficiency on workpiece surfaces with varying lengths of self-oscillation chambers. The simulation results reveal that the optimal length of the self-oscillation chamber for maximum erosion is 4 mm. SiC materials were used to evaluate the impact of self-oscillation chamber length (L), jet pressure (P), abrasive flow rate (M), and abrasive grain size (D) on erosion. Experimental results show that the self-oscillation chamber increases erosion depth by 33 μm. The maximum erosion depths recorded were 167 μm when L = 4 mm, 223 μm when P = 16 MPa, 193 μm when M = 80 g/min, and 268 μm when D = 2000 μm. Overall, the self-excited oscillation effect enhances the erosion efficiency of the waterjet by 14%. This study further elucidates the factors influencing erosion behaviors in oscillating abrasive water jet processing.

The accurate prediction of the collision force magnitude resulting from ship berthing on docks is crucial for the rationality and safety of dock structural design. This paper presents a novel framework for the calculation of berthing collision force for ships (CBCF), which integrates field data, finite element models, and surrogate models. Based on field data and finite element analysis, the framework constructs and compares four surrogate models with low sample requirements, ultimately selecting the optimal surrogate model for predicting collision force. Furthermore, a sensitivity analysis of the parameters is conducted based on the selected model, followed by a comparison with the various methods used for collision force prediction. The results illustrate the effectiveness of the proposed framework in replacing finite element models for the rapid and accurate prediction of collision force. Comparison with existing methods also underscores the advantages of the proposed framework, including low sample requirements, high calculation accuracy, and exceptional efficiency. In summary, this study not only introduces a novel and precise surrogate model framework for the swift prediction of berthing collision force, but it also offers valuable insights into the prevention of ship collision with wharf accidents and facilitates the rational and safe design of wharf structures.

Under the dual-carbon target, the popularization and application of building integrated photovoltaic (BIPV) and ground source heat pump systems have made active buildings a research hotspot in the field of architecture and energy. Aiming at this issue, based on the building energy consumption model of active buildings, an active building energy management system (EMS) control strategy based on multi-energy load collaborative optimization is proposed. Firstly, based on the thermal dynamic characteristics and building performance parameters of active buildings, the overall refined energy consumption model of active buildings is constructed. Secondly, based on the construction of BIPV, the ice storage air conditioning system, the ground source heat pump system, and the integrated demand response (IDR) model, a tiered carbon transaction cost model is introduced, and an energy management strategy that leverages the synergistic application of renewable and active technologies is proposed. This strategy aims to meet the comprehensive needs of active buildings in terms of economic benefits, comfort, and environmental protection. Finally, the strategy’s effectiveness is demonstrated through a practical example.

Abstract Background The prognosis of patients with small cell lung cancer (SCLC) and brain metastases (BM) was poor. This study aimed to explore the efficacy and safety of anlotinib as third‐line or above treatment in SCLC with BM. Methods This was a subgroup analysis of the ALTER1202 trial, which was a randomized, placebo‐controlled trial aimed to evaluate the role of anlotinib as third‐line treatment or above in patients with SCLC. This study included patients with BM at baseline. The efficacy and safety outcomes included progression‐free survival (PFS), overall survival (OS), central nervous system (CNS), objective response rate (ORR), CNS disease control rate (DCR), time to CNS progression, and adverse events (AEs). Results Twenty‐one and nine patients with BM were included in the anlotinib and placebo groups, respectively. The median PFS and OS were 3.8 months (95% confidence interval [CI]: 1.8–6.1) and 6.1 months (95% CI: 4.1–8.0) in the anlotinib group. Anlotinib was associated with a significant improvement in PFS (hazard ratio [HR] = 0.15, 95% CI: 0.04–0.51, p = 0.0005) and OS (HR = 0.26, 95% CI: 0.09–0.73, p = 0.0061) than placebo. Anlotinib significantly prolonged the time to CNS progression (p

Abstract Background Non-small cell lung cancer (NSCLC) with HER2 mutation has entered into the era of targeted therapy. However, both anti-HER2 antibody–drug conjugates (ADCs) and tyrosine kinase inhibitors (TKIs) showed moderate objective response rate (ORR) and median progression-free survival (PFS). The aim of this study was to investigate the molecular features of responders to pyrotinib in advanced NSCLC with HER2 mutation. Methods Patients from our two previous phase II trials were pooled analyzed. Their circulating tumor DNA (ctDNA) were detected by next-generation sequencing (NGS) panels, and the correlation with the efficacy of pyrotinib was investigated. Results This pooled analysis included 75 patients, and 50 of them with baseline plasma samples were finally enrolled with a median age of 57 years old. The overall ORR and median PFS were 28% and 7.0 months respectively. Biomarker analysis showed that 5 patients were ctDNA nonshedding. Patients with TP53 wild type were significantly associated with higher disease control rate (97.1%vs. 68.8%, p = 0.010), PFS (median 8.4 vs. 2.8 months, p = 0.001) and overall survival (OS, median 26.7 vs. 10.4 months, p

Abstract Background RNA 5-methylcytosine (m5C) modification plays critical roles in the pathogenesis of various tumors. However, the function and molecular mechanism of RNA m5C modification in tumor drug resistance remain unclear. Methods The correlation between RNA m5C methylation, m5C writer NOP2/Sun RNA methyltransferase family member 2 (NSUN2) and EGFR-TKIs resistance was determined in non-small-cell lung cancer (NSCLC) cell lines and patient samples. The effects of NSUN2 on EGFR-TKIs resistance were investigated by gain- and loss-of-function assays in vitro and in vivo. RNA-sequencing (RNA-seq), RNA bisulfite sequencing (RNA-BisSeq) and m5C methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR) were performed to identify the target gene of NSUN2 involved in EGFR-TKIs resistance. Furthermore, the regulatory mechanism of NSUN2 modulating the target gene expression was investigated by functional rescue and puromycin incorporation assays. Results RNA m5C hypermethylation and NSUN2 were significantly correlated with intrinsic resistance to EGFR-TKIs. Overexpression of NSUN2 resulted in gefitinib resistance and tumor recurrence, while genetic inhibition of NSUN2 led to tumor regression and overcame intrinsic resistance to gefitinib in vitro and in vivo. Integrated RNA-seq and m5C-BisSeq analyses identified quiescin sulfhydryl oxidase 1 (QSOX1) as a potential target of aberrant m5C modification. NSUN2 methylated QSOX1 coding sequence region, leading to enhanced QSOX1 translation through m5C reader Y-box binding protein 1 (YBX1). Conclusions Our study reveals a critical function of aberrant RNA m5C modification via the NSUN2-YBX1-QSOX1 axis in mediating intrinsic resistance to gefitinib in EGFR-mutant NSCLC.

Tumor-associated macrophages (TAMs) are critical in the tumor microenvironment (TME) of hepatocellular carcinoma (HCC). Major vault protein (MVP) mediates multidrug resistance, cell growth and development, and viral immunity. However, the relationship between MVP and TAMs polarization has not been clarified in HCC. We found that MVP significantly increased M2-TAMs infiltration levels in tumor tissues of HCC patients. MVP promoted HCC proliferation, metastasis, and invasion by regulating M2 polarization in vivo and in vitro. Mechanistically, MVP associated with signal transducer and activator of transcription 6 (STAT6) and enhanced STAT6 phosphorylation. STAT6 translocated from the cytosol to the nucleus and regulated M2 macrophage-associated gene transcription. These findings suggest that MVP modulates the macrophage M2 transcriptional program, revealing its potential role in the TAMs of TME.

Trace elements (TEs) are essential for the treatment of rheumatoid arthritis (RA). This study aimed to prepare a TEs solution enriched with various organic states to evaluate its preventive, therapeutic effects, and mechanism of action in RA and to provide a treatment method for RA treatment. The TEs in natural ore were extracted and added to 0.5% (W/V) L-alanyl-L-glutamine (LG) to obtain a TEs solution (LG-WLYS), which was examined for its concentration and quality. The antioxidant properties and effects of LG-WLYS on cell behavior were evaluated at the cellular level. The preventive and therapeutic effects and mechanism of action of LG-WLYS in rats with RA were explored. The LG-WLYS solution was clear, free from visible foreign matter, and had a pH of 5.33 and an osmolality of 305.67 mOsmol/kg. LG-WLYS inhibited cell migration and angiogenesis. LG-WLYS solution induced macrophages to change from M1-type to M2-type, increased the content of antioxidant enzymes (glutathione, superoxide dismutase, and IL-10), decreased the levels of nitric oxide, malondialdehyde, TNF-α, IL-1β, IL-6, COX-2, and iNOs, scavenging reactive oxygen species from the lesion site, inhibiting the apoptosis of chondrocytes, regulating inflammatory microenvironment, and decreasing inflammation response to exert the therapeutic effect for RA. In conclusion, LG-WLYS has outstanding therapeutic and preventive effects against RA and has enormous potential for further development.

Abstract Thymic epithelial tumors (TETs) are a relatively rare type of thoracic tumor, accounting for less than 1% of all tumors. The incidence of TETs is about 3.93/10000 in China, slightly higher than that of European and American countries. For resectable TETs, complete surgical resection is recommended. Radiotherapy or chemotherapy may be used as postoperative adjuvant treatment. Treatment for advanced, unresectable TETs consist mainly of radiotherapy and chemotherapy, but there is a lack of standard first‐ and second‐line treatment regimens. Recently, targeted therapies and immune checkpoint inhibitors have shown promising outcomes in TETs. Based on the currently available clinical evidences and the opinions of the national experts, the Thymic Oncology Group of Yangtze River Delta Lung Cancer Cooperation Group (East China LUng caNcer Group, ECLUNG; Youth Committee) established this Chinese expert consensus on the clinical diagnosis and treatment of TETs, covering the epidemiology, diagnosis, treatment, prognosis and follow‐up of TETs.

Abstract The transformation from non‐small‐cell lung cancer (NSCLC) to small‐cell lung cancer (SCLC) is one of the mechanisms of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) resistance. Previous studies exhibited that the median transformation time was 17.8 months for NSCLC to SCLC. Here we introduced a case of lung adenocarcinoma (LADC) with EGFR19 exon deletion mutation in which the pathological transformation emerged only 1 month after lung cancer surgery and receiving EGFR‐TKI inhibitor. Eventually, the pathological examination confirmed the patient experienced a transformation from LADC to SCLC with EGFR, tumor protein p53 (TP53), RB transcriptional corepressor 1 (RB1), and SRY‐box transcription factor 2 (SOX2) mutation. Although the transformation of LADC with EGFR‐mutant into SCLC after targeted therapy was frequent, the pathological results of most patients were only biopsy specimens, which cannot rule out the existence of mixed pathological components of the primary tumor. In this case, the patient's postoperative pathology was sufficient to exclude the probability of mixed tumor components, confirming that the patient's pathological change was indeed transformation from LADC to SCLC. In addition, primary drug resistance in such a short time after surgery and osimertinib‐targeted therapy has not been reported before. We detected the molecular state of this patient before and after SCLC transformation through targeted gene capture and high‐throughput sequencing, and also found for the first time that the mutations of EGFR, TP53, RB1, and SOX2 continue to exist before and after transformation, but the mutation abundance is different. In our paper, the occurrence of small‐cell transformation is affected largely by these gene mutations.

Agricultural soil microorganisms play a crucial role in farmland ecosystems and are integral to the material cycle in these environments. The composition and abundance of soil microorganisms are influenced by agronomic measures that alter the soil microenvironment. These changes are pivotal to enhancing crop resistance, maximizing yield, and facilitating nutrient cycling in farmlands. Drawing on prior research advancements, this study systematically examined the functions of soil microorganisms, the effects of various agronomic measures on their populations, and the ways in which agronomic measures regulate soil microorganisms, and this article offers a comprehensive study of agricultural influences on microorganisms. Additionally, it outlines key areas for future research on soil microorganisms in farmlands, aiming to provide valuable insights for the sustainable development of farmland ecosystems.

This study investigates wave-stratified flow in a horizontal pipe at high pressure, and flow characteristics are obtained, such as flow pattern map, liquid film thickness, and pressure drop. Compared with a flow pattern map of a gas-liquid two-phase flow carried out at atmosphere, stratified flow zone is depressed with increasing system pressure and the critical gas superficial velocity decreases for smooth-wave-stratified flow transition, while the critical liquid superficial velocity increases for stratified-intermittent transition. On one hand, the compressed air results in an increase in momentum transfer between gas and liquid phases, which accounts for the smaller gas superficial velocity that is encountered in both smooth-wave and stratified-annular flow transition at higher pressure. One the other hand, it slows down the liquid below the crest, and it makes the interface wave crest unstable and split for the vortex shedding behind the wave crest, which accounts for flow regime transition in gas-liquid two-phase flows in pipelines. As a result, stratified-intermittent flow transition is depressed and delayed. The pressure influence on the liquid film profile is analyzed, and relationships between film thickness and dimensionless numbers are studied, such as liquid Weber number and gas Weber number. Friction factors on different interfaces at high pressure are studied, and new empirical formulas are deduced.

Leptomeningeal metastasis (LM) is a serious complication of advanced non–small cell lung cancer (NSCLC), and the incidence of LM has been increasing yearly in recent times. There is no consensus on the best treatment modality for LM, which underscores a difficult problem in the management of advanced NSCLC patients. The existing treatments include molecular targeted therapy, systemic chemotherapy, local radiotherapy, antivascular tumor therapy, intrathecal chemotherapy, and immunotherapy, but their efficacy is not satisfactory. In this article, we briefly describe the clinical manifestations, diagnosis, and treatment of NSCLC-LM and discuss progress regarding evaluation of the efficacy of LM treatment to better provide a necessary reference for clinical practice and clinical trial evaluation.

Cadmium (Cd) contamination in rice (Oryza sativa) is particularly problematic due to its high risk to human health. Investigating the hidden roles of seed endophytes of rice in influencing Cd accumulation is essential to comprehensively understand the effects of biotic and abiotic factors to food security. Here, the content of Cd in soils and rice (Huanghuazhan) seeds from 19 sites along the Yangtze River exhibited considerable differences. From a biotic perspective, we observed the dominant endophytic bacteria, Stenotrophomonas (7.25 %), contribute to Cd control of rice (below 0.2 mg kg−1). Partial Least Squares (PLS) analysis further suggested that Enterobacteriaceae (15.48 %), altitude and pH were found to be the strong variables that might reduce the Cd uptake of rice. In contrast, Cytophagaceae (0.58 %), latitude and mean annual air pressure had the opposite effect. In pot experiments, after respectively inoculating the isolated endophytic bacteria Stenotrophomonas T4 and Enterobacter R1, N1 (f_Enterobacteriaceae), the Cd contents in shoot decreased by 47.6 %, 21.9 % and 33.0 % compared to controls. The distribution of Cd resistant genes (e.g., czcABC, nccAB, cznA) of Stenotrophomonas, Enterobacteriaceaea and Cytophagaceae further suggested their distinct manners in influencing the Cd uptake of rice. Overall, this study provides new insights into the food security threatened by globally widespread Cd pollution.

In recent years, the problem of Cd pollution in paddy fields has become more and more serious, which seriously threatens the safe production of food crops and human health. Using microorganisms to reduce cadmium pollution in rice fields is a green, safe and efficient method, the complicated interactions between the microbes in rice roots throughout the process of cadmium absorption by rice roots are poorly understood. In this investigation, a hydroponic pot experiment was used to examine the effects of bacteria R3 (Herbaspirillum sp) and T4 (Bacillus cereus) on cadmium uptake and the endophytic bacterial community in rice roots. The results showed that compared with CK (Uninoculated bacterial liquid), the two strains had significant inhibitory or promotive effects on cadmium uptake in rice plant, respectively. Among them, the decrease of cadmium content in rice plants by R3 strain reached 78.57-79.39%, and the increase of cadmium content in rice plants by T4 strain reached 140.49-158.19%. Further investigation showed that the cadmium content and root cadmium enrichment coefficient of rice plants were significantly negatively correlated with the relative abundances of Burkholderia and Acidovorax, and significantly positively correlated with the relative abundances of Achromobacter, Agromyces and Acidocella. Moreover, a more complex network of microbes in rice roots inhibited rice plants from absorbing cadmium. These results suggest that cadmium uptake by rice plants is closely related to the endophytic bacterial community of roots. This study provides a reference scheme for the safe production of crops in cadmium contaminated paddies and lays a solid theoretical foundation for subsequent field applications.

Abstract Human epidermal growth factor receptor 2 (HER2) possesses tyrosine kinase activity and participates in cell growth, differentiation and migration, and survival. Its alterations, mainly including mutations, amplifications, and overexpression are associated with poor prognosis and are one of the major drivers in non–small cell lung cancer (NSCLC). Several clinical trials had been investigating on the treatments of HER2‐altered NSCLC, including conventional chemotherapy, programmed death 1 (PD‐1) inhibitors, tyrosine kinase inhibitors (TKIs) and antibody‐drug conjugates (ADCs), however, the results were either disappointing or encouraging, but inconsistent. Trastuzumab deruxtecan (T‐DXd) was recently approved by the Food and Drug Administration as the first targeted agent for treating HER2‐mutant NSCLC. Effective screening of patients is the key to the clinical application of HER2‐targeted agents such as TKIs and ADCs. Various testing methods are nowadays available, including polymerase chain reaction (PCR), next‐generation sequencing (NGS), fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), etc. Each method has its pros and cons and should be reasonably assigned to appropriate patients for diagnosis and guiding treatment decisions. To help standardize the clinical workflow, our expert group reached a consensus on the clinical management of HER2‐altered NSCLC, focusing on the diagnosis and treatment strategies.

Cervical cancer (CC) is one of the most prevalent malignancies among females. Cytoprotective autophagy could confer cancer cell tolerance to hypoxic stress, promoting cell survival and adaptation. Aspartyl-tRNA synthetase 1 antisense 1 (DARS-AS1) is an oncogenic long non-coding RNA (lncRNA) in various cancers, but how DARS-AS1 regulates cytoprotective autophagy in hypoxic environment in CC remains unclear. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were conducted to explore the interaction between hypoxia-inducible factor 1 subunit alpha (HIF1α) and DARS-AS1 promoter. Methylated RNA immunoprecipitation (MeRIP) followed by quantitative real-time polymerase-chain reaction (RT-qPCR) detected methylated RNA level. The process of autophagic maturation was monitored by immunofluorescence staining. Higher DARS-AS1 expression was found in CC tissues and cytoprotective. We also uncovered that hypoxic exposure induced cytoprotective autophagy via HIF1α/DARS-AS1/DARS axis. Moreover, DARS-AS1 was validated to facilitate DARS translation via recruiting N6-adenosine-methyltransferase methyltransferase like 3 (METTL3) and methyltransferase like 14 (METTL14), which bound with DARS mRNA DARS mRNA 5’ untranslated region (5ʹUTR) and promoting its translation. The present study demonstrated that the ‘HIF1α/DARS-AS1/DARS/ATG5/ATG3’ pathway regulated the hypoxia-induced cytoprotective autophagy of CC and might be a promising target of therapeutic strategies for patients afflicted with CC.

Abstract Background Although programmed cell death 1 (PD‐1) blockade plus chemotherapy can significantly prolong the progression‐free survival (PFS) and overall survival (OS) in first‐line settings in patients with driver‐negative advanced non‐small‐cell lung cancer (NSCLC), the predictive biomarkers remain undetermined. Here, we investigated the predictive value of tumor immune microenvironmental marker expression to characterize the response features to PD‐1 blockade plus chemotherapy. Methods Tumor tissue samples at baseline were prospectively collected from 144 locally advanced or metastatic NSCLC patients without driver gene alterations who received camrelizumab plus chemotherapy or chemotherapy alone. Tumor immune microenvironmental markers, including PD‐1 ligand (PD‐L1), CD8, CD68, CD4 and forkhead box P3, were assessed using multiplex immunofluorescence (mIF) assays. Kaplan‐Meier curves were used to determine treatment outcome differences according to their expression status. Mutational profiles were compared between tumors with distinct expression levels of these markers and their combinations. Results Responders had significantly higher CD8/PD‐L1 (P = 0.015) or CD68/PD‐L1 co‐expression levels (P = 0.021) than non‐responders in the camrelizumab plus chemotherapy group, while no difference was observed in the chemotherapy group. Patients with high CD8/PD‐L1 or CD68/PD‐L1 co‐expression level was associated with significantly longer PFS (P = 0.002, P = 0.024; respectively) and OS (P = 0.006, P = 0.026; respectively) than those with low co‐expression in camrelizumab plus chemotherapy group. When comparing survival in the camrelizumab plus chemotherapy with chemotherapy by CD8/PD‐L1 co‐expression stratification, significantly better PFS (P = 0.003) and OS (P = 0.032) were observed in high co‐expression subgroups. The predictive value of CD8/PD‐L1 and CD68/PD‐L1 co‐expression remained statistically significant for PFS and OS when adjusting clinicopathological features. Although the prevalence of TP53 or KRAS mutations was similar between patients with and without CD8/PD‐L1 or CD68/PD‐L1 co‐expression, the positive groups had a significantly higher proportion of TP53/KRAS co‐mutations than the negative groups (both 13.0% vs. 0.0%, P = 0.023). Notably, enriched PI3K (P = 0.012) and cell cycle pathway (P = 0.021) were found in the CD8/PD‐L1 co‐expression group. Conclusion Tumor immune microenvironmental marker expression, especially CD8/PD‐L1 or CD68/PD‐L1 co‐expression, was associated with the efficacy of PD‐1 blockade plus chemotherapy as first‐line treatment in patients with advanced NSCLC.

Background: This study aimed to investigate the role of postoperative radiation therapy in a large population-based cohort of patients with stage I–III male breast cancer (MaBC). Methods: Patients with stage I–III breast cancer treated with surgery were selected from the Surveillance, Epidemiology, and End Results cancer database from 2010 to 2015. Multivariate logistic regression identified the predictors of radiation therapy administration. Multivariate Cox regression model was used to evaluate the predictors of survival. Results: We identified 1321 patients. Age, stage, positive regional nodes, surgical procedure, and HER2 status were strong predictors of radiation therapy administration. There was no difference between patients who received radiation therapy and those who did not (P = 0.46); however, after propensity score matching, it was associated with improved OS (P = 0.04). In the multivariate analysis of the unmatched cohort, the factors associated with better OS were administration of radiation therapy and chemotherapy. In the subset analysis of the unmatched cohort, postoperative radiation therapy was associated with improved OS in men undergoing breast-conserving surgery (BCS), with four or more node-positive or larger primary tumours (T3/T4). Furthermore, we found no benefit of radiation therapy, regardless of the type of axillary surgery in mastectomy (MS). In older MaBC patients with T1-2N1 who underwent MS, radiation therapy showed no significant effects, regardless of chemotherapy. Conclusion: Postoperative radiation therapy could improve the survival of MaBC patients undergoing BCS, with four or more node-positive or larger primary tumours. Moreover, it should be carefully considered in patients undergoing MS and older T1-2N1 patients.

Epidermal growth factor receptor (EGFR) mutations are common driver genes in nonsmall-cell lung cancer and have different sensitivities to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). EGFR is divided into classic mutations and rare mutations. Classic mutations are well known, but the understanding of rare mutations is not sufficient. In this article, we summarize the clinical research and treatment progress of rare mutations for different EGFR-TKIs and provide a basis for clinical treatment decisions.

Among enteroviruses, echovirus can cause severe illnesses in neonates or infants, with high morbidity and mortality. Autophagy, a central component of host defense mechanisms, can function against diverse infections. In the present study, we investigated the interplay between echovirus and autophagy. We demonstrated that echovirus infection increases LC3-II expression dose-dependently, accompanied by an increased intracellular LC3 puncta level. In addition, echovirus infection induces the formation of autophagosome. These results suggest that echovirus infection induces autophagy machinery. Furthermore, phosphorylated mTOR and ULK1 were both decreased upon echovirus infection. In contrast, both levels of the vacuolar protein sorting 34 (VPS34) and Beclin-1, the downstream molecules which play essential roles in promoting the formation of autophagic vesicles, increased upon virus infection. These results imply that the signaling pathways involved in autophagosome formation were activated by echovirus infection. Moreover, induction of autophagy promotes echovirus replication and viral protein VP1 expression, while inhibition of autophagy impairs VP1 expression. Our findings suggest that autophagy can be induced by echovirus infection via regulating mTOR/ULK1 signaling pathway and exhibits a proviral function, revealing the potential role of autophagy in echovirus infection.