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Terrestrial ecosystems have undergone significant changes as a result of climate change, profoundly affecting global carbon and water cycling processes. Notably, the synergistic changes in vegetation carbon use efficiency (CUE) and water use efficiency (WUE) and their response to patterns of climate change over the last 40 years are unknown. Therefore, in this study, global vegetation WUE and CUE were inverted using Gross primary productivity (GPP), Net primary productivity (NPP) and total evaporation (ET) data from 1981 to 2019 to reveal their temporal and spatial patterns of change through trend analysis and stability analysis. A stepwise regression algorithm was used to reveal the potential driving law of environmental factors on vegetation WUE and CUE. The results shows that (1) From 1981 to 2019, the global vegetation WUE and CUE showed in a relatively stable state, and the trends of WUE and CUE were -0.00004/year and 0.006 g C m -2  mm -1 /year, respectively; (2) the greening of vegetation was the most important cause of the changes in WUE and CUE, and the driving force of rain and heat conditions on the CUE of vegetation was smaller than that of solar radiation and soil water, the regions where CO 2 is the dominant factor affecting CUE and WUE are mainly in the north temperate zone; (3) the region of synergistic growth of WUE and CUE accounts for about 31.38 % of the global terrestrial area, and this pattern of change suggests that the global vegetation carbon sink potential is huge, and the popularization of vegetation planting patterns under the synergistic growth of CUE and WUE should be strengthened. The research has shown that vegetation greening is a key factor influencing changes in the WUE and CUE of vegetation, therefore, the implementation of ecological engineering will be an important step in combating climate change., Competing Interests: Declaration of competing interest No conflict of interest exits in the submission of this manuscript, and manuscript is approved by all authors for publication. I would like to declare on behalf of my co-authors that the work described was original research that has not been published previously, and not under consideration for publication elsewhere. All the authors listed have approved the manuscript that is enclosed., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Meningioma is a benign tumor with slow growth and long course. However, patients with recurrent malignant meningioma still face a lack of effective treatment. Here, we report a rare case of primary mediastinal malignant meningioma with lung and bone metastases, who benefited from the treatment of apatinib (≥33 months) and anlotinib (until the publication date). Retrospective molecular analysis revealed the frequent amplification of FGF6 in primary and metastatic lesions. Then we constructed the FGF6 over-expressed IOMM-LEE and CH157MN malignant meningioma cell lines, and in vitro and vivo experiments showed that overexpression of FGF6 can promote the proliferation, migration and invasion of malignant meningioma cells. Based on the Western analysis, we revealed that FGF6 can promote the phosphorylation of FGFR, AKT, and ERK1/2, which can be inhibited by anlotinib. Together, we were the first to verify that overexpression of FGF6 promotes the progression of malignant meningiomas by activating FGFR/AKT/ERK1/2 pathway and pointed out that anlotinib may effectively inhibit the disease progression of patients with FGF6 amplification., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Inc.)

Ovarian metastasis is one of the major causes of treatment failure in patients with gastric cancer (GC). However, the genomic characteristics of ovarian metastasis in GC remain poorly understood. In this study, we enroll 74 GC patients with ovarian metastasis, with 64 having matched primary and metastatic samples. Here, we show a characterization of the mutation landscape of this disease, alongside an investigation into the molecular heterogeneity and pathway mutation enrichments between synchronous and metachronous metastasis. We classify patients into distinct clonal evolution patterns based on the distribution of mutations in paired samples. Notably, the parallel evolution group exhibits the most favorable prognosis. Additionally, by analyzing the differential response to chemotherapy, we identify potential biomarkers, including SALL4, CCDC105, and CLDN18, for predicting the efficacy of paclitaxel treatment. Furthermore, we validate that CLDN18 fusion mutations improve tumor response to paclitaxel treatment in GC with ovarian metastasis in vitro and vivo., (© 2024. The Author(s).)

Background: Glycogen storage diseases (GSDs) are a group of heterogeneous inherited metabolic disorders with an incidence of 4%-5%. There are 19 types of GSDs, making diagnosis one of the greatest challenges., Methods: The proband and his parents were referred to our hospital for genetic diagnosis. Ultrasound screening suggested hepatomegaly. A novel insertion variant NM_000292 c.1155_1156insT (p. 386N>*) in PHKA2 gene was identified using trio whole exome sequencing (Trio-WES), which resulted in the codon of amino acid 386 from asparagine to termination (p. 386N>*). The 3D mutant protein structure was predicted using AlphaFold, and the results showed that the truncated PHKA2 protein contained 385 of the 1,235 amino acids of the mature protein., Conclusion: We describe a previously unreported case of a GSDs IXa type Chinese boy caused by a novel PHKA2 variant. This clinical case contributes to the understanding of the characteristics of GSDs type IXa and expands the variants spectrum of genes related to GSDs type IXa. Our findings demonstrated the significance of genetic testing in the diagnosis of GSDs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhu, Zhang, Yuan, Chen, Ding, Ding, Shi, Gu and Ma.)

Grasslands represent the largest ecosystem in China, accurate and efficient extraction of its integrated vegetation cover (IVC) plays a crucial role in supporting policy decisions. This study presented a method for grassland monitoring via IVC derived from high-resolution satellite data. Taking the multispectral data of Gaofen-1 (GF-1) and Gaofen-6 (GF-6) with 16 m resolution as the main data source, vegetation cover of six representative regions was assessed based on mixed-pixel decomposition model. Using grassland vegetation cover and ratio of grassland area, the IVC in each site was calculated and verified against ground-measured sample data. The results showed that the IVC of grassland was closely related to vegetation habitat driven by regional hydrothermal regime. Yichang grassland, dominated with warm-temperate shrub tussock type, had the highest IVC (80.06 %) due to its favorable hydrothermal conditions. For the main grassland types in Hulunbuir and Gansu Province (temperate meadow steppe and temperate typical steppe), the IVC was 79.38 % and 58.46 %, respectively. In both Xilin-Gol and Nagqu, vegetation cover decreased gradually from east to west, and the IVC was merely 42.83 % and 42.61 %, respectively. Both regions are endowed with less hydrothermal resources to different degrees. Alxa, with a predominately temperate desert landscape, had the lowest IVC of 15.58 % where precipitation is extremely scarce. Based on the grass species of measured samples, the dominant species and biodiversity of different grassland types in Gansu Province and Hulunbuir Municipality of Inner Mongolia Autonomous Region were analyzed. The results showed that the meadow grassland has the richest biodiversity. The temperate mountain meadows in Gansu Province have a high species diversity, with a total of 90 grass species, and the lowland meadows in Hulunbuir have a total of 49 grass species. This study utilizes high-resolution data to conduct large-scale vegetation monitoring, which is a viable alternative for efficient assessment of steppe ecology., Competing Interests: Declaration of competing interest No conflict of interest exits in the submission of this manuscript, and manuscript is approved by all authors for publication. I would like to declare on behalf of my co-authors that the work described was original research that has not been published previously, and not under consideration for publication elsewhere. All the authors listed have approved the manuscript that is enclosed., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Neurotrophic tyrosine kinase (NTRK) fusions involving NTRK1, NTRK2, and NTRK3 were found in a broad range of solid tumors as driver gene variants. However, the prevalence of NTRK fusions in Chinese solid tumor patients is rarely reported. Based on the next-generation sequencing data from 10,194 Chinese solid tumor patients, we identified approximately 0.4% (40/10,194) of Chinese solid tumor patients with NTRK fusion. NTRK fusions were most frequently detected in soft tissue sarcoma (3.0%), especially in the fibrosarcoma subtype (12.7%). A total of 29 NTRK fusion patterns were identified, of which 11 were rarely reported. NTRK fusion mostly co-occurred with TP53 (38%), CDKN2A (23%), and ACVR2A (18%) and rarely with NTRK amplification (5.0%) and single nucleotide variants (2.5%). DNA-based NTRK fusion sequencing exhibited a higher detection rate than pan-TRK immunohistochemistry (100% vs. 87.5%). Two patients with NTRK fusions showed clinical responses to larotrectinib, supporting the effective response of NTRK fusion patients to TRK inhibitors., (© 2023. Nature Publishing Group UK.)

Background: Neurodevelopmental disorders (NDDs) are a class of disorders affecting brain development and function, characterized by an inability to reach cognitive, emotional, and motor developmental milestones. The pathology of NDDs is complex. A recent study found that variants in the SRRM2 gene cause NDDs. However, genetic conditions play the most important role in the etiology of NDD. The genetic causes of NDD are extremely heterogeneous, leading to certain challenges in clinical diagnosis., Methods: A pregnant woman with congenital intelligence disorder came to our hospital for genetic diagnosis to predict the status of her fetus. Her mother and a brother also suffer from congenital intelligence disorder. She has a daughter with speech delay. Whole exome sequencing was used to identify a mutation (c.1415C>G) in the SRRM2 gene of this family that resulted in a change in the 472nd amino acid residue of the SRRM2 protein from serine to terminated., Conclusion: We report a family with an autosomal dominant genetic disorder caused by variants in the SRRM2 gene causing NDDs. Prenatal diagnosis can help patients with this genetic disorder to have healthy offspring., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Xu, Zhu, Ying, Ding, Ding, Shi, He, Jin and Xia.)

Purpose: We aimed to evaluate whether the addition of pemetrexed is effective in improving progression-free survival (PFS) in epidermal growth factor receptor (EGFR)-mutated patients with or without concomitant alterations., Materials and Methods: This multicenter clinical trial was conducted in China from June 15, 2018, to May 31, 2019. A total of 92 non-small cell lung cancer (NSCLC) patients harboring EGFR-sensitive mutations were included and divided into concomitant and non-concomitant groups. Patients in each group were randomly treated with EGFR-tyrosine kinase inhibitor (TKI) monotherapy or EGFR-TKI combined with pemetrexed in a ratio of 1:1. PFS was recorded as the primary endpoint., Results: The overall median PFS of this cohort was 10.1 months. There were no significant differences in PFS between patients with and without concomitant and between patients received TKI monotherapy and TKI combined with pemetrexed (p=0.210 and p=0.085, respectively). Stratification analysis indicated that patients received TKI monotherapy had a significantly longer PFS in non-concomitant group than that in concomitant group (p=0.002). In concomitant group, patients received TKI combined with pemetrexed had a significantly longer PFS than patients received TKI monotherapy (p=0.013). Molecular dynamic analysis showed rapidly emerging EGFR T790M in patients received TKI monotherapy. EGFR mutation abundance decreased in patients received TKI combined chemotherapy, which supports better efficacy for a TKI combined chemotherapy as compared to TKI monotherapy. A good correlation between therapeutic efficacy and a change in circulating tumor DNA (ctDNA) status was found in 66% of patients, supporting the guiding role of ctDNA minimal residual disease (MRD) in NSCLC treatment., Conclusion: EGFR-TKI monotherapy is applicable to EGFR-sensitive patients without concomitant alterations, while a TKI combined chemotherapy is applicable to EGFR-sensitive patients with concomitant alterations. CtDNA MRD may be a potential biomarker for predicting therapeutic efficacy.

Rationale: Rhabdomyosarcoma (RMS) is a rare sarcoma that rarely occurs in adults and accounts for only 1% of all adult tumors. The standard treatment for RMS is surgical resection, radiotherapy, and chemotherapy., Patient Concerns: Adult patients often present with an aggressive course and poor prognosis., Diagnoses: The patient was diagnosed with RMS in September 2019 and was confirmed by hematoxylin-eosin staining and immunohistochemistry after surgical resection., Interventions: The patient received surgical resection in September 2019. He was admitted to another hospital after the first recurrence in November 2019. After the second routine surgical resection, the patient underwent chemotherapy, radiotherapy, and anlotinib maintenance treatment. He relapsed again in October 2020 and was admitted to our hospital. Next-generation sequencing was performed on the punctured tissue of the patient's lung metastatic lesion, and high tumor mutational burden (TMB-H), high microsatellite instability (MSI-H), and positive programmed death-ligand 1 (PD-L1) were observed. The patient then received toripalimab and anlotinib combined therapy and was evaluated for a partial response after 2 months., Outcomes: This benefit has persisted for more than 17 months., Lessons: This is the longest progression-free survival for PD-1 inhibitors in RMS, and there is a trend of continued extension of progression-free survival in this patient. This case supports the hypothesis that positive PD-L1, TMB-H, and MSI-H could be beneficial biomarkers for immunotherapy in adult RMS., Competing Interests: Mian Xu, Hao Zhang, Jiaojiao Shen, and Xiaoliang Shi were employed by Shanghai OrigiMed Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

In today's booming society and in the age of science and technology, the diversification of food processing methods, the continuous extension of the food trade chain, and the potential hazard factors in the food production process all make people pay more and more attention to the establishment, development, and improvement of the hazard analysis and critical control points (HACCP) system. Only terminal control and post-processing supervision of food can guarantee the absolute safety of food. In the process of processing, it is particularly important to strictly identify and evaluate the food safety hazards. To better assist food production enterprises in establishing and implementing HACCP systems, to implement the primary responsibility of food safety, and to improve the theoretical level and practical application of HACCP system in China, an investigation of the current situation and development frontier of HACCP system in China was conducted. Based on the core journal database of China Knowledge Network, the Chinese Social Science Citation Index database, and the Chinese Science Citation Database as the literature search database platform, the study used the CiteSpace visual metrics software system to analyze 1,084 pieces of literature in the field of HACCP research, in order to track the dynamics and impact of research in this field by Chinese research institutions and major authors, and analyze the research hotspots in the field. It is important for further research on HACCP. The results of the study showed that (1) the number of publications in the field of HACCP in China increased steadily from 1992 to 2004 and then began to decrease; (2) the indexes of journals with more publications were more concentrated, and the journal Food Science published the most; (3) the indexes of major research institutions showed that the cultivation bases of the State Key Laboratory of Chinese Medicinal Materials in the Center of Chinese Medicine Resources of the Chinese Academy of Traditional Medicine, the Guangdong Institute of Occupational Diseases, the Nanchang University of Life Sciences, and the Guangdong Institute of Occupational Diseases were more concentrated. Prevention and Treatment Institute, School of Life Sciences of Nanchang University, China Aquatic Products Quality Certification Center, School of Food Science and Nutrition Engineering of China Agricultural University, and other research structures have the most publications and strong scientific research strength; (4) from the main author indicators, the research in the field of HACCP has formed a total of four more active research teams, involving Chinese herbal medicine, ecological planting, ecological agriculture, occupational disease prevention and treatment, light industry handicrafts, computer software and computer application, agricultural economy, and other research directions. The cooperation between the authors of each team is closer. It is suggested that in terms of food safety requirements, China should not only integrate the traditional supervision measures for food terminals and after the event but also reflect the role of food hazard analysis and assessment in the production process and comprehensively integrate the pre-production, production, and post-production management of food so that food can really be safe., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Shi, Zhang, A, Wang, Zhang and Liang.)

Drought is a complex and dynamic natural phenomenon. A single drought index can hardly reflect the multi-type characteristics of drought, and comprehensive drought indices that incorporate data from multiple sources have been proposed recently. In this study, an Optimized Comprehensive Drought Index (OCDI) was constructed by taking into account the lag time of meteorological drought, agricultural drought and hydrological drought. The Standardized Precipitation Evapotranspiration Index (SPEI), Vegetation Condition Index (VCI), and Water Storage Deficit Index (WSDI) represented the three types of droughts, respectively. Specifically, we used the Solar-induced Chlorophyll Fluorescence (SIF) to characterize the vegetation condition instead of the Normalized Difference Vegetation Index (NDVI). The application results of the proposed drought index in the middle reaches of Yellow River basin (MRYRB) showed that the lag time of different types of drought indices had seasonal differences, with a shorter lag time in summer (0-4 months) and a longer lag time in winter and spring (> 4 months). For typical drought events, the drought intensity and duration identified by OCDI were compatible with the drought evolution characteristics and consistent with the historical records, therefore, OCDI is more suitable for drought monitoring in the study area. Based on the monitoring results of the OCDI, the average number of droughts in the MRYRB was 16 times, with a duration of 2.8 months and an average drought intensity of 0.28 (at moderate drought grade). Drought times and intensity were higher in the northwestern part of the study area, and spring was a high-frequency period for drought occurrences., Competing Interests: Declaration of competing interest No conflict of interest exists in the submission of this manuscript, and manuscript is approved by all authors for publication. I would like to declare on behalf of my co-authors that the work described was original research that has not been published previously, and not under consideration for publication elsewhere. All the authors listed have approved the manuscript that is enclosed., (Copyright © 2022 Elsevier B.V. All rights reserved.)

As the primary source of carbon dioxide fixation, vegetation is critical to the carbon sink process. In this paper, the Net Primary Productivity (NPP) and the Gross Primary Productivity (GPP) were simulated using the Carnegie-Ames-Stanford Approach (CASA) model and the Vegetation Photosynthesis Model (VPM), respectively, and then the Potential Gross Primary Productivity (PGPP) and the GPP affected by human activities (AGPP) were simulated by combining Potential Net Primary Productivity (PNPP), and then the impact of climate change and human activities on GPP was assessed in the Heihe River Basin (HRB). The results showed that the GPP of grassland and Bare or Sparse Vegetation (BSV) exhibited a fluctuation rise, with increases of 0.709 gCm -2 a -1 and 0.115 gCm -2 a -1 , respectively, whereas the GPP of cropland showed a fluctuation reduction, with a decline rate of -0.465 gCm -2 a -1 . Climate change and human activity are both positive for vegetation growth, and human activity being the primary factor influencing GPP change. Human-dominated vegetation restoration accounted for 56.1% of the overall restoration area, with grassland GPP being the most visible response to human activities. The GPP changes in crop and grassland had a positive correlation with precipitation but a negative correlation with temperature among climate change factors, whereas the GPP changes in BSV had a negative correlation with both precipitation and temperature. Quantitative analyses of climate change and human activities' dynamic contributions to vegetation can give scientific and theoretical insight for dealing with global climate change., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: The progression of placental diseases such as preeclampsia is closely related to trophoblast dysfunction. Recent studies indicated the dysregulation of N6-methyladenosine (m 6 A) RNA modification in trophoblast disorders, while the function of METTL3, a methyltransferase of m 6 A, in trophoblasts remains to be studied., Methods: The expression of METTL3 was determined by real-time PCR and immunoblotting. METTL3 expression in trophoblast cell lines HTR-8/SVneo and JEG-3 was knocked down using shRNA. The invasion of trophoblast cells in Matrigel was determined using xCELLigence. The m 6 A-containing transcripts was determined by m 6 A-sequencing in HTR-8/SVneo cells. The myosin light chain kinase (MYLK) gene was transfected into HTR-8/SVneo cells., Results: The expression of METTL3 was downregulated in preeclamptic placentae compared to normal placentae. Knockdown of METTL3 repressed the invasion of extravillous trophoblast cells. Mechanistically, METTL3 promoted the stability of MYLK mRNA through m 6 A modification. Overexpression of MYLK rescued retarded cell invasion by METTL3 depletion., Discussion: Collectively, our results highlight an essential role of METTL3-MYLK axis in trophoblast invasion., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Droughts are the most expensive natural disasters on the planet. As a result of climate change and human activities, the incidence and impact of drought have grown in China. Timely and effective monitoring of drought is crucial for water resource management, drought mitigation, and national food security. In this study, we constructed a comprehensive drought index (YCDI) suitable for the Yellow River Basin using principal component analysis and the entropy weight-AHP method, which integrated a standardized precipitation evapotranspiration index (SPEI), self-calibrating Palmer drought severity index (scPDSI), vegetation condition index (VCI), and standardized water storage index (SWSI). SWSI is calculated by the terrestrial water storage anomaly (TWSA), which can more comprehensively reflect the impact of surface water resources on drought (as compared with soil moisture-based indexes). The study results showed that: (1) compared with single drought index, YCDI has stronger ability to monitor drought process. In terms of time scale and drought degree, the monitoring results based on YCDI were similar with data presented in the China Flood and Drought Bulletin and Meteorological Drought Yearbook, reaching ~87% and ~69%, respectively. The correlation between drought intensity and crop harvest area was 0.56. (2) By the combined analysis of the Mann-Kendall test and Moving T test, it was found that the abrupt change of YCDI index at the time of 2009, mainly due to the precipitation in 2009 reached the lowest value in the past 30 years in northern China and extreme high temperature weather. (3) The YCDI of Henan and Shandong provinces in the middle and lower reaches of the basin decreased more significantly, with the maximum value reaching 0.097/yr, while the index in the upper reaches showed an increasing trend with the maximum rate of 0.096/yr. (4) The frequency of mild drought, moderate drought, severe drought and extreme drought in the Yellow River basin during the study period was 15.84%, 12.52%, 4.03% and 0.97%, respectively. Among them, the highest frequency of droughts occurred in Ningxia, Inner Mongolia and central Shaanxi provinces. Drought causation in the Yellow River basin is more influenced by human activities than climate change in the middle and lower reaches, while climate change is the main factor in the upper reaches. Overall, YCDI is a reliable indicator for monitoring the spatial and temporal evolution of drought in the Yellow River basin, and it can be used for monitoring soil moisture changes and vegetation dynamics, which can provide scientific guidance for regional drought governance., Competing Interests: The authors declare that they have no competing interests., (© 2022 Shi et al.)

Hepatocellular carcinoma (HCC), one of the most common malignant tumors in China, severely threatens the life and health of patients. In recent years, precision medicine, clinical diagnoses, treatments, and innovative research have led to important breakthroughs in HCC care. The discovery of new biomarkers and the promotion of liquid biopsy technologies have greatly facilitated the early diagnosis and treatment of HCC. Progress in targeted therapy and immunotherapy has provided more choices for precise HCC treatment. Multiomics technologies, such as genomics, transcriptomics, and metabolomics, have enabled deeper understanding of the occurrence and development mechanisms, heterogeneity, and genetic mutation characteristics of HCC. The continued promotion and accurate typing of HCC, accurate guidance of treatment, and accurate prognostication have provided more treatment opportunities and prolonged survival timelines for patients with HCC. Innovative HCC research providing an in-depth understanding of the biological characteristics of HCC will be translated into accurate clinical practices for the diagnosis and treatment of HCC., Competing Interests: No potential conflicts of interest are disclosed., (Copyright © 2022 Cancer Biology & Medicine.)

Complexity and heterogeneity increases the difficulty of diagnosis and treatment of bone tumors. We aimed to identify the mutational characterization and potential biomarkers of bone tumors. In this study, a total of 357 bone tumor patients were recruited and the next generation sequencing (NGS)-based YuanSu450 panel, that includes both DNA and RNA sequencing, was performed for genomic alteration identification. The most common mutated genes in bone tumors included TP53 , NCOR1 , VEGFA , RB1 , CCND3 , CDKN2A , GID4, CCNE1 , TERT , and MAP2K4 . The amplification of genes such as NCOR1 , VEGFA , and CCND3 mainly occurred in osteosarcoma. Germline mutation analysis reveal a high frequency of HRD related mutations (46.4%, 13/28) in this cohort. With the assistance of RNA sequencing, 16.8% (19/113) gene fusions were independently detected in 20% (16/79) of patients. Nearly 34.2% of patients harbored actionable targeted mutations, of which the most common mutation is CDKN2A deletion. The different mutational characterizations between juvenile patients and adult patients indicated the potential effect of age in bone tumor treatment. According to the genomic alterations, the diagnosis of 26 (7.28%) bone tumors were corrected. The most easily misdiagnosed bone tumor included malignant giant cell tumors of bone (2.8%, 10/357) and fibrous dysplasia of bone (1.7%, 6/357). Meanwhile, we found that the mutations of MUC16 may be a potential biomarker for the diagnosis of mesenchymal chondrosarcomas. Our results indicated that RNA sequencing effectively complements DNA sequencing and increased the detection rate of gene fusions, supporting that NGS technology can effectively assist the diagnosis of bone tumors., Competing Interests: Authors XS, YQ, and LW were employed by Shanghai OrigiMed Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xie, Bian, Li, Yin, Tian, Jiang, Zeng, Shi, Lei, Hou, Qu, Wang and Shen.)

A study on the value accounting of forest carbon sink services can promote the rapid development of the carbon sink market and help better understand the impact of forest carbon sinks on climate change and economic development. However, few studies have evaluated the value of China's current forest carbon sink services. Based on research on carbon peak and carbon neutrality, according to the characteristics of China's forest ecosystems and forest resource inventory data, the stock volume method was used to measure the amount and value of forest carbon sinks in China in 2009-2013 and 2014-2018. The results showed that: (1) the physical amount of forest carbon aggregates in China increased from 2009 to 2013 and from 2014 to 2018. The carbon storage of natural and plantation forests both showed an upward trend. Among them, the growth rate of the carbon storage of plantation forests was higher than that of natural forests. (2) The state, adjoint, and coupling equations of forest carbon sinks were employed to ascertain the best price for China's forest carbon sinks in 2020. The results showed that the price of China's forest carbon sinks was slightly higher than the internationally accepted carbon sink price, reflecting that the changes in the value of China's forest carbon sinks and international carbon sinks were roughly the same. (3) We obtained an appropriate accounting model for China's forest carbon sinks. (4) The value of China's forest carbon sinks increased from 2009 to 2013 and from 2014 to 2018. Although the price of carbon sinks has declined, the overall forest resource stock has increased, especially in plantation forests. The increase in the value of carbon sinks was as high as 24.7%, resulting in an overall increase in the value of forest carbon sinks, which was also in line with the physical amount of forest carbon sinks. The measurement conclusions were consistent. Several key points to note based on these findings are as follows: (1) China's current forest carbon sink transactions are all project-level certified emission reduction transactions, and diversified non-market means should be constructed to comprehensively promote carbon sink transactions. (2) China's current carbon sink transactions are mainly clean development mechanism projects, with few transactions between enterprises, and the carbon trading market situation is not optimistic. (3) The key to effective forest carbon sequestration trading is the accurate accounting of forest carbon storage and carbon sequestration value. Thus, it is of great significance to establish a forest carbon sequestration measurement method that is economical, simple, and accurate. (4) The physical amount and value of carbon sequestration of China's forest resources are rising, and the contribution rate is increasing year by year. However, there is still a gap in per capita forest area and storage compared with those in other countries worldwide. Thus, China must be vigilant in times of peace and further strengthen the protection and construction of forest resources., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Aims: The clinical outcome of relapsed and refractory (RR) extranodal natural killer/T-cell lymphoma (ENKTL) is poor. It is necessary to identify RR patients in ENKTL and find novel therapeutic targets to improve the prognosis of patients with RR ENKTL., Methods: A total of 189 ENKTL patients with effective clinical characteristics were enrolled. Paraffin specimens were collected for PD-L1 expression identification. Kaplan-Meier curve analysis was performed for survival analysis. Whole exome sequencing (WES) was performed for identifying the mutational characterization of RR and effective treatment (ET) patients., Results: Univariate and multivariate Cox proportional hazards regression analysis showed that negative PD-L1 expression (HR = 1.132, 95% CI = 0.739-1.734, P = 0.036) was an independent predictor of poor prognosis in patients with ENKTL. The overall survival (OS) of PD-L1 positive patients was significantly higher than that of PD-L1 negative patients ( P = 0.009). Then, we added PD-L1 expression as a risk factor to the model of Prognostic Index of Natural Killer Lymphoma (PINK), and named as PINK+PD-L1. The PINK+PD-L1 model can significantly distinguish RR patients, ET patients, and the whole cohort. Moreover, our data showed that PD-L1 expression was lower than 25% in most RR patients, suggesting that RR subtypes may be associated with low expression of PD-L1 ( P = 0.019). According to the whole exome sequencing (WES), we found that the mutation frequencies of JAK-STAT ( P = 0.001), PI3K-AKT ( P = 0.02) and NF-kappa B ( P < 0.001) pathways in RR patients were significantly higher than those in ET patients., Conclusion: Patients tend to show RR when PD-L1 expression is lower than 25%. The model of PINK+PD-L1 can stratify the risk of different groups and predict OS in ENKTL patients. The mutational profile of ENKTL patients with RR is different from that of patients with ET., Competing Interests: Author XS, JW, and YL were employed by OrigiMed Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gao, Zhang, Shi, Liu, Wang, Zhang and Liu.)

The frequency and intensity of droughts are increasing in many parts of the world as a result of global climate change and human activity, posing a serious threat to regional ecological security. The climate in the middle reaches of the Yellow River Basin (MRYRB) has been warm and dry in recent years, with frequent droughts. In order to investigate the temporal trend of drought, and reveal the resistance of vegetation to drought in the MRYRB, this study used remotely-sensed vegetation index products (MODIS-NDVI and SPOT-NDVI) and the standardized precipitation evapotranspiration index (SPEI). The results indicated that: (1) drought intensity showed a weak upward trend in the study area from 2000 to 2018, with linear growth rates of SPEI at temporal scales of 1, 3, 6, 9 and 12 months of -0.002, 0.0034, 0.0198, 0.0234, and 0.0249, respectively; (2) drought was positively correlated with vegetation in most areas (97.6%), and vegetation was most affected by drought on long-term time scales (9 and 12 months); (3) with the extension of drought, vegetation resistance index decreased, then gradually recovered after the end of the drought. Forest had the longest resistance duration of 260 days, while grassland and cultivated land had resistance durations of only 170 days. This study adds to the understanding of vegetation's ability to withstand drought, and these findings provide evidence to support drought response in the MRYRB.

RHD variants in D¯ Chinese pregnant women arose difficulties in management during pregnancy. Therefore, this study aims to precisely manage D¯ pregnant women by evaluating the spectrum of RHD mutations in D¯ pregnant women and getting insight into the possible rare alleles of RHD. A total of 76 D¯ pregnant women were analyzed by performing polymerase chain reactions with sequence-specific primers (PCR-SSP), the 10 RHD exons Sanger sequencing, RHD zygosity detection, and mRNA sequencing (mRNA-seq). About 40% of alleles are variations of RHD, including RHD 1227A homozygous, RHD-CE(2-9)-D, et al. Therefore, we developed a molecular diagnostic strategy for Chinese women, and most D¯ pregnant women can be diagnosed with this simple decision tree. After RHD genotyping for D¯ pregnancy women, we eliminated at least 15% unnecessary ante- and postpartum injections of Rh immunoglobulin (RhIG). As the first pedigree study and the first functional analysis under physiological conditions, mRNA-seq revealed that c.336-1G>A mutation mainly led to the inclusion of the intron 2, which indirectly explained the D¯ phenotype in this family. We also developed a robust protocol for determining fetal RhD status from maternal plasma. All 31 fetuses were predicted as RhD positive and confirmed the RhD status after birth., Competing Interests: Authors XP, ZZ, LA, and YZ were employed by the company Tianjin Super Biotechnology Developing Co., Ltd. Authors JP and MW were employed by the company Zhejiang Biosan Biotechnology Co., Ltd. Author JZ was employed by the company BGI-Shenzhen. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhang, Zeng, Wang, Fan, Chen, Yang, Shi, Xu, Fu, Sheng, Xuan, Pan, Zhang, Ai, Zhang, Pan, Zhao and Wang.)

Workpiece will face corrosive problems during its application after the manufacturing process. As the common final process, grinding can generate special metamorphic layer on the surface of workpiece and change the initial corrosion resistance of workpiece. In order to study the corrosion resistance of workpiece after grinding process, the paper carries on combining experiment of grinding and electrochemical corrosion. The characteristic of corrosion resistance of grinding is revealed based on the association of grinding mechanism and electrochemical theory. The corrosion potential of workpiece after grinding is higher than matrix, which shows the grinding surface is difficult to begin to corrode. Electrochemical impedance spectroscopy (EIS) shows the grinding surface has large phase angle, impedance and capacitance characteristic because the metamorphic layer of grinding has good obstructive ability. They reveal that grinding improves the surface corrosion resistance of workpiece. Then the mechanism of the corrosion resistance of grinding is revealed. The special grain boundary formed in grinding with much C element, large clusters and complex shape prolongs the corrosion channel, which reduces the corrosive speed. While, the sensitive hardening structure generated in grinding hardening with much free energy is easy to form the corrosion cell, which will accelerate the corrosion., (© 2021. The Author(s).)

Background: Cholangiocarcinoma (CCA), which consists of intrahepatic CCA (iCCA), perihilar CCA (pCCA), and distal CCA (dCCA), is an aggressive malignancy worldwide. PCCA and dCCA are often classified as extrahepatic CCA (exCCA). However, the differences in mutational characteristics between pCCA and dCCA remain unclear., Methods: Deep sequencing targeting of 450 cancer genes was performed for genomic alteration detection. The tumor mutational burden (TMB) was measured by an algorithm developed in-house. Correlation analysis was conducted using Fisher's exact test., Results: FGFR2 and ERBB2 mutations mainly occurred in iCCA and exCCA, respectively. In exCCA, the frequencies of PIK3CA , FAT4 , KDM6A , MDM2 , and TCF7L2 mutations were significantly higher in pCCA compared to dCCA, while the frequencies of TP53 and KRAS mutations were markedly lower in pCCA than those in dCCA. The prognosis-related mutations were different among the CCA subtypes. NF1 mutation was associated with short disease-free survival (DFS) and overall survival (OS), and ERBB2 mutation was associated with short DFS in dCCA patients. Meanwhile, MAP2K4 mutation was associated with long DFS and OS, and TERT mutation was associated with short DFS in pCCA. A series of mutations in genes, including ARID1A , ARID2 , SMAD4 , TERT , TP53, and KRAS, were found to be associated with the TMB., Conclusions: In this study, we investigated the comprehensive genomic characterizations of CCA patients, identified the significant alterations in each subtype, and identified potential biomarkers for prognosis prediction. These results provide molecular evidence for the heterogeneity of CCA subtypes and evidence for further precision targeted therapy of CCA patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/jgo-21-776). Dr. JS, Dr. XS and Dr. KW report that they serve as employees of OrigiMed Co. Ltd, Shanghai, China. The other authors have no conflicts of interest to declare., (2021 Journal of Gastrointestinal Oncology. All rights reserved.)

Objective: To explore the molecular mechanism of a case where RhD genotyping did not match serological results., Methods: The serological results of 8 members from two generations of this family were analyzed. And according to Mendelian law of inheritance, RhD genotyping, zygotic type determination and gene sequencing were performed for the family members., Results: The proband and one of her cousins have the same RhD alleles, both of them have a 336-1G>A intron variant RhD allele and a complete RhD deletion allele. The variant alleles are inherited from two of their parents with blood relationship, while the complete-deleted alleles come from the other. 336-1G>A means that the last base G of the second intron of the RhD gene is mutated to A, which leads to a negative RhD serology and a positive genotype in the proband., Conclusion: There was a rare 336-1G> A intron variant gene (RhD * 01N.25) in this family, which was a recessive gene relative to the RhD gene and resulted in RhD phenotype negative.

Background: Racial disparities in the survival of patients with hepatocellular carcinoma (HCC) exist. Gene mutations have a profound effect on carcinogenesis, are easily affected by environment and etiology factors, and may result in survival divergences among patients with different racial backgrounds. This report explores the effects of gene mutations on the survival of American Caucasians and Asian patients., Methods: The sequencing and clinical data of 336 HCC patients were obtained from The Cancer Genome Atlas (TCGA) database. The sequencing data was subject to gene mutation profiling, and an analysis of immune cell infiltration was conducted. A multivariate analysis was performed to assess the independent effects of gene mutations on patients' overall survival (OS) and disease-free survival (DFS)., Results: Asian HCC patients had a significantly higher level of TP53 mutation frequency than Caucasian HCC patients (Asian vs. Caucasian, 39% vs. 23%; P=0.003). The TP53 mutation was associated with shorter OS [hazard ratio (HR), 2.33; 95% confidence interval (CI), 1.36-3.97; P=0.002] and DFS (HR, 2.2; 95% CI, 1.38-3.51; P<0.001) in Caucasian HCC patients, but had no effect on Asian HCC patients' survival. Compared to Asian HCC patients, Caucasian HCC patients with the TP53 mutation had a decreased proportion of infiltrating M2 macrophages and activating natural killer (NK) cells, and an increased proportion of follicular helper T cells. The RB1 mutation was associated with shorter OS (HR, 3.37; 95% CI, 1.73-6.57; P<0.001) in Asian HCC patients, and shorter DFS (HR, 2.11; 95% CI, 1.15-3.88; P=0.017) in Caucasian HCC patients. Asian HCC patients with the RB1 mutation had a decreased proportion of infiltrating CD8 T cells., Conclusions: The effects of the TP53 and RB1 mutations on survival differ among Asian and Caucasian HCC patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/jgo-21-312). TH, XS and JZ report that they are employees of OrigiMed. The other authors report funding from Natural Science Foundation of Hunan Province (Grant Number: 2018JJ3294), Natural Science Foundation of Hunan Province (Grant Number: 2019JJ80007) and Doctor Foundation Project of Hunan Provincial People’s Hospital (2020) during the conduct of the study., (2021 Journal of Gastrointestinal Oncology. All rights reserved.)

Background: Roughly 30-40% of lung cancer (LC) patients develop bone metastasis during the course of disease. The genetic differences between primary LC and matched bone metastasis are not yet fully understood., Methods: A total of 40 LC patients with bone metastasis were collected and 450 targeted cancer-related genes were sequenced for genomic-alteration (GA) identification., Results: Among the 40 LC patients, 33 had adenocarcinomas and 7 had squamous cell carcinomas. The metastatic sites of the 33 lung adenocarcinomas (LUADs) were the pelvis (6 patients), spine (16 patients), and limbs (11 patients). A total of 425 and 422 GAs were detected in the primary and metastatic lesions, respectively. The most common GAs were epidermal growth factor receptor (EGFR) mutations, which had mutation rates of 85.0% and 72.5% in the primary and metastatic lesions, respectively, and tumor protein 53 (TP53) mutations, which had mutation rates of 52.5% and 67.5% in the primary and metastatic lesions, respectively. Metastases to the pelvis and spine were most commonly accompanied by factor receptor substrate 2 (FRS2), cyclin-dependent kinase 4 (CDK4), and murine double minute 2 (MDM2) amplification, and cyclin-dependent kinase inhibitor 2A (CDKN2A) deletion. The concordance between primary lung squamous cell carcinoma (LUSC) and corresponding metastasis was significantly higher than that of primary LUAD and corresponding metastasis (P=0.033). Compared to limb and pelvis metastases, the shared mutation in spine metastasis was significantly lower (P=0.016 and P=0.023, respectively). In matched primary LUSCs and bone metastasis lesions, there was no significant difference in the distribution of the tumor mutational burden (TMB) (P=0.9). Conversely, a significant difference of the TMB distribution was detected in pairs of primary LUAD and corresponding bone metastasis lesions (P=0.021)., Conclusions: The consistency of mutation patterns between primary LC lesions and matched bone metastases may vary in terms of metastatic sites, but is very high in general. There was a significant difference in the TMB between primary LUAD and matched bone metastatic lesions. Our findings contribute to molecular understandings of primary LC and matched bone metastatic lesions.

Background: Ectopic thymic carcinoma (TC) is an extremely rare disease with a poor prognosis. The main treatment for early TC is surgery, although an effective treatment for advanced TC is lacking., Methods: We present the case of a 61-year-old man with advanced posterior mediastinum thymic squamous cell carcinoma. Amplification refractory mutation system (ARMS)-polymerase chain reaction (PCR) analysis was used to investigate the molecular and mutational characteristics of this tumour., Results: After chemotherapy and radiotherapy, the tumour showed disease progression. Immunohistochemistry revealed that the tumour was positive for CD117 (specific for primary TC), CK19, CD56 and Ki67. ARMS-PCR analysis revealed an EGFR exon 19 deletion in the patient. The patient subsequently received icotinib treatment and achieved complete remission for 3 years., Conclusions: This case report suggests that tyrosine kinase inhibitors are a potential treatment strategy for patients with TC harbouring EGFR alterations., (© 2021 The Authors. The Journal of Gene Medicine published by John Wiley & Sons Ltd.)

Sarcomas represent a heterogeneous group of mesenchymal malignancies arising at various locations in the soft tissue and bone. Though a rare disease, sarcoma affects ~200,000 patients worldwide every year. The prognosis of patients with sarcoma is poor, and targeted therapy options are limited; therefore, accurate diagnosis and classification are essential for effective treatment. Sarcoma samples were acquired from 199 patients, in which TP53 (39.70%, 79/199), CDKN2A (19.10%, 38/199), CDKN2B (15.08%, 30/199), KIT (14.07%, 28/199), ATRX (10.05%, 20/199) and RB1 (10.05%, 20/199) were identified as the most commonly mutated genes (>10% incidence). Among 64 soft-tissue sarcomas that were unclassified by immunohistochemistry, 15 (23.44%, 15/64) were subsequently classified using next-generation sequencing (NGS). For the most part, the sarcoma subtypes were evenly distributed between male and female patients, while a significant association with sex was detected in leiomyosarcomas. Statistical analysis showed that osteosarcoma, Ewing's sarcoma, gastrointestinal stromal tumors and liposarcoma were all significantly associated with the patient age, and that angiosarcoma was significantly associated with high tumor mutational burden. Furthermore, serially mutated genes associated with myxofibrosarcoma, gastrointestinal stromal tumor, osteosarcoma, liposarcoma, leiomyosarcoma, synovial sarcoma and Ewing's sarcoma were identified, as well as neurotrophic tropomyosin-related kinase ( NTRK) fusions of IRF2BP2-NTRK1, MEF2A-NTRK3 and ITFG1-NTRK3 . Collectively, the results of the present study suggest that NGS-targeting provides potential new biomarkers for sarcoma diagnosis, and may guide more precise therapeutic strategies for patients with bone and soft-tissue sarcomas., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Xu et al.)

Background: Cholangiocarcinoma (CCA) is a rare malignant tumor of the biliary system. The heterogeneity of CCA leads to the lack of effective targeted treatment for CCA subtypes. The molecular characteristic of hilar CCA (hCCA) is still unclear., Methods: A total of 63 hCCA patients were enrolled from Shanghai Eastern Hepatobiliary Surgery Hospital. Formalin-fixed, paraffin-embedded tumor tissues, and matched blood were collected and deep sequencing targeting 450 cancer genes were performed. Tumor mutation burden (TMB) was measured by an algorithm developed in-house. Correlation analysis was performed by Fisher's exact test., Results: The most commonly mutated genes were TP53 (51.7%), NF1 and KRAS (20%, for both), SMAD4 (16.7%), FAT3 and FRS2 (13.3%, for both), NF1 (11.7%), and KMT2C, MDM2, and ATM (10%, for each) in hCCA. ARID1A, GATA6, and PREX2 mutations commonly occurred in female and KMT2C mutations mainly occurred in patients under 60 years old. Statistical analysis showed the association between ARID1A mutation and tumor stage (P = 0.041) and between NF1 mutation and high TMB (P = 0.0095). Furthermore, ARID1B mutation was identified to associate with the poor prognosis of Chinese hCCA patients (P = 0.004)., Conclusion: The mutational characterization of hCCA is different from both extrahepatic CCA and intrahepatic CCA. ARID1B is a potential biomarker for prognosis prediction of Chinese hCCA patients.

Background: Hepatocellular carcinoma (HCC) is one of the most common causes of cancer worldwide. Although many studies have focused on oncogene characteristics, the genomic landscape of Chinese HCC patients has not been fully clarified., Methods: A total of 165 HCC patients, including 146 males and 19 females, were enrolled. The median age was 55 years (range, 27-78 years). Corresponding clinical and pathological information was collected for further analysis. A total of 168 tumor tissues from these patients were selected for next-generation sequencing (NGS)-based 450 panel gene sequencing. Genomic alterations including single nucleotide variations (SNV), short and long insertions and deletions (InDels), copy number variations, and gene rearrangements were analyzed. Tumor mutational burden (TMB) was measured by an algorithm developed in-house. The top quartile of HCC was classified as TMB high., Results: A total of 1,004 genomic alterations were detected from 258 genes in 168 HCC tissues. TMB values were identified in 160 HCC specimens, with a median TMB of 5.4 Muts/Mb (range, 0-28.4 Muts/Mb) and a 75% TMB of 7.7 Muts/Mb. The most commonly mutated genes were TP53, TERT, CTNNB1, AXIN1, RB1, TSC2, CCND1, ARID1A , and FGF19 . SNV was the most common mutation type and C:G>T:A and guanine transformation were the most common SNVs. Compared to wild-type patients, the proportion of Edmondson grade III-IV and microvascular invasion was significantly higher in TP53 mutated patients (P<0.05). The proportion of tumors invading the hepatic capsule was significantly higher in TERT mutated patients (P<0.05). The proportion of Edmondson grade I-II, alpha fetoprotein (AFP) <25 µmg/L, and those without a history of hepatitis B was significantly higher in CTNNB1 mutated patients (P<0.05). CTNNB1 mutations were associated with TMB high in HCC patients (P<0.05). Based on correlation analysis, the mutation of TP53 was independently correlated with microvascular invasion (P=0.002, OR =3.096) and Edmondson grade III-IV (P=0.008, OR =2.613). The mutation of TERT was independently correlated with tumor invasion of the liver capsule (P=0.001, OR =3.030), and the mutation of CTNNB1 was independently correlated with AFP (<25 µmg/L) (P=0.009, OR =3.414)., Conclusions: The most frequently mutated genes of HCC patients in China were TP53 , TERT , and CTNNB1 , which mainly lead to the occurrence and development of HCC by regulating the P53 pathway, Wnt pathway, and telomere repair pathway. There were more patients with microvascular invasion and Edmondson III-IV grade in TP53 mutated patients and more patients with hepatic capsule invasion in TERT mutated patients, while in CTNNB1 mutated patients, there were more patients with Edmondson I-II grade, AFP <25 µmg/L, and a non-hepatitis B background. Also, the TMB values were significantly higher in CTNNB1 mutated patients than in wild type patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/hbsn.2019.09.17). The authors have no conflicts of interest to declare., (2021 Hepatobiliary Surgery and Nutrition. All rights reserved.)

Background: The prognostic value of polybromo 1 ( PBRM1 ) gene mutations in clear cell renal carcinoma (CCRCC) with anti-programmed death-ligand 1 (PD-L1) therapy remains controversial, and few studies have reported the impact of PBRM1 mutations in other cancer types., Methods: The patient information was obtained from cBioPortal and the Tumor Immune Estimation Resource (TIMER) databases. Mann-Whitney U test were used for correlation analysis. For survival analyses, Kaplan-Meier survival curves were used and compared using the log-rank test. Cox's regression model was used to perform univariable and multivariable analyses., Results: Our study, for the first time, performed comprehensive analyses of PBRM1 mutation frequency, PBRM1 expression, relationship of PBRM1 mutations with clinical benefit from immunotherapy, and PBRM1 expression with immune infiltrates in diverse cancer types. The results showed that the expression of PBRM1 was significantly lower in diverse cancer types compared with normal tissues. Based on multivariable analysis, PBRM1 mutations trended towards worse clinical outcomes from anti-PD-L1 in CCRCC, lung adenocarcinoma (LUAD), bladder urothelial carcinoma (BLCA), and skin cutaneous melanoma (SKCM), and a significant association was observed in LUAD and BLCA. PBRM1 mutations were associated with higher TMB in diverse cancer types and significant associations were observed in LUAD and BLCA. The expression of PBRM1 was found to positively correlate with immune infiltrates in diverse cancer types., Conclusions: Our findings suggested caution in starting immunotherapy alone in PBRM1 mutant patients. Further studies are needed to improve treatment for PBRM1 mutant patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-21-289). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Ovarian cancer is one of the most common cancers in women and is often diagnosed as advanced stage because of the subtle symptoms of early ovarian cancer. To identify the somatic alterations and new biomarkers for the diagnosis and targeted therapy of Chinese ovarian cancer patients, a total of 65 Chinese ovarian cancer patients were enrolled for detection of genomic alterations. The most commonly mutated genes in ovarian cancers were TP53 (86.15%, 56/65), NF1 (13.85%, 9/65), NOTCH3 (10.77%, 7/65), and TERT (10.77%, 7/65). Statistical analysis showed that TP53 and LRP1B mutations were associated with the age of patients, KRAS, TP53, and PTEN mutations were significantly associated with tumor differentiation, and MED12, LRP2, PIK3R2, CCNE1, and LRP1B mutations were significantly associated with high tumor mutational burden. The mutation frequencies of LRP2 and NTRK3 in metastatic ovarian cancers were higher than those in primary tumors, but the difference was not significant (P = 0.072, for both). Molecular characteristics of three patients responding to olapanib supported that BRCA mutation and HRD related mutations is the target of olaparib in platinum sensitive patients. In conclusion we identified the somatic alterations and suggested a group of potential biomarkers for Chinese ovarian cancer patients. Our study provided a basis for further exploration of diagnosis and molecular targeted therapy for Chinese ovarian cancer patients.

Objective: Colorectal cancer is one of the most prevalent types of cancer worldwide. Right-sided and left-sided colorectal cancer (RCC and LCC) patients respond differently to treatment. We aimed to identify the different mutational profile between RCC and LCC and provided evidence for future precision therapy., Methods: A total of 630 Chinese colorectal cancer patients, including 467 (74.1%) LCC and 163 (25.9%) RCC, were enrolled in this cohort. Both formalin-fixed paraffin-embedded tumor tissues and matching blood samples were collected and deep sequenced targeting 450 cancer genes for genomic alteration analysis. Tumor mutational burden was measured by an algorithm developed in-house. Correlation analysis was performed by Fisher's exact test., Results: The most common mutated genes were TP53 (77.0%), APC (71.7%), KRAS (50.0%), SMAD4 (19.8%), PIK3CA (18.3%), FBXW7 (17.5%), TCF7L2 (12.5%), SOX9 (11.3%), LRP1B (10.8%), ARID1A (10.3%) and FAT4 (10.3%). The mutation frequencies of TP53 and APC in LCC were significantly higher than that of RCC, while the mutation frequency of PIK3CA was lower than that of RCC. Six gene fusions were specifically detected in RCC patients. Colorectal cancer sites were associated with gender (P = 4.15 × 10-5) and tumor differentiation (P = 0.059). In LCC, the gender-associated genes were FAT4, EP300, FAT1, LRP1, ARID1B, AR, FYN and TAF1, while in RCC, they were ARID1A, SMARCA4, LRP1 and GRIN2A. The mutations of 18 genes were associated with tumor differentiation (8 for LCC and 10 for RCC). High tumor mutational burden was more common in RCC. Our results implied more potential targeted drug therapy opportunities for RCC., Conclusion: We describe the different molecular characteristics of LCC and RCC. Our result supported a better prognosis of RCC than LCC in Chinese colorectal cancer patients., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Esophageal squamous cell carcinoma (ESCC) is the most common type of esophageal cancer in China and the 5-year mortality rate is up to 70%. Studies on the ESCC genetic landscape are needed to further explore clinical therapeutic strategies. In this study, we evaluated the genetic landscape of ESCC to aid the search for clinical therapeutic strategies., Patients and Methods: A total of 225 ESCC patients were enrolled in this study. Deep sequencing of 450 cancer genes was performed on formalin-fixed paraffin-embedded tumor biopsies and matched blood samples from patients. Tumor mutational burden (TMB) was calculated using an algorithm developed in-house., Results: Our results showed that the most commonly mutated genes in ESCC were TP53 (96%), CCND1 (46%), FGF4 (44%), FGF19 (44%), FGF3 (44%), CDKN2A (31%), PIK3CA (26%), NOTCH1 (24%), KMT2D (18%), FAT1 (16%), and LRP1B (16%). We found that TMB correlated with patient drinking status. We identified mutations associated with sex, early ESCC, high TMB, and metastasis lymph nodes. KMT2D mutations associated with sex ( P = 0.035), tumor stage ( P = 0.016), high TMB ( P = 0.0072), and overall survival of patients ( P = 0.0026). SPEN mutations associated with high TMB ( P = 0.0016) and metastasis-positive lymph nodes ( P = 0.027). These results suggested that SPEN and KMT2D could be potential prognosis biomarkers for Chinese patients with ESCC. We also found that the number of positive lymph nodes was associated with disease-free survival. Clinical target gene analysis indicated that nearly half of Chinese ESCC patients might benefit from treatment with gene-specific target drugs., Conclusion: Our study revealed the ESCC mutational landscape in 225 Chinese patients and uncovered the potential prognosis biomarker for Chinese patients with ESCC., Competing Interests: Junping Shi, Xiaoliang Shi, and Wenting Chen are employees of Origimed Co. Ltd. The authors report no other potential conflicts of interest for this work., (© 2020 Zhang et al.)

Lung cancer is the leading causes of cancer-related death worldwide. Precise treatment based on next-generation sequencing technology has shown advantages in the diagnosis and treatment of lung cancer. This cohort study included 371 lung cancer patients. The lung cancer subtype was related to the smoking status and sex of the patients. The most common mutated genes were TP53 (62%), EGFR (55%), and KRAS (11%). The mutation frequencies of EGFR, TP53, PIK3CA, NFE2L2, KMT2D, FGFR1, CCND1, and CDKN2A were significantly different between lung adenocarcinoma and lung squamous cell carcinoma. We identified the age-associated mutations in ALK, ERBB2, KMT2D, RBM10, NRAS, NF1, PIK3CA, MET, PBRM1, LRP2, and CDKN2B; smoking-associated mutations in CDKN2A, FAT1, FGFR1, NFE2L2, CCNE1, CCND1, SMARCA4, KEAP1, KMT2C, and STK11; tumor stage-associated mutations in ARFRP1, AURKA, and CBFB; and sex-associated mutations in EGFR. Tumor mutational burden (TMB) is associated with tumor subtype, age, sex, and smoking status. TMB-associated mutations included CDKN2A, LRP1B, LRP2, TP53, and EGFR. EGFR amplification was commonly detected in patients with acquired lcotinib/gefitinib resistance. DNMT3A and NOTCH4 mutations may be associated with the benefit of icotinib/gefitinib treatment.

Background : Non-invasive prenatal testing (NIPT) is a commonly employed clinical method to screen for fetal aneuploidy, while the Y chromosome-based NIPT method is regarded as the gold standard for the estimation of fetal fraction (FF) of male fetuses. However, when the fetus has a derivative Y chromosome thereby containing a partial Y chromosome, the Y chromosome-based NIPT method cannot accurately calculate FF. Therefore, alternative methods to precisely calculate FF are required. Methods : Two prenatal cases could not be detected effectively using the Y chromosome-based NIPT method because of low FF. According to the Y chromosome-based method, the FF of the fetuses were 1.730 ± 0.050% (average gestation week: 18 +1 ) and 2.307 ± 0.191% (average gestation week: 20 +0 ) for cases 1 and 2, respectively. Using various genetic diagnostic techniques, including the BoBs™ assay, karyotype analysis, improved nucleolus-organizing region (NOR)-banding analysis, Affymetrix CytoScan 750K Array, and fluorescence in situ hybridization (FISH) analysis, we determined the genetic defects of two fetuses with translocations of the SRY locus. Further, we reassessed the FF using FF-QuantSC and X chromosome-based methods. The distribution diagram of reads for chromosome Y was also analyzed. Results : The FF of the fetuses determined by FF-QuantSC were 10.330% (gestation week: 18 +4 ) in case 1 and 9.470% (gestation week: 21 +4 ) in case 2, while the FF of the fetuses determined using the X chromosome-based method were 8.889% (gestation week: 18 +4 ) in case 1 and 2.296% (gestation week: 21 +4 ) in case 2. Both the distribution diagrams of reads for chromosome Y of the two cases showed the deletion in the long arm of the Y chromosome. Conclusion : For repeatedly low FF samples detected using the Y chromosome-based NIPT method for a long gestational week, we believe that FF-QuantSC and distribution diagrams of reads could be used as a supplement to NIPT, especially for rare cases of sex reversal caused by SRY translocation., (Copyright © 2020 Zeng, Gao, Yuan, Zhou, Cheng, Che, Qian, Fan, Zhang, Qian, Gao, Luo, Chen, Wang, Jin, Zhao, Shi, Li, Pan, Xiong, Ni, Qiu and Zhang.)

Objective: Cholangiocarcinoma (CCA) is a primary malignancy, which is often diagnosed as advanced and inoperable due to the lack of effective biomarkers and poor sensitivity of clinical diagnosis. Here, we aimed to identify the genomic profile of CCA and provided molecular evidence for further biomarker development., Methods: The formalin-fixed paraffin-embedded and matching blood samples were sequenced by deep sequencing targeting 450 cancer genes and genomic alteration analysis was performed. Tumor mutational burden (TMB) was measured by an algorithm developed in-house. Correlation analysis was performed by Fisher's exact test., Results: The most commonly altered genes in this cohort were TP53 (41.27%, 26/63), KRAS (31.75%, 20/63), ARID1A and IDH1 (15.87%, 10/63, for both), SMAD4 (14.29%, 9/63), FGFR2 and BAP1 (12.70%, 8/63, for both), and CDKN2A (11.11%, 7/63). BAP1 mutations were significantly correlated with the CCA subtype. LRP2 mutations were significantly associated with the younger intrahepatic CCA (iCCA) patients, while BAP1 was associated with iCCA patients aged 55-65 years old. BAP1 and LRP2 mutations were associated with TMB., Conclusions: Most Chinese CCA patients were 50-70 years old. BAP1 and LRP2 mutations were associated with the age of iCCA patients., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Communication between myeloid cells and epithelium plays critical role in maintaining intestinal epithelial barrier integrity. Myeloid cells interact with intestinal epithelial cells (IECs) by producing various mediators; however, the molecules mediating their crosstalk remain incompletely understood. Here, we report that deficiency of angiogenin (Ang) in mouse myeloid cells caused impairment of epithelial barrier integrity, leading to high susceptibility to DSS-induced colitis. Mechanistically, myeloid cell-derived angiogenin promoted IEC survival and proliferation through plexin-B2-mediated production of tRNA-derived stress-induced small RNA (tiRNA) and transcription of ribosomal RNA (rRNA), respectively. Moreover, treatment with recombinant angiogenin significantly attenuated the severity of experimental colitis. In human samples, the expression of angiogenin was significantly down-regulated in patients with inflammatory bowel disease (IBD). Collectively, we identified, for the first time to our knowledge, a novel mediator of myeloid cell-IEC crosstalk in maintaining epithelial barrier integrity, suggesting that angiogenin may serve as a new preventive agent and therapeutic target for IBD., (©2020 The Authors.)

Lung cancer is the most prevalent cancer worldwide and non‑small cell lung cancer (NSCLC) is the most common subtype and accounts for 75% of all lung cancer cases. Although programmed death‑1/programmed death‑ligand‑1 (PD‑1/PD‑L1) blockade has shown good results in the clinic, numerous NSCLC patients still fail to respond to this therapy. In the current study, formalin‑fixed, paraffin‑embedded tumor and matched blood samples from 1,984 Chinese NSCLS patients were collected for detection of genomic alterations including single nucleotide variations, short and long insertions/deletions, copy number variations and gene rearrangements. The most common mutated genes were tumor protein p53 (55.70%; 1,105/1,984), epidermal growth factor receptor (52.47%; 1,041/1,184), KRAS proto‑oncogene GTPase (13.36%, 265/1084), cyclin dependent kinase inhibitor 2A (12.30%; 244/1,984), LDL receptor related protein 1B (11.09%; 220/1,984) and telomerase reverse transcriptase (10.58%; 210/1,984). Tumor mutational burden was calculated and results revealed that it was associated with PI3K/mTOR pathway gene mutations, and patient's gender, age, smoking status, and tumor stage. In addition, mutations of phosphatidylinositol‑4,5‑bisphosphate 3‑kinase catalytic subunit α or F‑box and WD repeat domain containing 7 were detected in 3 patients with NSCLC who were resistant to PD‑1 inhibitors nivolumab and pembrolizumab. Disease stabilization and tumor shrinkage were observed in these patients after mTOR inhibitor everolimus treatment. The current data showed that NSCLC with PI3K/mTOR mutations are sensitive to mTOR inhibitors.

In this paper, a glutathione functionalized gold nanocluster (GSH-AuNCs) was prepared. GSH-AuNCs can catalyze the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) in the presence of hydrogen peroxide to produce a blue-green ox-TMB. By using its peroxidase activity and the GSH-AuNCs-TMB-H 2 O 2 system, the visualization of Fe 3+ and Cu 2+ and the high sensitivity detection of Fe 3+ and Cu 2+ can be realized according to the change of absorbance value and color of the system. The results showed that the sensitivity of the system to detect Fe 3+ and Cu 2+ in industrial wastewater reached 1.25 × 10 -9 M and 1.25 × 10 -10 M, respectively. At the same time, the chelating agents NH 4 F and EDTA · 2Na were introduced to realize the selective detection of the two ions under the coexistence of Fe 3+ and Cu 2+ ions.

Metastasis of colorectal cancer (CRC) is the leading cause of CRC-associated mortality. Angiogenin (ANG), a member of the ribonuclease A superfamily, not only activates endothelial cells to induce tumor angiogenesis, but also targets tumor cells to promote cell survival, proliferation and/or migration. However, its clinical significance and underlying mechanism in CRC metastasis are still largely unknown. Here, we reported that ANG was upregulated in CRC tissues and associated with metastasis in CRC patients. We then revealed that ANG enhanced CRC growth and metastasis in both in vitro and in vivo systems. Intriguingly, we characterized a bunch of tRNA-derived stress-induced small RNAs (tiRNAs), produced through ANG cleavage, that was enriched in both CRC tumor tissues and highly metastatic cells, and functioned in ANG-promoted CRC metastasis. Moreover, higher level of a 5'-tiRNA from mature tRNA-Val (5'-tiRNA-Val) was observed in CRC patients and was correlated with tumor metastasis. Taken together, we propose that a novel ANG-tiRNAs-cell migration and invasion regulatory axis promotes CRC metastasis, which might be of potential target for CRC diagnosis and treatment., (© 2019 UICC.)

Accumulation of toxic heavy metals and metalloids (THMMs) in crop grain remarkably affects food safety and human health. Reducing the content of THMMs in grain requires the identification and manipulation of the genes regulating their accumulation. This study aimed to determine the genetic variations affecting grain THMM accumulation in rice by using association mapping. We used 276 accessions with 416 K single nucleotide polymorphisms (SNPs) and performed genome-wide association analysis of grain THMM concentrations in rice grown in heavily multi-contaminated farmlands. We detected 22, 17, and 21 quantitative trait loci (QTLs) for grain arsenic, cadmium, and lead concentrations, respectively. Both inter- and intra-subpopulation variants accounted for these QTLs. Most QTLs contained no known THMM-related genes and represented unidentified novel genes. We examined the candidate genes in qGAS1 , a QTL for grain arsenic concentration with the best P -value detected for the entire population. We speculated that a transport protein of the multidrug and toxin extrusion family could be the candidate gene for this QTL. Our study suggested that the genetic regulation of grain THMM accumulation is very complex and largely unknown. The QTLs and SNPs identified in this study might help in the identification of new genes regulating THMM accumulation and aid in marker-assisted breeding of rice with low grain THMM content.

We study experimentally the formation of a dual hierarchical jetting pattern in dry dense particle media subjected to the radially divergent shock loadings in a radial Hele-Shaw cell. The distinct internal and external jetting patterns were formed on the internal and external surfaces of a ring at different times, respectively. The former features dozens of radially aligned fine filaments. By contrast, the latter consists of a large number of small spikes. Once the internal jets are fully developed, a novel proportionate growth is observed, in which distinguishable structures of the overall pattern all grow at the same rate until the interaction between the internal and external jets becomes significant, leading to the inversion of the internal jetting pattern. Although the external jetting is found to be an instability of a Rayleigh-Taylor (RT) type, the internal jetting exhibits a much delayed onset and slower early-stage growth compared with the RT instability, indicating different underlying physics.

Silent information regulator 6 (SIRT6) is broadly considered as a tumor suppressor due to its function in the suppression of oncogene expression. However, the role of SIRT6 in colorectal cancer stem cells (CSCs) remains uncharacterized. In the present study, it was demonstrated that SIRT6 expression was reduced in colorectal CSCs. Overexpression of SIRT6 in colorectal CSCs did not induce cell apoptosis. However, SIRT6 significantly inhibited cell proliferation, colony formation and induced G0/G1 phase arrest in colorectal CSCs. In addition, SIRT6 repressed the expression of cell division cycle 25A (CDC25A), an oncogenic phosphatase. Chromatin immunoprecipitation experiments indicated that SIRT6 directly bound to the CDC25A promoter and decreased the acetylation level of histone H3 lysine 9. Altogether, these data indicated that SIRT6 inhibits colorectal cancer stem cell proliferation by targeting CDC25A.

Since its domestication from wild rice thousands of years ago, rice has been cultivated largely through transplantation. During transplantation from the nursery to the paddy field, rice seedlings experience transplantation shock which affects their physiology and production. However, the mechanisms underlying transplantation shock and rice adaptation to this shock are largely unknown. Here, we isolated a transplant-sensitive chloroplast-deficient (tsc1) rice mutant that produces albino leaves after transplantation. Blocking light from reaching the juvenile leaves and leaf primordia caused chloroplast deficiencies in transplanted tsc1 seedlings. TSC1 encodes a noncanonical adenosine triphosphate-binding cassette (ABC) transporter homologous to AtNAP14 and is of cyanobacterial origin. We demonstrate that TSC1 controls plastid development in rice under dark conditions, and functions independently of light signaling. However, light rescued the tsc1 mutant phenotype in a spectrum-independent manner. TSC1 was upregulated following transplantation, and modulated the iron and copper levels, thereby regulating prolamellar body formation during the early P4 stage of leaf development. Therefore, TSC1 is indispensable for plastid development in the absence of light, and contributes to adaptation to transplantation shock. Our study provides insight into the regulation of plastid development and establishes a framework for improving recovery from transplantation shock in rice., (© 2017 Institute of Botany, Chinese Academy of Sciences.)

Preeclampsia (PE) is a major contributor to maternal morbidity and mortality. However, the molecular mechanisms underlying PE progression are not well characterized. Here, we investigated the role of miR-218 in PE development. The expression of miR-218 and its host genes SLIT2 and SLIT3 was up-regulated in preeclamptic placentae compared to normal placentae. miR-218 expression was induced by hypoxia and decreased after knockdown of HIF-1α in an extravillous trophoblast cell line (HTR-8/SVneo). Chromatin immunoprecipitation assays showed direct binding of HIF-1α to the promoters of SLIT2 and SLIT3. Bioinformatics analysis identified LASP1 as a direct target of miR-218. Overexpression of miR-218 repressed the expression of LASP1 at both the mRNA and protein level. Meanwhile, miR-218 repressed the activity of a luciferase reporter containing the 3'-untranslated region of the LASP1 gene. Furthermore, expression of LASP1 rescued the inhibitory effect of miR-218 on HTR-8/SVneo cell invasion. Together, these results indicated that miR-218 contributes to PE by targeting LASP1 to inhibit trophoblast invasion., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Chloroplasts are essential for photosynthesis and play critical roles in plant development. In this study, we characterized the temperature-sensitive chlorophyll-deficient rice mutant tcd5, which develops albino leaves at low temperatures (20 °C) and normal green leaves at high temperatures (32 °C). The development of chloroplasts and etioplasts is impaired in tcd5 plants at 20 °C, and the temperature-sensitive period for the albino phenotype is the P4 stage of leaf development. The development of thylakoid membranes is arrested at the mid-P4 stage in tcd5 plants at 20 °C. We performed positional cloning of TCD5 and then complementation and knock-down experiments, and the results showed that the transcript LOC&#95;Os05g34040.1 from the LOC&#95;Os05g34040 gene corresponded to the tcd5 phenotype. TCD5 encodes a conserved plastid-targeted monooxygenase family protein which has not been previously reported associated with a temperature-sensitive albino phenotype in plants. TCD5 is abundantly expressed in young leaves and immature spikes, and low temperatures increased this expression. The transcription of some genes involved in plastid transcription/translation and photosynthesis varied in the tcd5 mutant. Although the phenotype and temperature dependence of the TCD5 orthologous mutant phenotype were different in rice and Arabidopsis, OsTCD5 could rescue the phenotype of the Arabidopsis mutant, suggesting that TCD5 function is conserved between monocots and dicots., (© The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology.)