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Background: Hepatitis C virus (HCV) infection remains a major public health problem in Chinese mainland. Investigation of the distribution of genotypes contributed to the prevention, diagnosis and treatment of HCV infection. Therefore, we conducted a study on the distribution of HCV genotypes and phylogenetic analysis to provide an up-to-date understanding of the molecular epidemiology of genotypes in Chinese mainland. Methods: Our retrospective multicenter study enrolled 11,008 samples collected between August 2018 and July 2019 from 29 provinces/municipalities (Beijing, Hebei, Inner Mongolia, Shanxi, Tianjin, Gansu, Ningxia, Shaanxi, Xinjiang, Heilongjiang, Jilin Liaoning, Henan, Hubei Hunan, Anhui, Fujian, Jiangsu, Jiangxi, Shandong, Shanghai Zhejiang, Guangdong, Guangxi, Hainan, Chongqing, Guizhou, Sichuan and Yunnan). Phylogenetic analysis of each subtype was performed to infer the evolutionary relationship of sequences from diverse regions. Two independent samples t tests were used for the comparison of continuous variables, and chi-square tests were used for the comparison of categorical variables. Results: Four genotypes (1, 2, 3 and 6) were found, including 14 subtypes. HCV genotype 1 was dominant, accounting for 49.2%, followed by genotypes 2, 3 and 6, accounting for 22.4%, 16.4%, and 11.9%, respectively. Additionally, the top five subtypes were 1b, 2a, 3b, 6a and 3a. Proportions of genotypes 1 and 2 decreased while genotypes 3 and 6 increased over past years (P < 0.001). Genotypes 3 and 6 were concentrated in the population aged 30 to 50 years, and male carriers had lower proportions of subtypes 1b and 2a than female carriers (P < 0.01). Genotypes 3 and 6 were more prevalent in southern parts of Chinese mainland. Nationwide spreads of subtypes 1b and 2a were associated with sequences from northern parts of Chinese mainland, while subtypes 3a, 3b and 6a were associated with sequences from southern parts of Chinese mainland. Conclusions: HCV subtypes 1b and 2a remained the most common subtypes in Chinese mainland, and their proportions decreased over the past years, while the proportions of genotypes 3 and 6 increased. Our investigation provided an accurate epidemiological picture of the circulating viral strains in Chinese mainland, contributing to the prevention, diagnosis and treatment of HCV infection. Trial registration: Not applicable. [ABSTRACT FROM AUTHOR]

Background: Hepatic fibrosis is characterized by the excessive deposition of extracellular matrix (ECM) which is mainly secreted by activated hepatic stellate cells (HSCs). Lamiophlomis rotata (L. rotata) was recorded to treat jaundice in the traditional Tibetan medical system with the potential of hepatoprotection. However, the bioactivities and the possible mechanism of L. rotata on hepatic fibrosis is still largely unknown. Aim of the study: To investigate the anti-hepatic fibrosis effects of bioactivities in L. rotata and the probable mechanism of action. Materials and methods: Herein, total polyphenolic glycosides of L. rotata (TPLR) was purified with the selectivity adsorption resin and was analyzed by ultrahigh-performance liquid chromatography coupled with time-of-flight mass spectrometry (UPLC-Q/TOF/MSn). The anti-hepatic fibrosis effect of TPLR was evaluated by carbon tetrachloride (CCl4)-induced liver fibrosis, and was evaluated with the apoptosis of activated HSCs. Results: In total, sixteen compounds, including nine phenylpropanoids and six flavonoids, were identified in the UPLC-TOF-MSn profile of the extracts. TPLR significantly ameliorated hepatic fibrosis in CCl4-induced mice and inhibited HSCs proliferation, Moreover, TPLR notably increased the apoptosis of activated HSCs along with up-regulated caspase-3, -8, -9, and -10. Furthermore, TPLR inhibited TGF-β/Smad pathway ameliorating hepatic fibrosis though downregulation the expression of Smad2/3, Smad4, and upregulation the expression of Smad7 in vivo and in vitro. Simultaneously, the expression of fibronectin (FN), α-smooth muscle actin (α-SMA), and Collagen I (Col1α1) were decreased in tissues and in cells with TPLR administration. Conclusion: These results initially demonstrated that TPLR has the potential to ameliorate hepatic fibrosis through an apoptosis mechanism via TGF-β/Smad signaling pathway. Highlights: Chemical composition of TPRL was identified by UPLC-Q/TOF/MSn in the profile of total ion current. TPRL was initially demostrated the effects of anti-hepatic fibrosis in vitro and in vivo. TPRL ameliorates hepatic fibrosis through apoptosis by TGF-β/Smad signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Software for nuclear magnetic resonance (NMR) spectrometers offer general functionality of instrument control and data processing; these applications are often developed with non-scripting languages. NMR users need to flexibly integrate rapidly developing NMR applications with emerging technologies. Scripting systems offer open environments for NMR users to write custom programs. However, existing scripting systems have limited capabilities for both extending the functionality of NMR software's non-script main program and using advanced native script libraries to support specialized application domains (e.g., biomacromolecules and metabolomics). Therefore, it is essential to design a novel scripting system to address both of these needs. Result: Here, a novel NMR scripting system named SpinSPJ is proposed. It works as a plug-in in the Java based NMR spectrometer software SpinStudioJ. In the scripting system, both Java based NMR methods and original CPython based libraries are supported. A module has been developed as a bridge to integrate the runtime environments of Java and CPython. The module works as an extension in the CPython environment and interacts with Java via the Java Native Interface. Leveraging this bridge, Java based instrument control and data processing methods of SpinStudioJ can be called with the CPython style. Compared with traditional scripting systems, SpinSPJ better supports both extending the non-script main program and implementing advanced NMR applications with a rich variety of script libraries. NMR researchers can easily call functions of instrument control and data processing as well as developing complex functionality (such as multivariate statistical analysis, deep learning, etc.) with CPython native libraries. Conclusion: SpinSPJ offers a user-friendly environment to implement custom functionality leveraging its powerful basic NMR and rich CPython libraries. NMR applications with emerging technologies can be easily integrated. The scripting system is free of charge and can be downloaded by visiting http://www.spinstudioj.net/spinspj. [ABSTRACT FROM AUTHOR]

Background: Sucrose nonfermenting-1 (SNF1)-related protein kinases (SnRKs) play important roles in regulating metabolism and stress responses in plants, providing a conduit for crosstalk between metabolic and stress signalling, in some cases involving the stress hormone, abscisic acid (ABA). The burgeoning and divergence of the plant gene family has led to the evolution of three subfamilies, SnRK1, SnRK2 and SnRK3, of which SnRK2 and SnRK3 are unique to plants. Therefore, the study of SnRKs in crops may lead to the development of strategies for breeding crop varieties that are more resilient under stress conditions. In the present study, we describe the SnRK gene family of barley (Hordeum vulgare), the widespread cultivation of which can be attributed to its good adaptation to different environments. Results: The barley HvSnRK gene family was elucidated in its entirety from publicly-available genome data and found to comprise 50 genes. Phylogenetic analyses assigned six of the genes to the HvSnRK1 subfamily, 10 to HvSnRK2 and 34 to HvSnRK3. The search was validated by applying it to Arabidopsis (Arabidopsis thaliana) and rice (Oryza sativa) genome data, identifying 50 SnRK genes in rice (four OsSnRK1, 11 OsSnRK2 and 35 OsSnRK3) and 39 in Arabidopsis (three AtSnRK1, 10 AtSnRK2 and 26 AtSnRK3). Specific motifs were identified in the encoded barley proteins, and multiple putative regulatory elements were found in the gene promoters, with light-regulated elements (LRE), ABA response elements (ABRE) and methyl jasmonate response elements (MeJa) the most common. RNA-seq analysis showed that many of the HvSnRK genes responded to ABA, some positively, some negatively and some with complex time-dependent responses. Conclusions: The barley HvSnRK gene family is large, comprising 50 members, subdivided into HvSnRK1 (6 members), HvSnRK2 (10 members) and HvSnRK3 (34 members), showing differential positive and negative responses to ABA. [ABSTRACT FROM AUTHOR]

Background: Reducing the dependence of crop production on chemical fertilizer with its associated costs, carbon footprint and other environmental problems is a challenge for agriculture. New solutions are required to solve this problem, and crop breeding for high nitrogen use efficiency or tolerance of low nitrogen availability has been widely considered to be a promising approach. However, the molecular mechanisms of high nitrogen use efficiency or low-nitrogen tolerance in crop plants are still to be elucidated, including the role of long non-coding RNAs (lncRNAs). Results: In this study, we identified 498 lncRNAs in barley (Hordeum vulgare) landrace B968 (Liuzhutouzidamai), of which 487 were novel, and characterised 56 that were responsive to low-nitrogen stress. For functional analysis of differentially-expressed lncRNAs, the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment of co-expressed and co-located protein-coding genes were analyzed, and interactions with annotated co-expressed protein coding genes or micro RNAs (miRNAs) were further predicted. Target mimicry prediction between differentially-expressed lncRNAs and miRNAs identified 40 putative target mimics of lncRNAs and 58 target miRNAs. Six differentially-expressed lncRNAs were further validated by qPCR, and one in particular showed consistent differential expression using both techniques. Expression levels of most of the lncRNAs were found to be very low, and this may be the reason for the apparent inconsistency between RNA-seq and qPCR data. Conclusions: The analysis of lncRNAs that are differentially-expressed under low-nitrogen stress, as well as their co-expressed or co-located protein coding genes and target mimics, could elucidate complex and hitherto uncharacterised mechanisms involved in the adaptation to low-nitrogen stress in barley and other crop plants. [ABSTRACT FROM AUTHOR]

Background: Tumor-infiltrating lymphocytes (TILs), investigated using routine hematoxylin and eosin (H&E)-stained section slides (H&E-sTILs), provide a robust prognostic biomarker in various types of solid cancer. The purpose of the present study was to investigate the prognostic significance of H&E-sTILs in patients with small cell lung cancer (SCLC). Methods: The clinical data of patients with SCLC who had been treated in our cancer center between January 2013 and October 2019 were collected and retrospectively reviewed. The H&E-sTILs were re-assessed by two experienced pathologists independently. H&E-sTILs that affected the overall survival (OS), progression free survival (PFS) and brain-metastasis free survival (BMFS) rates were explored using the Kaplan–Meier method, and the log-rank test was used to assess the differences. Multivariate analysis was subsequently performed using the Cox proportion hazards model. Results: A total of 159 patients with SCLC who fulfilled the inclusion criteria were enrolled in the current study. The OS rates at 1, 2 and 3 years were 59.8, 28.6 and 19.8%, respectively, for the whole group. The 3-year OS, PFS and BMFS rates for the H&E-sTILs(+) and H&E-sTILs(−) groups were 25.1% cf. 5.1% (P = 0.030), 14.0% cf. 4.0% (P = 0.013), and 66.0% cf. 11.4% (P = 0.023), respectively. Multivariate analyses subsequently revealed that H&E-sTILs, clinical M stage, the cycles of chemotherapy and short-term response to thoracic radiotherapy were independent factors affecting OS, whereas H&E-sTILs, clinical N stage, clinical M stage and short-term response to chemotherapy were factors affecting PFS. The H&E-sTILs affected OS, PFS and BMFS simultaneously. Conclusions: The results of this retrospective study have shown that H&E-sTILs may be considered as a prognostic biomarker affecting the short-term response to treatment, and they are the one and only risk factor for BMFS. However, due to the limitations of the nature of the retrospective design and shortcomings in visually assessing the TILs based on the H&E-stained slides, further prospective studies are required to confirm these conclusions. [ABSTRACT FROM AUTHOR]

Background: Isolated microspore culture is a useful biotechnological technique applied in modern plant breeding programs as it can produce doubled haploid (DH) plants and accelerate the development of new varieties. Furthermore, as a single-cell culture technique, the isolated microspore culture provides an excellent platform for studying microspore embryogenesis. However, the reports on isolated microspore culture are rather limited in rice due to the low callus induction rate, poor regeneration capability, and high genotypic dependency. The present study developed an effective isolated microspore culture protocol for high-frequency androgenesis in four japonica rice genotypes. Several factors affecting the isolated microspore culture were studied to evaluate their effects on callus induction and plantlet regeneration. Results: Low-temperature pre-treatment at 4 ℃ for 10–15 days could effectively promote microspore embryogenesis in japonica rice. A simple and efficient method was proposed for identifying the microspore developmental stage. The anthers in yellow-green florets located on the second type of primary branch on the rice panicle were found to be the optimal stage for isolated microspore culture. The most effective induction media for callus induction were IM2 and IM3, depending on the genotype. The optimal concentration of 2, 4-D in the medium for callus induction was 1 mg/L. Callus induction was negatively affected by a high concentration of KT over 1.5 mg/L. The differentiation medium suitable for japonica rice microspore callus comprised 1/2 MS, 2 mg/L 6-BA, 0.5 mg/L NAA, 30 g/L sucrose, and 6 g/L agar. The regeneration frequency of the four genotypes ranged from 61–211 green plantlets per 100 mg calli, with Chongxiangjing showing the highest regeneration frequency. Conclusions: This study presented an efficient protocol for improved callus induction and green plantlet regeneration in japonica rice via isolated microspore culture, which could provide valuable support for rice breeding and genetic research. [ABSTRACT FROM AUTHOR]

Background: Tumor-infiltrating lymphocytes (TILs), investigated using routine hematoxylin and eosin (H&E)-stained section slides (H&E-sTILs), provide a robust prognostic biomarker in various types of solid cancer. The purpose of the present study was to investigate the prognostic significance of H&E-sTILs in patients with small cell lung cancer (SCLC).Methods: The clinical data of patients with SCLC who had been treated in our cancer center between January 2013 and October 2019 were collected and retrospectively reviewed. The H&E-sTILs were re-assessed by two experienced pathologists independently. H&E-sTILs that affected the overall survival (OS), progression free survival (PFS) and brain-metastasis free survival (BMFS) rates were explored using the Kaplan-Meier method, and the log-rank test was used to assess the differences. Multivariate analysis was subsequently performed using the Cox proportion hazards model.Results: A total of 159 patients with SCLC who fulfilled the inclusion criteria were enrolled in the current study. The OS rates at 1, 2 and 3 years were 59.8, 28.6 and 19.8%, respectively, for the whole group. The 3-year OS, PFS and BMFS rates for the H&E-sTILs(+) and H&E-sTILs(-) groups were 25.1% cf. 5.1% (P = 0.030), 14.0% cf. 4.0% (P = 0.013), and 66.0% cf. 11.4% (P = 0.023), respectively. Multivariate analyses subsequently revealed that H&E-sTILs, clinical M stage, the cycles of chemotherapy and short-term response to thoracic radiotherapy were independent factors affecting OS, whereas H&E-sTILs, clinical N stage, clinical M stage and short-term response to chemotherapy were factors affecting PFS. The H&E-sTILs affected OS, PFS and BMFS simultaneously.Conclusions: The results of this retrospective study have shown that H&E-sTILs may be considered as a prognostic biomarker affecting the short-term response to treatment, and they are the one and only risk factor for BMFS. However, due to the limitations of the nature of the retrospective design and shortcomings in visually assessing the TILs based on the H&E-stained slides, further prospective studies are required to confirm these conclusions. [ABSTRACT FROM AUTHOR]

Background: Although extensive use of tyrosine kinase inhibitors has resulted in high and durable response rate and prolonged survival time in patients with BCR-ABL1 positive chronic myeloid leukemia (CML) and acute leukemia, relapse and drug resistance still remain big challenges for clinicians. Monitoring the expression of BCR-ABL1 fusion gene and identifying ABL kinase mutations are effective means to predict disease relapse and resistance. However, the prognostic impact of BCR-ABL1 signal patterns detected by fluorescence in situ hybridization (FISH) remains largely unaddressed.Methods: BCR-ABL1 signal patterns were analyzed using FISH in 243 CML-chronic phase (CML-CP), 17 CML-blast phase (CML-BP) and 52 BCR-ABL1 positive acute lymphoblastic leukemia (ALL) patients.Results: The patterns of BCR-ABL1 signals presented complexity and diversity. A total of 12 BCR-ABL1 signals were observed in this cohort, including 1R1G2F, 1R1G1F, 2R1G1F, 1R2G1F, 2R2G1F, 1R2G2F, 1R1G3F, 1G3F, 2G3F, 1G4F, 1R1G4F and 1R4F. Complex BCR-ABL1 signal patterns (≥ two types of signal patterns) were observed in 52.9% (n = 9) of the CML-BP patients, followed by 30.8% (n = 16) of the ALL patients and only 2.1% (n = 5) of the CML-CP patients. More importantly, five clonal evolution patterns related to disease progression and relapse were observed, and patients with complex BCR-ABL1 signal patterns had a poorer overall survival (OS) time compared with those with single patterns (5.0 vs.15.0 months, p = 0.006).Conclusions: Our data showed that complex BCR-ABL1 signal patterns were associated with leukemic clonal evolution and poorer prognosis in BCR-ABL1 positive leukemia. Monitoring BCR-ABL1 signal patterns might be an effective means to provide prognostic guidance and treatment choices for these patients. [ABSTRACT FROM AUTHOR]

Surgical resection is an important avenue for cancer treatment, which, in most cases, can effectively alleviate the patient symptoms. However, accumulating evidence has documented that surgical resection potentially enhances metastatic seeding of tumor cells. In this review, we revisit the literature on surgical stress, and outline the mechanisms by which surgical stress, including ischemia/reperfusion injury, activation of sympathetic nervous system, inflammation, systemically hypercoagulable state, immune suppression and effects of anesthetic agents, promotes tumor metastasis. We also propose preventive strategies or resolution of tumor metastasis caused by surgical stress. [ABSTRACT FROM AUTHOR]

Background: To compare the clinical characteristics and prognoses of patients with isolated regional lymph node recurrent nasopharyngeal carcinoma (irrNPC) who underwent surgery or re-irradiation treatment. Methods: We retrospectively reviewed 124 irrNPC patients who underwent initial radiotherapy between January 2010 and December 2020. The staging of regional lymph node recurrence was as follows: 75.8% for rN1, 14.5% for rN2, and 9.7% for rN3. Fifty-five patients underwent regional lymph node surgery (Surgery group), and sixty-nine patients received salvage radiotherapy with or without chemotherapy (Re-irradiation group). The survival rate was compared using Kaplan‒Meier analysis and evaluated by the log-rank test. Cox proportional hazard models were used to analyze prognostic factors. Results: The median follow-up time was 70 months, the 5-year overall survival (OS) was 74%, and the median survival time was 60.8 months. There were no significant differences in 5-year OS (75.6% vs. 72.4%, P = 0.973), regional recurrence-free survival (RRFS, 62.7% vs. 71.1%, P = 0.330) or distant metastasis-free survival (DMFS, 4.2% vs.78.7%, P = 0.677) between the Surgery group and Re-irradiation group. Multivariate analysis revealed age at recurrence, radiologic extra-nodal extension (rENE) status, and recurrent lymph node (rN) classification as independent prognostic factors for OS. The rENE status was an independent prognostic factor for DMFS. Subgroup analysis of the Surgery group revealed that the rN3 classification was an adverse prognostic factor for OS. Age at recurrence ≥ 50 years, GTV-N dose, and induction chemotherapy were found to be independent prognostic factors for OS, RRFS, and DMFS, respectively, in the Re-irradiation group. Conclusions: For NPC patients with isolated regional lymph node recurrence after initial radiotherapy, those who underwent surgery had survival prognosis similar to those who underwent re-radiotherapy with or without chemotherapy. A prospective study is needed to validate these findings. [ABSTRACT FROM AUTHOR]

After publication of this supplement article [1], it was brought to our attention that the Results section of the abstract contained a partial sentence. [ABSTRACT FROM AUTHOR]

Background: In the past few years, neural word embeddings have been widely used in text mining. However, the vector representations of word embeddings mostly act as a black box in downstream applications using them, thereby limiting their interpretability. Even though word embeddings are able to capture semantic regularities in free text documents, it is not clear how different kinds of semantic relations are represented by word embeddings and how semantically-related terms can be retrieved from word embeddings.Methods: To improve the transparency of word embeddings and the interpretability of the applications using them, in this study, we propose a novel approach for evaluating the semantic relations in word embeddings using external knowledge bases: Wikipedia, WordNet and Unified Medical Language System (UMLS). We trained multiple word embeddings using health-related articles in Wikipedia and then evaluated their performance in the analogy and semantic relation term retrieval tasks. We also assessed if the evaluation results depend on the domain of the textual corpora by comparing the embeddings of health-related Wikipedia articles with those of general Wikipedia articles.Results: Regarding the retrieval of semantic relations, we were able to retrieve diverse semantic relations in the nearest neighbors of a given word. Meanwhile, the two popular word embedding approaches, Word2vec and GloVe, obtained comparable results on both the analogy retrieval task and the semantic relation retrieval task, while dependency-based word embeddings had much worse performance in both tasks. We also found that the word embeddings trained with health-related Wikipedia articles obtained better performance in the health-related relation retrieval tasks than those trained with general Wikipedia articles.Conclusion: It is evident from this study that word embeddings can group terms with diverse semantic relations together. The domain of the training corpus does have impact on the semantic relations represented by word embeddings. We thus recommend using domain-specific corpus to train word embeddings for domain-specific text mining tasks. [ABSTRACT FROM AUTHOR]

Background: Patients with type 2 diabetes mellitus (T2DM) have been reported to be more susceptible to 2019 novel coronavirus (2019-nCoV) and more likely to develop severe pneumonia. However, the safety and immunological responses of T2DM patients after receiving the inactivated vaccines are not quite definite. Therefore, we aimed to explore the safety, antibody responses, and B-cell immunity of T2DM patients who were vaccinated with inactivated coronavirus disease 2019 (COVID-19) vaccines. Methods: Eighty-nine patients with T2DM and 100 healthy controls (HCs) were enrolled, all of whom had received two doses of full-course inactivated vaccines. At 21–105 days after full-course vaccines: first, the safety of the vaccines was assessed by questionnaires; second, the titers of anti-receptor binding domain IgG (anti-RBD-IgG) and neutralizing antibodies (NAbs) were measured; third, we detected the frequency of RBD-specific memory B cells (RBD-specific MBCs) to explore the cellular immunity of T2DM patients. Results: The overall incidence of adverse events was similar between T2DM patients and HCs, and no serious adverse events were recorded in either group. Compared with HCs, significantly lower titers of anti-RBD-IgG (p = 0.004) and NAbs (p = 0.013) were observed in T2DM patients. Moreover, the frequency of RBD-specific MBCs was lower in T2DM patients than in HCs (p = 0.027). Among the 89 T2DM patients, individuals with lower body mass index (BMI) had higher antibody titers (anti-RBD-IgG: p = 0.009; NAbs: p = 0.084). Furthermore, we found that sex, BMI, and days after vaccination were correlated with antibody titers. Conclusions: Inactivated COVID-19 vaccines were safe in patients with T2DM, but the antibody responses and memory B-cell responses were significantly decreased compared to HCs. Trial registration number and date: NCT05043246. September 14, 2021. (Clinical Trials.gov) [ABSTRACT FROM AUTHOR]

Background: Recurrence represents a well-known poor prognostic factor for colorectal cancer (CRC) patients. This study aimed to establish an effective prognostic prediction model based on noninvasive circulating tumor DNA methylation markers for CRC patients receiving radical surgery. Results: Two methylation markers (cg11186405 and cg17296166) were identified by Cox regression and receiver operating characteristics, which could classify CRC patients into high recurrence risk and low recurrence risk group. The 3-year disease-free survival was significantly different between CRC patients with low and high recurrence risk [Training set: hazard ratio (HR) 28.776, 95% confidence interval (CI) 3.594–230.400; P = 0.002; Validation set: HR 7.796, 95% CI 1.425–42.660, P = 0.018]. The nomogram based on the above two methylation markers and TNM stage was established which demonstrated robust prognostic prediction potential, as evidenced by the decision curve analysis result. Conclusions: A cell-free DNA methylation model consisting of two DNA methylation markers is a promising method for prognostic prediction in CRC patients. [ABSTRACT FROM AUTHOR]

Background: Neoadjuvant immunotherapy is emerging as novel effective intervention in lung cancer, but study to unearth effective surrogates indicating its therapeutic outcomes is limited. We investigated the genetic changes between non-small cell lung cancer (NSCLC) patients with varied response to neoadjuvant immunotherapy and discovered highly potential biomarkers with indicative capability in predicting outcomes. Methods: In this study, 3 adenocarcinoma and 11 squamous cell carcinoma NSCLC patients were treated by neoadjuvant immunotherapy with variated regimens followed by surgical resection. Treatment-naive FFPE or fresh tissues and blood samples were subjected to whole-exome sequencing (WES). Genetic alternations were compared between differently-responded patients. Findings were further validated in multiple public cohorts. Results: DNA damage repair (DDR)-related InDel signatures and DDR-related gene mutations were enriched in better-responded patients, i.e., major pathological response (MPR) group. Besides, MPR patients exhibited provoked genome instability and unique homologous recombination deficiency (HRD) events. By further inspecting alternation status of homology-dependent recombination (HR) pathway genes, the clonal alternations were exclusively enriched in MPR group. Additionally, associations between HR gene alternations, percentage of viable tumor cells and HRD event were identified, which orchestrated tumor mutational burden (TMB), mutational intratumor heterogeneity (ITH), somatic copy number alteration (SCNA) ITH and clonal neoantigen load in patients. Validations in public cohorts further supported the generality of our findings. Conclusions: We reported for the first time the association between HRD event and enhanced neoadjuvant immunotherapy response in lung cancer. The power of HRD event in patient therapeutic stratification persisted in multifaceted public cohorts. We propose that HR pathway gene status could serve as novel and additional indicators guiding immune-neoadjuvant and immunotherapy treatment decisions for NSCLC patients. [ABSTRACT FROM AUTHOR]

Background: Lymph node metastasis (LNM) is an important factor for both treatment and prognosis of early gastric cancer (EGC). Current methods are insufficient to evaluate LNM in EGC due to suboptimal accuracy. Herein, we aim to identify methylation signatures for LNM of EGC, facilitate precision diagnosis, and guide treatment modalities. Methods: For marker discovery, genome-wide methylation sequencing was performed in a cohort (marker discovery) using 47 fresh frozen (FF) tissue samples. The identified signatures were subsequently characterized for model development using formalin-fixed paraffin-embedded (FFPE) samples by qPCR assay in a second cohort (model development cohort, n = 302, training set: n = 151, test set: n = 151). The performance of the established model was further validated using FFPE samples in a third cohorts (validation cohort, n = 130) and compared with image-based diagnostics, conventional clinicopathology-based model (conventional model), and current standard workups. Results: Fifty LNM-specific methylation signatures were identified de novo and technically validated. A derived 3-marker methylation model for LNM diagnosis was established that achieved an AUC of 0.87 and 0.88, corresponding to the specificity of 80.9% and 85.7%, sensitivity of 80.6% and 78.1%, and accuracy of 80.8% and 83.8% in the test set of model development cohort and validation cohort, respectively. Notably, this methylation model outperformed computed tomography (CT)-based imaging with a superior AUC (0.88 vs. 0.57, p < 0.0001) and individual clinicopathological features in the validation cohort. The model integrated with clinicopathological features demonstrated further enhanced AUCs of 0.89 in the same cohort. The 3-marker methylation model and integrated model reduced 39.4% and 41.5% overtreatment as compared to standard workups, respectively. Conclusions: A novel 3-marker methylation model was established and validated that shows diagnostic potential to identify LNM in EGC patients and thus reduce unnecessary gastrectomy in EGC. [ABSTRACT FROM AUTHOR]

Background: Liver fibrosis develops from various chronic liver diseases, and there is currently a lack of specific treatment strategies. Yiqi Rougan decoction (YQRG) is a traditional Chinese medicine that has shown durative effects in the treatment of liver fibrosis; however, the mechanism associated with YQRG-related improvements in liver fibrosis remains to be experimentally determined. This study evaluated the therapeutic effect of YQRG on carbon tetrachloride (CCl4)-induced liver fibrosis in rats and its molecular mechanism. Methods: We used low-, medium-, and high-dose YQRG to treat CCl4-induced liver fibrosis in rats, followed by assessment of liver injury and fibrosis according to liver appearance, body weight, liver mass index, histopathologic examination, and serum testing. Additionally, we performed transcriptome analysis using RNA-sequencing (RNA-seq) technology, including cluster, Gene Ontology (GO), and pathway analyses, to identify differentially expressed genes (DEGs), and protein and gene expression were detected by immunofluorescence (IFC), western blot and real-time quantitative PCR. Results: The results showed that YQRG effectively alleviated CCl4-induced liver injury and fibrosis in rats, including observations of improved liver function, decreased activity of hepatic stellate cells (HSCs), and decreased extracellular matrix (ECM) deposition. Moreover, we identified downregulated and upregulated DEGs in the model group relative to the control and YQRG-treated groups, with GO analysis revealing their enrichment in biological processes, such as endoplasmic reticulum stress (ERS), apoptosis, and autophagy. Furthermore, pathway analysis showed that YQRG treatment downregulated the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase/Akt (PI3K/AKT) signalling pathways and upregulated other signalling pathways, including those related to peroxisome proliferator-activated receptors(PPAR) and AMP-activated protein kinase(AMPK), with these findings subsequently verified experimentally. Conclusion: These findings showed that YQRG improved CCl4-induced liver fibrosis through multiple mechanisms and pathways, offering critical insight into the YQRG-related therapeutic mechanism and promoting further research into its potential application. [ABSTRACT FROM AUTHOR]

Background: Lung cancer is the leading cause of cancer-related mortality. The alteration of DNA methylation plays a major role in the development of lung cancer. Methylation biomarkers become a possible method for lung cancer diagnosis. Results: We identified eleven lung cancer-specific methylation markers (CDO1, GSHR, HOXA11, HOXB4-1, HOXB4-2, HOXB4-3, HOXB4-4, LHX9, MIR196A1, PTGER4-1, and PTGER4-2), which could differentiate benign and malignant pulmonary nodules. The methylation levels of these markers are significantly higher in malignant tissues. In bronchoalveolar lavage fluid (BALF) samples, the methylation signals maintain the same differential trend as in tissues. An optimal 5-marker model for pulmonary nodule diagnosis (malignant vs. benign) was developed from all possible combinations of the eleven markers. In the test set (57 tissue and 71 BALF samples), the area under curve (AUC) value achieves 0.93, and the overall sensitivity is 82% at the specificity of 91%. In an independent validation set (111 BALF samples), the AUC is 0.82 with a specificity of 82% and a sensitivity of 70%. Conclusions: This model can differentiate pulmonary adenocarcinoma and squamous carcinoma from benign diseases, especially for infection, inflammation, and tuberculosis. The model's performance is not affected by gender, age, smoking history, or the solid components of nodules. [ABSTRACT FROM AUTHOR]

Background: Standard therapy for human epidermal growth factor receptor 2 (HER2)-mutant non-small-cell lung cancer (NSCLC) is lacking. The clinical benefits with pan-HER inhibitors (afatinib, neratinib, and dacomitinib), anti-HER2 antibody drug conjugate (ADC) trastuzumab emtansine, and an emerging irreversible tyrosine kinase inhibitor (TKI) poziotinib were modest. Another new ADC trastuzumab deruxtecan showed encouraging outcomes, but only phase I study was completed. Pyrotinib, another emerging irreversible epidermal growth factor receptor (EGFR)/HER2 dual TKI, has been approved in HER2-positive breast cancer in 2018 in China. It has shown promising antitumor activity against HER2-mutant NSCLC in phase II trials, but pyrotinib-related diarrhea remains an issue. The antiangiogenic and immunomodulatory drug thalidomide is a cereblon-based molecular glue that can induce the degradation of the IKAROS family transcription factors IKZF1 and IKZF3. The use of thalidomide can also decrease gastrointestinal toxicity induced by anti-cancer therapy.Methods: This is an open-label, single-arm phase II trial. A total of 39 advanced NSCLC patients with HER2 exon 20 insertions and ≤ 2 lines of prior chemotherapy will be recruited, including treatment-naïve patients who refuse chemotherapy. Patients are allowed to have prior therapy with immune checkpoint inhibitors and/or antiangiogenic agents. Those who have prior HER2-targeting therapy or other gene alterations with available targeted drugs are excluded. Eligible patients will receive oral pyrotinib 400 mg once daily and oral thalidomide 200 mg once daily until disease progression or intolerable toxicity. The primary endpoint is objective response rate.Discussion: The addition of thalidomide to pyrotinib is expected to increase the clinical benefit in advanced NSCLC patients with HER2 exon 20 insertions, and reduce the incidence of pyrotinib-related diarrhea. We believe thalidomide is the stone that can hit two birds.Trial Registration: ClinicalTrials.gov Identifier: NCT04382300 . Registered on May 11, 2020. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Early detection of CRC can significantly reduce its mortality rate. Current method of CRC diagnosis relies on the invasive endoscopy. Non-invasive assays including fecal occult blood testing (FOBT) and fecal immunological test (FIT) are compromised by low sensitivity and specificity, especially at early stages. Thus, a non-invasive and accurate approach for CRC screening would be highly desirable. Results: A new qPCR-based assay combining the simultaneous detection of the DNA methylation status of ten candidate genes was used to examine plasma samples from 56 normal controls, 6 hyperplastic polys, 9 non-advanced adenomas (NAAs), 22 advanced adenomas (AAs) and 175 CRC patients, using 10 ng of cfDNA. We further built a logistic regression model for CRC diagnosis. We tested ten candidate methylation markers including twist1, vav3-as1, fbn1, c9orf50, sfmbt2, kcnq5, fam72c, itga4, kcnj12 and znf132. All markers showed moderate diagnostic performance with AUCs ranging from 0.726 to 0.815. Moreover, a 4-marker model, comprised of two previously reported markers (c9orf50 and twist1) and two novel ones (kcnj12 and znf132), demonstrated high performance for detecting colorectal cancer in an independent validation set (N = 69) with an overall AUC of 0.911 [95% confidence interval (CI) 0.834–0.988], sensitivity of 0.800 [95% CI 0.667–0.933] and specificity of 0.971 [95% CI 0.914–1.000]. The stage-stratified sensitivity of the model was 0.455 [95% CI 0.227–0.682], 0.667 [95% CI 0.289–1.000], 0.800 [95% CI 0.449–1.000], 0.800 [95% CI 0.449–1.000] and 0.842 [95% CI 0.678–1.000] for advanced adenoma and CRC stage I-IV, respectively. Conclusion: kcnj12 and znf132 are two novel methylation biomarkers for CRC diagnosis. The 4-marker methylation model provides a new non-invasive choice for CRC screening and interception. [ABSTRACT FROM AUTHOR]

Background: Current non-invasive tests have limited sensitivities and lack capabilities of pre-operative risk stratification for bladder cancer (BC) diagnosis. We aimed to develop and validate a urine-based DNA methylation assay as a clinically feasible test for improving BC detection and enabling pre-operative risk stratifications. Methods: A urine-based DNA methylation assay was developed and validated by retrospective single-center studies in patients of suspected BC in Cohort 1 (n = 192) and Cohort 2 (n = 98), respectively. In addition, a prospective single-center study in hematuria patient group (Cohort 3, n = 174) was used as a second validation of the model. Results: The assay with a dual-marker detection model showed 88.1% and 91.2% sensitivities, 89.7% and 85.7% specificities in validation Cohort 2 (patients of suspected BC) and Cohort 3 (patients of hematuria), respectively. Furthermore, this assay showed improved sensitivities over cytology and FISH on detecting low-grade tumor (66.7–77.8% vs. 0.0–22.2%, 0.0–22.2%), Ta tumor (83.3% vs. 22.2–41.2%, 44.4–52.9%) and non-muscle invasive BC (NMIBC) (80.0–89.7% vs. 51.5–52.0%, 59.4–72.0%) in both cohorts. The assay also had higher accuracies (88.9–95.8%) in diagnosing cases with concurrent genitourinary disorders as compared to cytology (55.6–70.8%) and FISH (72.2–77.8%). Meanwhile, the assay with a five-marker stratification model identified high-risk NMIBC and muscle invasive BC with 90.5% sensitivity and 86.8% specificity in Cohort 2. Conclusions: The urine-based DNA methylation assay represents a highly sensitive and specific approach for BC early-stage detection and risk stratification. It has a potential to be used as a routine test to improve diagnosis and prognosis of BC in clinic. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Early detection of CRC can significantly reduce its mortality rate. Current method of CRC diagnosis relies on the invasive endoscopy. Non-invasive assays including fecal occult blood testing (FOBT) and fecal immunological test (FIT) are compromised by low sensitivity and specificity, especially at early stages. Thus, a non-invasive and accurate approach for CRC screening would be highly desirable. Results: A new qPCR-based assay combining the simultaneous detection of the DNA methylation status of ten candidate genes was used to examine plasma samples from 56 normal controls, 6 hyperplastic polys, 9 non-advanced adenomas (NAAs), 22 advanced adenomas (AAs) and 175 CRC patients, using 10 ng of cfDNA. We further built a logistic regression model for CRC diagnosis. We tested ten candidate methylation markers including twist1, vav3-as1, fbn1, c9orf50, sfmbt2, kcnq5, fam72c, itga4, kcnj12 and znf132. All markers showed moderate diagnostic performance with AUCs ranging from 0.726 to 0.815. Moreover, a 4-marker model, comprised of two previously reported markers (c9orf50 and twist1) and two novel ones (kcnj12 and znf132), demonstrated high performance for detecting colorectal cancer in an independent validation set (N = 69) with an overall AUC of 0.911 [95% confidence interval (CI) 0.834–0.988], sensitivity of 0.800 [95% CI 0.667–0.933] and specificity of 0.971 [95% CI 0.914–1.000]. The stage-stratified sensitivity of the model was 0.455 [95% CI 0.227–0.682], 0.667 [95% CI 0.289–1.000], 0.800 [95% CI 0.449–1.000], 0.800 [95% CI 0.449–1.000] and 0.842 [95% CI 0.678–1.000] for advanced adenoma and CRC stage I-IV, respectively. Conclusion: kcnj12 and znf132 are two novel methylation biomarkers for CRC diagnosis. The 4-marker methylation model provides a new non-invasive choice for CRC screening and interception. [ABSTRACT FROM AUTHOR]

Background: The toxicity and side effects caused by adjuvant chemotherapy (ACT) after radical surgery for lung adenocarcinoma (LAC) lead to early termination frequently. This study was conducted to provide an objective basis for the effect of Chinese herbal medicine formulas (CHMFs) combined with chemotherapy in reducing toxicity and enhancing efficacy of ACT. Method: From February 17th, 2012 to March 20th, 2015, 233 patients from 7 hospitals diagnosed with LAC in IB~IIIA stage were randomly assigned into ACT + CHMF group (116 patients) and ACT + placebo group (117 patients). CHMF was taken orally until the end of chemotherapy. Chemotherapy-related toxic, side effects were investigated as the primary outcome. Disease-free survival (DFS) and overall survival (OS) were used as the secondary outcome. Results: At one week following chemotherapy, the incidence of dry mouth, diarrhea and thrombocytopenia significantly decreased in CHMF group (P = 0.017, P = 0.033, P = 0.019, respectively). At two weeks following chemotherapy, fatigue and diarrhea were more obvious in the placebo group (P = 0.028, P = 0.025, respectively). In addition, patients in the CHMF group showed an increase in median DFS from 37.1 to 51.5 months compared with placebo group although there was no statistical significance (P = 0.16). In the stage IB subgroup, the CHMF group had a significantly better DFS (HR (95% CI) = 0.53 (0.28–0.99), P = 0.046). There was no significant difference in OS between the groups (P = 0.72). Conclusion: For patients with LAC, ACT combined with CHMF after radical surgery can prolong the DFS time especially in the early stage, and reduces the chemotherapy-related toxic and side effects. Trial Registration: NCT 01441752. Registered 14 July, 2011. [ABSTRACT FROM AUTHOR]

Zhiwei Chen, Shun Lu, Qingquan Luo, Jia Huang and Ziming Li have agreed to this retraction but not to the wording of this retraction notice. The online version of the original article can be found at https://doi.org/10.1186/s13046-018-0984-z. [Extracted from the article]

Osteosarcoma (OS) is the most common primary bone malignancy and responsible for considerable morbidity and mortality due to its high rates of pulmonary metastasis. Although neoadjuvant chemotherapy has improved 5-year survival rates for patients with localized OS from 20% to over 65%, outcomes for those with metastasis remain dismal. In addition, therapeutic regimens have not significantly improved patient outcomes over the past four decades, and metastases remains a primary cause of death and obstacle in curative therapy. These limitations in care have given rise to numerous works focused on mechanisms and novel targets of OS pathogenesis, including tumor niche factors. OS is notable for its hallmark production of rich extracellular matrix (ECM) of osteoid that goes beyond simple physiological growth support. The aberrant signaling and structural components of the ECM are rich promoters of OS development, and very recent works have shown the specific pathogenic phenotypes induced by these macromolecules. Here we summarize the current developments outlining how the ECM contributes to OS progression and metastasis with supporting mechanisms. We also illustrate the potential of tumorigenic ECM elements as prognostic biomarkers and therapeutic targets in the evolving clinical management of OS. [ABSTRACT FROM AUTHOR]

Purpose: To validate and propose revision of the 8th edition American Joint Committee on Cancer (AJCC) clinical staging system for esophageal squamous cell cancer (ESCC) patients treated with definitive intensity-modulated radiation therapy combined with concurrent chemotherapy (Chemo-IMRT) based on computed tomography (CT) imaging.Methods: The clinical data of patients with ESCC treated with Chemo-IMRT were collected and retrospectively reviewed. All CT images were independently reevaluated and restaged according to the 8th edition AJCC staging system. The overall survival (OS) rates were analyzed statistically. ROC curves of the various parameters of the primary tumor and metastatic lymph nodes were generated in order to identify the cutoff values correlated to patient survival using the area under curve.Results: The gross tumor volume of the primary tumor (GTV-prT) and the clinical N stage (cN) were independent factors that influenced OS. The 5-year OS rate of patients with GTV-prT ≤28 cm3, GTV-prT > 28 and ≤ 56 cm3, and GTV-prT > 56 cm3 were 54.6, 31.1 and 18.6%, respectively. The 5-year OS rate of patients with cN0, cN1 SLNM (-), cN2 SLNM (-), cN3 SLNM (-) and SLNM (+) were 62.8 (P < 0.001), 34.0 (P = 0.16), 20.0 (P = 0.785), 0 (P < 0.001) and 26.9%, respectively. After restaging the SLNM as regional MLNs, the 5-year OS rates of the patients with cN0, 1, 2 and 3 were 62.8, 36.3, 23.7 and 7.8%, respectively. Various GTV-prT were combined with the cN to establish a new clinical TNM staging system: I, GTV-prT1 and cN0; II, GTV-prT2 or 3 and cN0, GTV-prT1 and cN1; III, GTV-prT1 and cN2, GTV-prT2 and cN1,2; Iva, GTV-prT3 and cN1,2; IVb, GTV-prTany and cN3; IVc, TanyNanyM1. Subsequently, the OS differed significantly between the adjacent GTV-prT cN categories, except those of stage I vs. II.Conclusion: The SLNM should be dealt with as a regional rather than a distant disease in patients with ESCC when treated with CRT. The proposed nonsurgical staging system based on the GTV-prT and N appears to be a simple and accurate prognosis predictor for patients with ESCC who have undergone definitive Chemo-IMRT. [ABSTRACT FROM AUTHOR]

Background: Epithelial-to-mesenchymal transition (EMT) contributes to the invasion and metastasis of epithelial tumors. Sirtuin 6 (SIRT6), an NAD-dependent deacetylase, is known to promote metastasis of non-small cell lung cancer (NSCLC). Methods: In this work, we determined the role of SIRT6 in the EMT of NSCLC cells and identified the key EMT-related genes involved in the oncogenic activity of SIRT6. Results: We report that depletion of SIRT6 inhibits transforming growth factor-β1 (TGF-β1)-induced EMT in A549 and H1299 NSCLC cells, which is rescued by ectopic expression of SIRT6. Knockdown of SIRT6 leads to a reduction in Snail protein without affecting the mRNA level. Immunoprecipitation experiments demonstrate a physical association between SIRT6 and Snail. SIRT6 deacetylates Snail and prevents its proteasomal degradation. Silencing of Snail blunts SIRT6-induced NSCLC cell migration and invasion, while overexpression of Snail restores the invasion and EMT in SIRT6-depleted NSCLC cells. SIRT6 depletion leads to an upregulation of kruppel-like factor 4 (KLF4) and reduced Snail binding to the promoter of Klf4 in NSCLC cells. Knockdown of KLF4 rescues the invasive capacity in SIRT6-depleted NSCLC cells. Conversely, co-expression of KLF4 impairs SIRT6-induced aggressive behavior. In vivo data further demonstrate that SIRT6-induced NSCLC metastasis is antagonized by overexpression of KLF4. Conclusions: These findings provide mechanistic insights into the pro-metastatic activity of SIRT6 and highlight the role of the SIRT6/Snail/KLF4 axis in regulating EMT and invasion of NSCLC cells. [ABSTRACT FROM AUTHOR]