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Abstract The importance of uncommon/rare oncogenic drivers in non‐small cell lung cancer (NSCLC) was underscored during the 20th China Lung Cancer Summit. These drivers, while present in a significant proportion of NSCLC patients, remain a challenge for diagnosis and therapeutic targeting. In the never‐smokers/low smokers category with mutations such as EGFR and HER2, the efficacy of immune checkpoint inhibitors (ICIs) remains suboptimal, attributed to lower PD‐L1 expression and tumor mutation burden (TMB). However, heavy smokers, often with mutations like KRAS, may derive benefits from ICIs, as supported by trials like CheckMate‐057. With the complex landscape of these drivers and their clinical implications, the summit culminated in six pivotal consensus points, aiming to guide future research and clinical decisions. Despite the advancements, the detection, interpretation, and therapeutic strategies involving these drivers necessitate further exploration and standardization.

Effective monitoring of atmospheric concentrations is vital for assessing the Stockholm Convention's effectiveness on persistent organic pollutants (POPs). This task, particularly challenging in polar regions due to low air concentrations and temperature fluctuations, requires robust sampling techniques. Furthermore, the influence of temperature on the sampling efficiency of polyurethane foam discs remains unclear. Here we employ a flow-through sampling (FTS) column coupled with an active pump to collect air samples at varying temperatures. We delved into breakthrough profiles of key pollutants, such as polycyclic aromatic hydrocarbons (PAHs), polychlorobiphenyls (PCBs), and organochlorine pesticides (OCPs), and examined the temperature-dependent behaviors of the theoretical plate number (N) and breakthrough volume (VB) using frontal chromatography theory. Our findings reveal a significant relationship between temperature dependence coefficients (KTN, KTV) and compound volatility, with decreasing values as volatility increases. While distinct trends are noted for PAHs, PCBs, and OCPs in KTN, KTV values exhibit similar patterns across all chemicals. Moreover, we establish a binary linear correlation between log (VB/m3), 1/(T/K), and N, simplifying breakthrough level estimation by enabling easy conversion between N and VB. Finally, an empirical linear solvation energy relationship incorporating a temperature term is developed, yielding satisfactory results for N at various temperatures. This approach holds the potential to rectify temperature-related effects and loss rates in historical data from long-term monitoring networks, benefiting polar and remote regions.

ObjectivesDysphagia is a common complication in stroke patients, widely affecting recovery and quality of life after stroke. The objective of this systematic review is to identify the gaps that between evidence and practice by critically assessing the quality of clinical practice guidelines (CPGs) for management of dysphagia in stroke.MethodsWe systematically searched academic databases and guideline repositories between January 1, 2014, and August 1, 2023. The Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument was used by two authors to independently assess CPG quality.ResultsIn a total of 14 CPGs included, we identified that three CPGs obtained a final evaluation of “high quality,” nine CPGs achieved “moderate quality” and two CPGs received “low quality.” The domain of “scope and purpose” achieved the highest mean score (91.1%) and the highest median (IQR) of 91.7% (86.1, 94.4%), while the domain of “applicability” received the lowest mean score (55.8%) and the lowest median (IQR) of 55.4% (43.2, 75.5%).ConclusionThe CPG development group should pay more attention to improving the methodological quality according to the AGREE II instrument, especially in the domain of “applicability” and “stakeholder involvement;” and each item should be refined as much as possible.

Summary: Background: Central nervous system (CNS) metastases is inevitable for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). AZD3759 is a novel EGFR-TKI with impressive CNS penetration. Methods: We initiated a phase 2, multi-center, umbrella trial (CTONG1702, NCT03574402). The eighth arm assessed the efficacy and safety of AZD3759 in untreated EGFR-mutated NSCLC with CNS metastases. The primary objective was the objective response rate (ORR). Simon’s minimax two-stage design was used to calculate the sample size. Dose optimal selection was performed using 200- and 300-mg bid cohorts. Findings: Between Oct 18, 2018 and Sep 14, 2020, 30 patients received AZD3759 at 200 mg (n = 15) or 300 mg (n = 15) bid. At data cutoff (Dec 31, 2022), median follow-up was 35.4 months. The primary endpoint was reached, with a confirmed ORR of 70% (21/30) (200 mg, 80%; 300 mg, 60%). The median progression-free survival was 12.9 months (200 mg, 15.8 months; 300 mg, 10.7 months). Grade 3 or 4 treatment-related adverse events occurred in 73% (22/30) of the patients (200 mg: 60%; 300 mg: 87%). 59% (10/17) of the patients developed a T790M mutation at disease progression. The median overall survival was 33.7 months, and 34.1 months and 25.3 months in patient treated with or without osimertinib in a later-line setting, respectively. Interpretation: AZD3759 showed promising efficacy and tolerable safety as a first-line therapy in EGFR-mutated NSCLC with CNS metastases. The 200-mg bid cohort had better clinical outcomes. Sequential use of AZD3759 and third-generation EGFR-TKIs represents a new option. Funding: Chinese Thoracic Oncology Group (CTONG).

Abstract. Cell death occurs in various tissues and organs in the body. It is a physiological or pathological process that has different effects. It is of great significance in maintaining the morphological function of cells and clearing abnormal cells. Pyroptosis, apoptosis, and necrosis are all modes of cell death that have been studied extensively by many experts and scholars, including studies on their effects on the liver, kidney, the heart, other organs, and even the whole body. The heart, as the most important organ of the body, should be a particular focus. This review summarizes the mechanisms underlying the various cell death modes and the relationship between the various mechanisms and heart diseases. The current research status for heart therapy is discussed from the perspective of pathogenesis.

Abstract Background Rearranged during transfection (RET) has been proven to be a tumorigenic target in non-small cell lung cancers (NSCLCs). In RET-rearranged NSCLCs, molecular features and their impact on prognosis were not well illustrated, and the activity of mainstay therapeutics has not currently been well compared. Methods Patients diagnosed with NSCLCs with RET rearrangements were analyzed for concomitant mutations, tumor mutation burden (TMB), PD-L1 expression, T cell receptor repertoire and clinical outcomes with chemotherapy, immune checkpoint inhibitors (ICIs), and multikinase inhibitors (MKIs). Results Among 129 patients with RET-rearranged NSCLC who were analyzed, 41.1% (53/129) had co-occurring genetic alterations by next-generation sequencing, and concomitant TP53 mutation appeared most frequently (20/53, 37.7%). Patients with concurrent TP53 mutation (n = 15) had shorter overall survival than those without (n = 30; median, 18.4 months [95% CI, 8.6–39.1] vs 24.8 months [95% CI, 11.7–52.8]; P < 0.05). Patients with lower peripheral blood TCR diversity (n = 5) had superior overall survival compared with those with higher diversity (n = 6; median, 18.4 months [95% CI, 16.9–19.9] vs 4.8 months [95% CI, 4.5–5.3]; P = 0.035). An association with overall survival was not observed for PD-L1 expression nor for tumor mutation burden level. Median progression-free survival was not significantly different across chemotherapy, ICIs, and MKIs (median, 3.5 vs 2.5 vs 3.8 months). For patients treated with ICIs, the disease control rate was 60% (6/10) and the objective response rate was 20% (2/10). Conclusions RET-rearranged lung cancers can be heterogeneous in terms of concomitant genetic alterations. Patients with concurrent TP53 mutation or high peripheral blood TCR repertoire diversity have relatively inferior overall survival in this series. Outcomes with traditional systemic therapies in general are suboptimal.

Abstract Background To understand the gene expression networks controlling flower color formation in alfalfa, flowers anthocyanins were identified using two materials with contrasting flower colors, namely Defu and Zhongtian No. 3, and transcriptome analyses of PacBio full-length sequencing combined with RNA sequencing were performed, across four flower developmental stages. Results Malvidin and petunidin glycoside derivatives were the major anthocyanins in the flowers of Defu, which were lacking in the flowers of Zhongtian No. 3. The two transcriptomic datasets provided a comprehensive and systems-level view on the dynamic gene expression networks underpinning alfalfa flower color formation. By weighted gene coexpression network analyses, we identified candidate genes and hub genes from the modules closely related to floral developmental stages. PAL, 4CL, CHS, CHR, F3’H, DFR, and UFGT were enriched in the important modules. Additionally, PAL6, PAL9, 4CL18, CHS2, 4 and 8 were identified as hub genes. Thus, a hypothesis explaining the lack of purple color in the flower of Zhongtian No. 3 was proposed. Conclusions These analyses identified a large number of potential key regulators controlling flower color pigmentation, thereby providing new insights into the molecular networks underlying alfalfa flower development.

Objective: This study investigated survival in selected Chinese patients with advanced lung adenocarcinoma who received initial chemotherapy with pemetrexed. We also explored the relationship between genetic biomarkers and pemetrexed efficacy.Methods: We retrospectively collected patients (n = 1,047) enrolled in the Chinese Patient Assistance Program from multiple centers who received pemetrexed alone or combined with platinum as initial chemotherapy and continued pemetrexed maintenance therapy for advanced lung adenocarcinoma from November 2014 to June 2017. The outcomes were duration of treatment (DOT) and overall survival (OS). Clinical features were analyzed for their influence on the treatment effect and prognosis. Next-generation sequencing (NGS) was performed to identify genetic biomarkers associated with the efficacy of pemetrexed.Results: The median DOT was 9.1 months (95% CI: 8.5–9.8), and the median OS was 26.2 months (95% CI: 24.2–28.1). OS was positively correlated with DOT (r = 0.403, P < 0.001). Multivariable analysis showed that smoking status and Eastern Cooperative Oncology Group (ECOG) performance status (PS) were independently associated with DOT; smoking status, ECOG PS, targeted therapy, and EGFR/ALK/ROS1 status were independently associated with OS. NGS in 22 patients with available samples showed genes with high mutation rates were: TP53 (54.5%), EGFR (50.0%), MYC (18.2%), and PIK3CA (13.6%). When grouped based on progression-free survival (PFS) reported in the PARAMOUNT study, the DOT > 6.9 months set was associated with PIK3CA, ALK, BRINP3, CDKN2A, CSMD3, EPHA3, KRAS, and RB1 mutations, while ERBB2 mutation was observed only in the DOT ≤ 6.9 months set.Conclusion: This study shows that initial chemotherapy with pemetrexed is an effective regimen for advanced lung adenocarcinoma in selected Chinese patients. There is no specific genetic profile predicting the benefit of pemetrexed found by NGS. Biomarkers predicting the efficacy of pemetrexed need further exploration.

Abstract Background Brain metastasis (BM) is associated with poor prognosis in patients with non-small cell lung cancer (NSCLC). Recent studies demonstrated that microRNA-330-3p (miR-330-3p) was involved in NSCLC brain metastasis (BM). However, the exact parts played by miR-330-3p in BM of NSCLC remain unknown. Discovery and development of biomarkers and elucidation of the mechanism underlying BM in NSCLC is critical for effective prophylactic interventions. Here, we evaluated the expression and biological effects of miR-330-3p in NSCLC cells and explored the underlying mechanism of miR-330-3p in promoting cell migration and invasion in NSCLC. Methods Stable over-expression and knockdown of miR-330-3p in NSCLC cells was constructed with lentivirus. Expression levels of miR-330-3p in NSCLC cells were quantified by quantitive real-time PCR (qRT-PCR). The effects of miR-330-3p on NSCLC cells were investigated using assays of cell viability, migration, invasion, cell cycle, apoptosis, western blotting, immunohistochemical, and immunofluorescence staining. A xenograft nude mouse model and in situ brain metastasis model were used to observe tumor growth and brain metastasis. The potential target of miR-330-3p in NSCLC cells was explored using the luciferase reporter assay, qRT-PCR, and western blotting. The miR-330-3p targets were identified using bioinformatics analysis and verified by luciferase reporter assay. The correlation between GRIA3 and DNA methyltransferase (DNMT) 1 and DNMT3A was tested by RT-PCR, western blotting, and co-immunoprecipitation (IP). Results miR-330-3p was significantly up-regulated in NSCLC cell lines. MTT assay, transwell migration, and invasion assays showed that miR-330-3p promoted the growth, migration, and invasion of NSCLC cells in vitro and induced tumor growth and metastasis in vivo. Luciferase reporter assays showed that GRIA3 was a target of miR-330-3p. qRT-PCR and western blotting exhibited that miR-330-3p promoted the growth, invasion, and migration of NSCLC cells by activating mitogen-activated protein kinase (MAPK)/extracellular-regulated protein kinases (ERK) signaling pathway. Furthermore, miR-330-3p up-regulated the total DNA methylation in NSCLC cells, and co-IP-demonstrated GRIA3 was directly related with DNMT1 and DNMT3A. Conclusions miR-330-3p promoted the progression of NSCLC and might be a potential target for the further research of NSCLC brain metastasis.

Abstract The original article [1] contained incorrect affiliations for the authors.

The base excision repair (BER) pathway removes DNA damage caused by ionizing radiation, reactive oxidative species and methylating agents. ADPRT and APE1 are two important genes in the BER pathway. Several studies have evaluated the association between polymorphisms in the two BER genes (ADPRT Val762Ala and APE1 Asp148Glu) and breast cancer risk. However, the results are inconsistent.In this study, we conducted a meta-analysis to derive a more precise estimation. A total of 8 studies were included in the meta-analysis (6 studies with 2,521 cases and 2,652 controls for ADPRT Val762Ala polymorphism and 5 studies with 2,539 cases and 2,572 controls for APE1 Asp148Glu polymorphism). For ADPRT Val762Ala polymorphism, no obvious associations were found for all genetic models (Val/Ala vs. Val/Val: OR = 0.960, 95% CI = 0.845-1.090; Ala/Ala vs. Val/Val: OR = 0.897, 95% CI = 0.683-1.178; dominant model: OR = 0.953, 95% CI = 0.843-1.077; and recessive model: OR = 1.084, 95% CI = 0.838-1.403). For APE1 Asp148Glu polymorphism, also no obvious associations were found for all genetic models (Asp/Glu vs. Asp/Asp: OR = 0.947, 95% CI = 0.829-1.082; Glu/Glu vs. Asp/Asp: OR = 0.958, 95% CI = 0.813-1.129; dominant model: OR = 0.946, 95% CI = 0.835-1.072; and recessive model: OR = 1.004, 95% CI = 0.873-1.155). In the subgroup analysis by ethnicity or study design, still no obvious associations were found.This meta-analysis indicates that ADPRT Val762Ala and APE1 Asp148Glu polymorphisms are not associated with increased breast cancer risk.

BACKGROUND: In auditory fear conditioning, repeated presentation of the tone in the absence of shock leads to extinction of the acquired fear responses. The glutamate N-methyl-D-aspartate receptor (NMDAR) is thought to be involved in the extinction of the conditioned fear responses, but its detailed role in initiating and consolidating or maintaining the fear extinction memory is unclear. Here we investigated this issue by using a NMDAR antagonist, MK-801. METHODS/MAIN FINDINGS: The effects of immediate (beginning at 10 min after the conditioning) and delayed (beginning at 24 h after conditioning) extinctions were first compared with the finding that delayed extinction caused a better and long-lasting (still significant on the 20(th) day after extinction) depression on the conditioned fear responses. In a second experiment, MK-801 was intraperitoneally (i.p.) injected at 40 min before, 4 h or 12 h after the delayed extinction, corresponding to critical time points for initiating, consolidating or maintaining the fear extinction memory. i.p. injection of MK-801 at either 40 min before or 4 h after delayed extinction resulted in an impairment of initiating and consolidating fear extinction memory, which caused a long lasting increased freezing score that was still significant on the 7th day after extinction, compared with extinction group. However, MK-801 administered at 12 h after the delayed extinction, when robust consolidation has been occurred and stabilized, did not affect the established extinction memory. Furthermore, the changed freezing behaviors was not due to an alteration in general anxiety levels, since MK-801 treatment had no effect on the percentage of open-arm time or open-arm entries in an Elevated Plus Maze (EPM) task. CONCLUSIONS/SIGNIFICANCE: Our data suggested that the activation of NMDARs plays important role in initiation and consolidation but not maintenance of fear extinction memory. Together with the fact that NMDA receptor is very important for memory, our data added experimental evidence to the concept that the extinction of conditioned fear responses is a procedure of initiating and consolidating new memory other than simply "erasing" the fear memory.

Objective: To understand the current status of paragonimiasis epidemic in western mountain areas in Hubei Province., Methods: Four counties (cities) of Western Hubei Province (Xingshan, Enshi, Yunxi, Baokang) were selected as the investigation sites for active surveillance. Crabs were captured and the metacercariae of Paragonimus were detected. Meanwhile, the blood samples were collected from the residents in the surveillance sites and the unique IgG and IgM antibodies against Paragonimus in the sera were detected by ELISA. In addition, a questionnaire survey about knowledge and behavior of prevention and control of paragonimiasis was taken among the residents., Results: A total of 1 143 residents were investigated in the active surveillance, the total positive rate of the serology test was 1.84% (21/1 143), while the rates of the male and the female were 1.78% (10/562) and 1.89% (11/581), respectively, with no statistical significance between them ( χ 2 = 0.002, P > 0.05). The average weight of 161 fresh-water crabs captured was 11.72 g, with the positive rate of 9.32% (15/161) and the infective density of 7.07 metacercariae per positive crab. The positive rates of the male and female crabs were 11.54% (9/78) and 7.23% (6/83), respectively ( χ 2 = 0.884, P > 0.05), and the infective densities were 6.67 and 7.67 metacercariae per positive crab, respectively. Totally 1 143 residents were investigated by questionnaires, and 0.44% of them had the behavior of eating raw or half-done fresh-water crab, and 0.87% of them had the behavior of drinking un-boiled stream water., Conclusions: The transmission chain of paragonimiasis still exists in the nature environment of mountain area in Western Hubei Province. The positive rate of the second intermediate host rebounds in some investigation sites. Therefore, the measures of continuous surveillance and health education should be taken to avoid the appearance of the prevalence or outbreak.

Objective: To understand the malaria epidemic situation in Hubei Province from 2010 to 2014, so as to provide the evidence for formulating the effective malaria elimination strategies and measures in this province., Methods: The data from the Disease Reporting Information System of Chinese Center for Disease Control and Prevention were collected and analyzed with the descriptive epidemiological method for the epidemiological characteristics of malaria in Hubei Province from 2010 to 2014., Results: A total of 997 malaria cases were reported in Hubei Province from 2010 to 2014, there were 618 cases of vivax malaria, 352 cases of falciparum malaria, 18 cases of Plasmodium ovale infection, and 9 cases of Plasmodium malariae infection. Among all the reported cases, 479 were local cases and 518 were imported cases. No local malaria cases were reported from Hubei Province since 2013. The overall imported malaria cases showed a gradual increasing trend from 2010 to 2014, the proportion of falciparum malaria increased quite significantly from 2010 to 2014. The malaria cases were mainly distributed in Xiangyang, Wuhan, Xiaogan, Yichang, Jingmen and Suizhou cities, reaching 81.85% of the cases of the whole province. There were 810 male cases and 187 female cases, with a sex ratio of 4.33:1. The local malaria cases were mainly aged from 40 to 69 years, accounted for 78.29% of the total local cases, and 88.22% (457/518) of the whole local cases were concentrated in 20-49 age groups. The local cases were mainly farmers (67.01%). Among the imported malaria cases, the occupation distribution concentrated mainly on the worker, migrant worker, and farmer (63.90%)., Conclusions: The local malaria epidemic situation has been effectively controlled in Hubei Province, which reflects the initiative achievements of malaria elimination. However, there are still many imported malaria cases from abroad. Therefore, the imported malaria from abroad still remains the key of malaria control in Hubei Province.

Objective: To predict the incidence of local malaria of Hubei Province applying the Autoregressive Integrated Moving Average model (ARIMA)., Methods: SPSS 13.0 software was applied to construct the ARIMA model based on the monthly local malaria incidence in Hubei Province from 2004 to 2009. The local malaria incidence data of 2010 were used for model validation and evaluation., Results: The model of ARIMA (1, 1, 1) (1, 1, 0) 12 was tested as relatively the best optimal with the AIC of 76.085 and SBC of 84.395. All the actual incidence data were in the range of 95% CI of predicted value of the model. The prediction effect of the model was acceptable., Conclusions: The ARIMA model could effectively fit and predict the incidence of local malaria of Hubei Province.