Hallmarks of cancer resistance.

This review explores the hallmarks of cancer resistance, including drug efflux mediated by ATP-binding cassette (ABC) transporters, metabolic reprogramming characterized by the Warburg effect, and the dynamic interplay between cancer cells and mitochondria. The role of cancer stem cells (CSCs) in treatment resistance and the regulatory influence of non-coding RNAs, such as long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), are studied. The chapter emphasizes future directions, encompassing advancements in immunotherapy, strategies to counter adaptive resistance, integration of artificial intelligence for predictive modeling, and the identification of biomarkers for personalized treatment. The comprehensive exploration of these hallmarks provides a foundation for innovative therapeutic approaches, aiming to navigate the complex landscape of cancer resistance and enhance patient outcomes.

Transcriptome analysis revealed the new mechanism of the intra-myocardial injectable alginate-hydrogel in the treatment of ventricular function degradation.

Background: Myocardial infarction (MI) is one of the most lethal cardiovascular diseases. The loss of cardiomyocytes and the degradation of the extracellular matrix leads to high ventricular wall stress, which further drives the pathological thinning of the ventricular wall during MI. Injecting biomaterials to thicken the infarct ventricular wall provides mechanical support, thereby inhibiting the continued expansion of the heart. As an injectable biomaterial, alginate hydrogel has achieved exciting results in clinical trials, but further research needs to be conducted to determine whether it can improve cardiac function in addition to providing mechanical support. This study sought to explore these mechanisms in an animal model of MI. Methods: A MI model was established in male C57BL/6J mice by ligation of the proximal left anterior descending (LAD) coronary artery. Intramyocardial injections (hydrogel or saline group) were performed in the proximal wall regions bordering the infarct area (with one 20-µL injection). Four weeks after MI, RNA sequencing revealed that 342 messenger RNAs (mRNAs) from the infarcted hearts were differentially expressed between the saline group and hydrogel group. We subsequently conducted a Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis to analyze the RNA sequencing data. In addition, we employed both western blotting and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) techniques to verify a number of genes that were differentially expressed and could potentially affect cardiac function after MI. Subsequently, we confirmed these findings through in vitro experiments. Results: We found that compared with hydrogel treatment group, 250 mRNAs were upregulated and 92 mRNAs were downregulated in saline group (P<0.05). And by exploring the GO and KEGG signaling pathways as well as the protein-protein interaction (PPI) network, we found that administration of alginate hydrogel modulated cardiomyocyte inflammation-associated proteins as well as chemokine-related proteins during the inflammatory response phase after MI. In addition, our analysis at both the protein and RNA level revealed that B2M was effective in improving cardiac function after MI in the hydrogel treatment group, which was consistent in the myocardium oxygen and glucose deprivation (OGD) injury model. Conclusions: We explored the transcriptome changes of infarcted hearts after alginate-hydrogel injection during the inflammatory response period. Our findings suggest that the injectable hydrogel directly alters the inflammatory response and the chemokine-mediated signaling pathway of cardiomyocytes, ultimately improving cardiac function.

Chromosome-level genome assembly of Hippophae tibetana provides insights into high-altitude adaptation and flavonoid biosynthesis.

BACKGROUND: As an endemic shrub of the Qinghai-Tibetan Plateau (QTP), the distribution of Hippophae tibetana Schlecht. ranges between 2800 and 5200 m above sea level. As the most basal branch of the Hippophae genus, H. tibetana has an extensive evolutionary history. The H. tibetana is a valuable tree for studying the ecological evolution of species under extreme conditions. RESULTS: Here, we generated a high-quality chromosome-level genome of H. tibetana. The total size of the assembly genome is 917 Mb. The phylogenomic analysis of 1064 single-copy genes showed a divergence between 3.4 and 12.8 Mya for H. tibetana. Multiple gene families associated with DNA repair and disease resistance were significantly expanded in H. tibetana. We also identified many genes related to DNA repair with signs of positive selection. These results showed expansion and positive selection likely play important roles in H. tibetana's adaptation to comprehensive extreme environments in the QTP. A comprehensive genomic and transcriptomic analysis identified 49 genes involved in the flavonoid biosynthesis pathway in H. tibetana. We generated transgenic sea buckthorn hairy root producing high levels of flavonoid. CONCLUSIONS: Taken together, this H. tibetana high-quality genome provides insights into the plant adaptation mechanisms of plant under extreme environments and lay foundation for the functional genomic research and molecular breeding of H. tibetana.

High Frankia abundance and low diversity of microbial community are associated with nodulation specificity and stability of sea buckthorn root nodule.

Introduction: Actinorhizal symbioses are gaining attention due to the importance of symbiotic nitrogen fixation in sustainable agriculture. Sea buckthorn (Hippophae L.) is an important actinorhizal plant, yet research on the microbial community and nitrogen cycling in its nodules is limited. In addition, the influence of environmental differences on the microbial community of sea buckthorn nodules and whether there is a single nitrogen-fixing actinomycete species in the nodules are still unknown. Methods: We investigated the diversity, community composition, network associations and nitrogen cycling pathways of the microbial communities in the root nodule (RN), nodule surface soil (NS), and bulk soil (BS) of Mongolian sea buckthorn distributed under three distinct ecological conditions in northern China using 16S rRNA gene and metagenomic sequencing. Combined with the data of environmental factors, the effects of environmental differences on different sample types were analyzed. Results: The results showed that plants exerted a clear selective filtering effect on microbiota, resulting in a significant reduction in microbial community diversity and network complexity from BS to NS to RN. Proteobacteria was the most abundant phylum in the microbiomes of BS and NS. While RN was primarily dominated by Actinobacteria, with Frankia sp. EAN1pec serving as the most dominant species. Correlation analysis indicated that the host determined the microbial community composition in RN, independent of the ecological and geographical environmental changes of the sea buckthorn plantations. Nitrogen cycle pathway analyses showed that RN microbial community primarily functions in nitrogen fixation, and Frankia sp. EAN1pec was a major contributor to nitrogen fixation genes in RN. Discussion: This study provides valuable insights into the effects of eco-geographical environment on the microbial communities of sea buckthorn RN. These findings further prove that the nodulation specificity and stability of sea buckthorn root and Frankia sp. EAN1pec may be the result of their long-term co-evolution.

A chromosome-scale genome of Rhus chinensis Mill. provides new insights into plant-insect interaction and gallotannins biosynthesis.

Rhus chinensis Mill., an economically valuable Anacardiaceae species, is parasitized by the galling aphid Schlechtendalia chinensis, resulting in the formation of the Chinese gallnut (CG). Here, we report a chromosomal-level genome assembly of R. chinensis, with a total size of 389.40 Mb and scaffold N50 of 23.02 Mb. Comparative genomic and transcriptome analysis revealed that the enhanced structure of CG and nutritional metabolism contribute to improving the adaptability of R. chinensis to S. chinensis by supporting CG and galling aphid growth. CG was observed to be abundant in hydrolysable tannins (HT), particularly gallotannin and its isomers. Tandem repeat clusters of dehydroquinate dehydratase/shikimate dehydrogenase (DQD/SDH) and serine carboxypeptidase-like (SCPL) and their homologs involved in HT production were determined as specific to HT-rich species. The functional differentiation of DQD/SDH tandem duplicate genes and the significant contraction in the phenylalanine ammonia-lyase (PAL) gene family contributed to the accumulation of gallic acid and HT while minimizing the production of shikimic acid, flavonoids, and condensed tannins in CG. Furthermore, we identified one UDP glucosyltransferase (UGT84A), three carboxylesterase (CXE), and six SCPL genes from conserved tandem repeat clusters that are involved in gallotannin biosynthesis and hydrolysis in CG. We then constructed a regulatory network of these genes based on co-expression and transcription factor motif analysis. Our findings provide a genomic resource for the exploration of the underlying mechanisms of plant-galling insect interaction and highlight the importance of the functional divergence of tandem duplicate genes in the accumulation of secondary metabolites.

Predictive, preventive, and personalized medicine in breast cancer: targeting the PI3K pathway.

Breast cancer (BC) is a multifaceted disease characterized by distinct molecular subtypes and varying responses to treatment. In BC, the phosphatidylinositol 3-kinase (PI3K) pathway has emerged as a crucial contributor to the development, advancement, and resistance to treatment. This review article explores the implications of the PI3K pathway in predictive, preventive, and personalized medicine for BC. It emphasizes the identification of predictive biomarkers, such as PIK3CA mutations, and the utility of molecular profiling in guiding treatment decisions. The review also discusses the potential of targeting the PI3K pathway for preventive strategies and the customization of therapy based on tumor stage, molecular subtypes, and genetic alterations. Overcoming resistance to PI3K inhibitors and exploring combination therapies are addressed as important considerations. While this field holds promise in improving patient outcomes, further research and clinical trials are needed to validate these approaches and translate them into clinical practice.

Histone H3K9 acetylation modulates gene expression of key enzymes in the flavonoid and abscisic acid pathways and enhances drought resistance of sea buckthorn.

The effect of histone H3K9 acetylation modification on gene expression and drought resistance in drought-resistant tree species is not clear. Using the chromatin immunoprecipitation (ChIP) method, this study obtained nine H3K9 acetylated protein-interacting DNAs from sea buckthorn seedlings, and the ChIP sequencing result predicted about 56,591, 2217 and 5119 enriched region peaks in the control, drought and rehydration comparative groups, respectively. Gene functional analysis of differential peaks from three comparison groups revealed that 105 pathways were involved in the drought resistance process, and 474 genes were enriched in the plant hormone signaling transduction pathways. Combined ChIP-seq and transcriptome analysis revealed that six genes related to abscisic acid synthesis and signaling pathways, 17 genes involved in flavonoid biosynthesis, and 15 genes involved in carotenoid biosynthesis were positively regulated by H3K9 acetylation modification under drought stress. Under drought stress conditions, the content of abscisic acid and the expression of related genes were significantly up-regulated, while the content of flavonoids and the expression of key enzymes involved in their synthesis were largely down-regulated. Meanwhile, after exposure to histone deacetylase inhibitors (trichostatin A), the change of abscisic acid and flavonoids content and their related gene expression were slowed down under drought stress. This study will provide an important theoretical basis for understanding the regulatory mechanisms of histone acetylation modifications in sea buckthorn drought resistance.

The polymorphism rs4705342 in the promoter of miR-143/145 is related to the risk of epithelial ovarian cancer and patient prognosis.

Objective: To evaluate the effects of two genetic variants in the promoter of the miR-143/145 cluster on the risk of epithelial ovarian cancer (EOC) and the prognosis of EOC patients. Study design: Genotypes were determined by the polymerase chain reaction and ligase detection reaction method in 563 EOC patients and 576 healthy women. The expression of miR-143 and miR-145 were detected by quantitative real-time polymerase chain reaction (qRT-PCR) in fifty-two EOC tissues. Results: The rs4705342 CC genotype frequencies in EOC patients were higher than those in the controls (P = 0.014). Furthermore, the CC genotype of rs4705342 was associated with an advanced FIGO stage of EOC patients (P = 0.046). Patients with the rs4705342 CC genotype had shorter progression-free survival (PFS) and overall survival (OS) times than those carrying the TT genotype in multivariable analysis adjusting for clinical variables (HR = 1.30, 95% CI = 1.04-1.62, P = 0.020; HR = 1.33, 95% CI = 1.05-1.70, P = 0.020). In addition, the miR-145 levels were lower in EOC tissues with the rs4705342 CC genotype than in those with the TT genotype (P = 0.005). Conclusion: The CC genotype of rs4705342 was related to an increased risk of EOC and poor prognosis of EOC patients, and rs4705342 may serve as a molecular marker for predicting the development of EOC and the clinical outcome of EOC patients.

Tyrosine sulphation of CXCR4 induces the migration of fibroblast in OSF.

Oral submucous fibrosis (OSF) caused by areca nut chewing is a prevalent fibrotic disease in Asia-Pacific countries. Arecoline-induced migration of fibroblasts (FBs) plays a vital role in the development of OSF. However, the specific molecular mechanisms involved remain unclear. Many studies have shown that tyrosine sulphation of chemokines can influence cell migration. Herein, we demonstrated that arecoline stimulates tyrosine sulphation of the chemokine receptor 4 (CXCR4) through the tyrosylprotein sulphotransferase-1 (TPST-1) to enhance the migration ability of FBs. Moreover, by RNA-Seq analysis, we found that the most significantly altered pathway was the EGFR pathway after the arecoline stimulation for FBs. After the knockdown of arecoline-induced EGFR expression, the tyrosine sulphation of CXCR4 was significantly decreased by the inhibition of TPST-1 induction. Finally, in human OSF specimens, TPST-1 expression was directly correlated with the expression of CXCR4. These data indicate that the arecoline-induced tyrosine sulphation of CXCR4, which is regulated by TPST-1, might be a potential mechanism that contributes to FB migration in OSF.

Whole-Exome Sequencing Among Chinese Patients With Hereditary Diffuse Gastric Cancer.

Importance: The E-cadherin gene, CDH1, and the α-E-catenin gene, CTNNA1, were previously identified as hereditary diffuse gastric cancer (HDGC) susceptibility genes, explaining 25% to 50% of HDGC cases. The genetic basis underlying disease susceptibility in the remaining 50% to 75% of patients with HDGC is still unknown. Objective: To assess the incidence rate of CDH1 germline alterations in HDGC, identify new susceptibility genes that can be used for screening of HDGC, and provide a genetic landscape for HDGC. Design, Setting, and Participants: This cohort study conducted retrospective whole-exome and targeted sequencing of 284 leukocyte samples and 186 paired tumor samples from Chinese patients with HDGC over a long follow-up period (median, 21.7 [range, 0.6-185.9] months). Among 10 431 patients diagnosed with gastric cancer between January 1, 2002, and August 31, 2018, 284 patients who met the criteria for HDGC were included. Data were analyzed from August 1 to 30, 2020. Main Outcomes and Measures: Incidence rate of CDH1 germline alterations, identification of new HDGC susceptibility genes, and genetic landscape of HDGC. Results: Among 284 Chinese patients, 161 (56.7%) were female, and the median age was 35 (range, 20-75) years. The frequency of CDH1 germline alterations was 2.8%, whereas the frequency of CDH1 somatic alterations was 25.3%. The genes with the highest incidence (>10%) of private germline alterations (including insertions and deletions) in the HDGC cohort were MUC4, ABCA13, ZNF469, FCGBP, IGFN1, RNF213, and SSPO, whereas previously reported germline alterations of CTNNA1, BRCA2, STK11, PRSS1, ATM, MSR1, PALB2, BRCA1, and RAD51C were observed at low frequencies (median, 4 [range, 1-12] cases). Furthermore, enrichment of the somatic variant signature of exposure to aflatoxin suggested potential interaction between genetics and environment in HDGC. Double-hit events in genes such as CACNA1D were observed, which suggested that these events might serve as important mechanisms for HDGC tumorigenesis. In addition, germline variants of FSIP2, HSPG2, and NCKAP5 and somatic alterations of FGFR3, ASPSCR1, CIC, DGCR8, and LZTR1 were associated with poor overall survival among patients with HDGC. Conclusions and Relevance: This study provided a genetic landscape for HDGC. The study's findings challenged the previously reported high germline alteration rate of CDH1 in HDGC and identified new potential susceptibility genes. Analyses of variant signatures and double-hit events revealed potentially important mechanisms for HDGC tumorigenesis. Findings from the present study may provide helpful information for further investigations of HDGC.

Lateral approach is a more aesthetical option for radical resection of BSCC: assessment of its surgical, oncological, functional, and aesthetic outcomes.

BACKGROUND: The purpose of this study was to introduce a modified lateral approach for combined radical resection of buccal squamous cell carcinoma (BSCC) and evaluate its surgical, oncological, functional, and aesthetic outcomes in comparison with the conventional lower-lip splitting approach. METHODS: This single-center study retrospectively reviewed 80 patients with BSCC, of which 37 underwent the lateral approach and 43 underwent the conventional approach. Surgical, functional, oncological, and aesthetic evaluations, as well as follow-ups, were recorded and compared. RESULTS: Compared to the conventional approach group, the lateral approach group had a longer surgical time (P = 0.000), but there was no significant difference in other surgical and oncological parameters. Moreover, the scar in the head and neck had a significantly discreet appearance in the lateral approach group, whose satisfaction was better than those in the conventional approach group (P = 0.000). Other oral function parameters, postoperative mouth-opening, and 3-year survival rate were not significantly different between the two groups. CONCLUSION: The lateral approach could provide superior aesthetic results while maintaining equal surgical, functional, and oncological outcomes compared to the conventional approach for radical resection of BSCC.

SWI/SNF complex gene variations are associated with a higher tumor mutational burden and a better response to immune checkpoint inhibitor treatment: a pan-cancer analysis of next-generation sequencing data corresponding to 4591 cases.

BACKGROUND: Genes related to the SWItch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex are frequently mutated across cancers. SWI/SNF-mutant tumors are vulnerable to synthetic lethal inhibitors. However, the landscape of SWI/SNF mutations and their associations with tumor mutational burden (TMB), microsatellite instability (MSI) status, and response to immune checkpoint inhibitors (ICIs) have not been elucidated in large real-world Chinese patient cohorts. METHODS: The mutational rates and variation types of six SWI/SNF complex genes (ARID1A, ARID1B, ARID2, SMARCA4, SMARCB1, and PBRM1) were analyzed retrospectively by integrating next-generation sequencing data of 4591 cases covering 18 cancer types. Thereafter, characteristics of SWI/SNF mutations were depicted and the TMB and MSI status and therapeutic effects of ICIs in the SWI/SNF-mutant and SWI/SNF-non-mutant groups were compared. RESULTS: SWI/SNF mutations were observed in 21.8% of tumors. Endometrial (54.1%), gallbladder and biliary tract (43.4%), and gastric (33.9%) cancers exhibited remarkably higher SWI/SNF mutational rates than other malignancies. Further, ARID1A was the most frequently mutated SWI/SNF gene, and ARID1A D1850fs was identified as relatively crucial. The TMB value, TMB-high (TMB-H), and MSI-high (MSI-H) proportions corresponding to SWI/SNF-mutant cancers were significantly higher than those corresponding to SWI/SNF-non-mutant cancers (25.8 vs. 5.6 mutations/Mb, 44.3% vs. 10.3%, and 16.0% vs. 0.9%, respectively; all p < 0.0001). Furthermore, these indices were even higher for tumors with co-mutations of SWI/SNF genes and MLL2/3. Regarding immunotherapeutic effects, patients with SWI/SNF variations showed significantly longer progression-free survival (PFS) rates than their SWI/SNF-non-mutant counterparts (hazard ratio [HR], 0.56 [95% confidence interval {CI} 0.44-0.72]; p < 0.0001), and PBRM1 mutations were associated with relatively better ICI treatment outcomes than the other SWI/SNF gene mutations (HR, 0.21 [95% CI 0.12-0.37]; p = 0.0007). Additionally, patients in the SWI/SNF-mutant + TMB-H (HR, 0.48 [95% CI 0.37-0.54]; p < 0.0001) cohorts had longer PFS rates than those in the SWI/SNF-non-mutant + TMB-low cohort. CONCLUSIONS: SWI/SNF complex genes are frequently mutated and are closely associated with TMB-H status, MSI-H status, and superior ICI treatment response in several cancers, such as colorectal cancer, gastric cancer, and non-small cell lung cancer. These findings emphasize the necessity and importance of molecular-level detection and interpretation of SWI/SNF complex mutations.

Circulating Epstein-Barr virus DNA associated with hepatic impairment and its diagnostic and prognostic role in patients with gastric cancer.

Epstein-Barr virus (EBV) infection may affect all tissues and organs of the body. Little is known about the impact of this entity on its systematic incorporation in patients with gastric cancer (GC). This study enrolled a total of 113 GC patients with EBV infection (EBVaGC) and 167 GC patients without EBV infection (EBVnGC). It was found that the CRP levels (indicative of inflammatory status) were significantly increased in EBVaGC compared with those in EBVnGC (12.11 mg/L vs. 5.72 mg/L, P = 0.008), but WBC and neutrophils counts were similar in both groups (P > 0.05). Consistent elevations in the levels of liver enzymes, ALP and GGT, with incompatible alterations in ALT or AST were observed in EBVaGC. Slightly prolonged coagulation indices, PT and INR, and decreased albumin consistently suggested impaired synthesis capability of the liver in EBVaGC (all P < 0.05). The level of circulating EBV DNA was positively correlated with the level of GGT, tumor marker CA72-4 and the lymphocyte infiltration in tumor tissues (all P < 0.05). Of note, the EBV associated high-lymphocyte infiltrated tissues presented rich CD8 + T cells. Circulating EBV DNA further showed a predictive role in distinguishing EBVaGC from EBVnGC (AUC 0.79, 95% CI 0.73 to 0.85, P < 0.001), and was associated closely with better overall survival (HR 0.45, 95% CI 0.21 to 0.96, P = 0.039). EBV infection in patients with gastric cancer may be linked to hepatic impairment and immune response. Circulating cell-free EBV DNA is not only a biomarker for the screening of an EBV-related GC subtype but is also an independently prognosis factor for the long-term survival benefit in GC patients.

Comparison of response evaluation criteria in solid tumors and tumor regression grade in evaluating the effect of preoperative systemic therapy of gastric cancer.

BACKGROUND: Both Response Evaluation Criteria in Solid Tumors (RECIST) and tumor regression grade (TRG) play key roles in evaluating tumor response. We analyzed the consistency of TRG and RECIST 1.1 for gastric cancer (GC) patients and compared their prognostic values. METHODS: Patients with GC who received preoperative chemotherapy or chemoimmunotherapy and had records of TRG from December 2013 to October 2021 were enrolled retrospectively. TRG 0-1 and 2-3 are considered as corresponding to complete response (CR)/partial response (PR) and stable disease (SD)/progress disease (PD) in RECIST 1.1, respectively. The primary endpoints were disease-free survival (DFS) and overall survival (OS). The consistency of RECIST and TRG was examined by kappa statistics. Survival analysis was performed using the Kaplan Meier method. RESULT: One hundred fifty seven GC patients were enrolled, including 125 with preoperative chemotherapy and 32 with chemoimmunotherapy. Among them, 56 patients had measurable lesions. Only 19.6% (11/56) of the patients had consistent results between RECIST 1.1 and TRG. TRG was correlated with both OS and DFS (P = 0.02 and 0.03, respectively) while response according to RECIST1.1 was not (P = 0.86 and 0.23, respectively). The median DFS had not reached in the TRG 0-1 group and was 16.13 months in TRG 2-3 group. TRG 2-3 was associated with young age and peritoneal or liver metastasis. Besides, preoperative chemoimmunotherapy had a significantly higher pCR rate than chemotherapy alone (34.4% vs 8.0%, P < 0.001). CONCLUSION: TRG was in poor agreement with RECIST 1.1. TRG was better than RECIST 1.1 in predicting DFS and OS for GC patients who received preoperative therapy.

Gene Polymorphisms of m6A Erasers FTO and ALKBH1 Associated with Susceptibility to Gastric Cancer.

Purpose: Fat mass and obesity-associated protein (FTO) and AlkB homolog 1 (ALKBH1) are m6A demethylases that have been demonstrated to be associated with the overall survival of patients with gastric cancer (GC). This study investigates the influence of genetic variants of FTO and ALKBH1 on susceptibility to GC. Patients and Methods: Potentially functional single nucleotide polymorphisms (SNPs) of FTO and ALKBH1 were genotyped in 419 patients with GC and 569 healthy controls by Kompetitive allele-specific PCR. Results: The AG and AG/AA variants of FTO rs2287142 were significantly associated with a decreased GC risk (for AG/AA vs GG: adjusted OR = 0.73, p = 0.020). The GA and GA/GG variants of ALKBH1 rs1076496 were closely correlated with an increased risk of GC in people aged ≥ 55 years (for GA/GG vs AA: adjusted OR = 1.51, p = 0.041) but showed a decreasing tendency of risk of GC in people aged <55 years (adjusted OR = 0.85, p = 0.444). FTO rs2287142 and ALKBH1 rs1076496 conformed to the principle of a dominant model. FTO haplotype rs1421091-rs1421092-rs2287142-rs9939609 CTAT was closely associated with a lower risk of total GC (adjusted OR = 0.62, p = 0.023), while CTGA was linked with an increased risk of intestinal GC (adjusted OR = 2.51, p = 0.005). ALKBH1 rs1048147-rs1076496-rs11159286 CAC haplotype was significantly associated with a decreased risk of GC in people aged ≥ 55 years (adjusted OR = 0.41, p = 0.008). The FTO rs2287142-rs9939609 AG/AA-TT combination was associated with a decreased risk of GC only in the presence of rs1421091 TC/TT (adjusted OR = 0.70, p = 0.047), demonstrating that these FTO SNPs might have a cooperative effect on susceptibility to GC. Conclusion: FTO and ALKBH1 SNPs may have predictive value in evaluating susceptibility to GC with differing age or Lauren classification.

A diagnostic and predictive lncRNA lnc-MPEG1-1 promotes the proliferation and metastasis of papillary thyroid cancer cells by occupying miR-766-5p.

Long non-coding RNAs (lncRNAs) act as important biological regulators in human cancers. The purpose of this study was to identify promising biomarkers for improved diagnosis and prognosis of papillary thyroid cancer (PTC). We analyzed the lncRNA expression profile of PTC patients and identified five upregulated and three downregulated lncRNAs as diagnostic biomarkers for PTC in our cohorts, which were confirmed using The Cancer Genome Atlas (TCGA) data. Several lncRNAs have been linked with lymph node (LN) metastasis in patients with PTC. A nomogram combining two lncRNAs, lnc-MPEG1-1:1 and lnc-ABCA12-5:2, with age, T stage, histological type, and predicted LN metastasis was developed. The area under the curve of the developed nomogram was 0.77 (0.73-0.81) in the TCGA training cohort and 0.88 (0.79-0.96) in our validation cohort. In particular, in vivo and in vitro experiments showed that overexpression of lnc-MPEG1-1:1 in PTC cell lines promoted the proliferation and migration of PTC. lnc-MPEG1-1:1 is overexpressed in the cytoplasm of PTC cells and functionally promotes cellular proliferation and migration and functions as a competitive endogenous RNA (ceRNA) by competitively occupying the shared binding sequences of miR-766-5p. lnc-MPEG1-1:1 knockdown suppressed epithelial-mesenchymal transition by miR-766-5p in PTC cells. Collectively, these results revealed a lnc-MPEG1-1:1/miR-766-5p pathway for thyroid cancer progression and suggest that a nomogram effectively predicted the LN metastasis in PTC.

Genome sequence and population genomics provide insights into chromosomal evolution and phytochemical innovation of Hippophae rhamnoides.

Plants of the Elaeagnaceae family are widely used to treat various health disorders owing to their natural phytochemicals. Seabuckthorn (Hippophae rhamnoides L.) is an economically and ecologically important species within the family with richness of biologically and pharmacologically active substances. Here, we present a chromosome-level genome assembly of seabuckthorn (http://hipp.shengxin.ren/), the first genome sequence of Elaeagnaceae, which has a total length of 849.04 Mb with scaffold N50 of 69.52 Mb and 30 864 annotated genes. Two sequential tetraploidizations with one occurring ~36-41 million years ago (Mya) and the last ~24-27 Mya were inferred, resulting in expansion of genes related to ascorbate and aldarate metabolism, lipid biosynthesis, and fatty acid elongation. Comparative genomic analysis reconstructed the evolutionary trajectories of the seabuckthorn genome with the predicted ancestral genome of 14 proto-chromosomes. Comparative transcriptomic and metabonomic analyses identified some key genes contributing to high content of polyunsaturated fatty acids and ascorbic acid (AsA). Additionally, we generated and analysed 55 whole-genome sequences of diverse accessions, and identified 9.80 million genetic variants in the seabuckthorn germplasms. Intriguingly, genes in selective sweep regions identified through population genomic analysis appeared to contribute to the richness of AsA and fatty acid in seabuckthorn fruits, among which GalLDH, GMPase and ACC, TER were the potentially major-effect causative genes controlling AsA and fatty acid content of the fruit, respectively. Our research offers novel insights into the molecular basis underlying phytochemical innovation of seabuckthorn, and provides valuable resources for exploring the evolution of the Elaeagnaceae family and molecular breeding.

Transcriptome and DNA methylome provide insights into the molecular regulation of drought stress in sea buckthorn.

Sea buckthorn is a typical drought-resistant tree species. However, there is a general lack of understanding of the pattern of DNA methylation linked with sea buckthorn responses to drought, and its relationship with drought tolerance mechanisms. In this study, we performed whole-transcriptome RNA sequencing and methylome sequencing in response to drought stress to explore differentially expressed mRNAs, miRNAs, lncRNAs and circRNAs in sea buckthorn leaves. Based on predicted DE pairs, we constructed a competitive endogenous RNA network, which revealed potential transcriptional regulatory roles in response to drought stress. The results of methylome sequencing revealed that the DNA methylation level was increased in sea buckthorn leaves under drought stress. We identified 13,405 differentially methylated regions between CK and TR. We found one DMR-associated DEG (Vacuolar-sorting receptor 6) involved in the ABA accumulation pathway. In addition, two DNA methyltransferases (HrMET1 and HrDRM1) were closely associated with drought-induced hypermethylation in sea buckthorn. Together, we firstly conducted a comprehensive transcriptomic and epigenetic analysis of sea buckthorn under drought stress, providing a resource for further study of the potential functions of genes, miRNAs, lncRNAs, circRNAs and DNA methyltransferases.

Genome-wide DNA N6-adenine methylation in sea buckthorn (Hippophae rhamnoides L.) fruit development.

As a new epigenetic mark, DNA N6-adenine (6mA) methylation plays an important role in various biological processes and has been reported in many prokaryotic organisms in recent years. However, the distribution patterns and functions of DNA 6mA modification have been poorly studied in non-model crops. In this study, we observed that the methylation ratio of 6mA was about 0.016% in the sea buckthorn (Hippophae rhamnoides L.) genome using mass spectrometry. We first constructed a comprehensive 6mA landscape in sea buckthorn genome using nanopore sequencing at single-base resolution. Distribution analysis suggested that 6mA methylated sites were widely distributed in the sea buckthorn chromosomes, which were similar to those in Arabidopsis and rice. Furthermore, reduced 6mA DNA methylation is associated with different expression of genes related to the fruit-ripening process in sea buckthorn. Our results revealed that 6mA DNA modification could be considered an important epigenomic mark and contributes to the fruit ripening process in plants.

Inherited rare and common variants in PTCH1 and PTCH2 contributing to the predisposition to reproductive cancers.

PTCH1 and PTCH2 are associated with nevoid basal cell carcinoma syndrome and basal cell carcinoma. We determined the prevalence of their common and rare variants in 877 patients with various reproductive cancers and 296 healthy subjects. Using targeted next-generation sequencing, we found significantly statistical associations of the minor alleles at seven common variants of PTCH1 and PTCH2 with a decreased risk of reproductive cancers (P = 9.69 × 10-12). Among these variants, two haplotype blocks in high linkage disequilibrium were consisted of rs2277184, rs2066829 and rs2236405 sites at PTCH1 and rs3795720, rs11573590 and rs11211040 sites at PTCH2. Single marker and haplotype-based analysis consistently revealed a decreased risk of reproductive cancers especially breast and prostate cancers in the subjects carrying the minor alleles, and on the contrary, an increased risk for major alleles. Healthy control subjects showed a higher rate of rare variants than that of cancer patients (P = 0.017). Notably, two frameshift variants (p.Ser391* and p.Cys101Alafs*48) of PTCH2 with deleterious effects were found in only four cancer patients. Higher frequencies of variants of PTCH genes might have a protective role against the development of reproductive cancers, whereas rare deleterious variants of PTCH2 might predispose a carrier to reproductive cancers.