HigA2 (Rv2021c) Is a Transcriptional Regulator with Multiple Regulatory Targets in Mycobacterium tuberculosis.

Toxin-antitoxin (TA) systems are the major mechanism for persister formation in Mycobacterium tuberculosis (Mtb). Previous studies found that HigBA2 (Rv2022c-Rv2021c), a predicted type II TA system of Mtb, could be activated for transcription in response to multiple stresses such as anti-tuberculosis drugs, nutrient starvation, endure hypoxia, acidic pH, etc. In this study, we determined the binding site of HigA2 (Rv2021c), which is located in the coding region of the upstream gene higB2 (Rv2022c), and the conserved recognition motif of HigA2 was characterized via oligonucleotide mutation. Eight binding sites of HigA2 were further found in the Mtb genome according to the conserved motif. RT-PCR showed that HigA2 can regulate the transcription level of all eight of these genes and three adjacent downstream genes. DNA pull-down experiments showed that twelve functional regulators sense external regulatory signals and may regulate the transcription of the HigBA2 system. Of these, Rv0903c, Rv0744c, Rv0474, Rv3124, Rv2603c, and Rv3583c may be involved in the regulation of external stress signals. In general, we identified the downstream target genes and possible upstream regulatory genes of HigA2, which paved the way for the illustration of the persistence establishment mechanism in Mtb.

Digital measurement of deciduous tooth dimensions in China: A cross-sectional survey.

OBJECTIVE: Crown dimensions data of deciduous teeth hold anthropological, forensic, and archaeological value. However, such information remains scarce for the Chinese population. This multi-center study aimed to collect a large sample of deciduous crown data from Chinese children using three-dimensional measurement methods and to analyze their dimensions. DESIGN: A total of 1592 children's deciduous dentition samples were included, and the sample size was distributed according to Northeast, North, East, Northwest, Southwest and South China. Digital dental models were reconstructed from plaster dental models. Independent sample t test, paired t test, principal component analysis (PCA), and factor analysis (FA) were used to analyze the tooth crown dimensions. RESULT: 18,318 deciduous teeth from 1592 children were included. Males exhibited slightly larger values than females. The range of sexual dimorphism percentages for each measurement was as follows: mesiodistal diameter (0.40-2.08), buccolingual diameter (0.13-2.24), and maxillogingival diameter (0.48-3.37). The FA results showed that the main trend of crown dimensions changes was the simultaneous increase or decrease in mesiodistal diameter, buccolingual diameter and maxillogingival diameter in three directions. CONCLUSION: This is the first large-scale survey of deciduous tooth crown dimensions in China, which supplements the data of deciduous tooth measurement and provides a reference for clinical application.

BRG1 mediates epigenetic regulation of TNFα-induced CCL2 expression in oral tongue squamous cell carcinoma cells.

Strong evidence has indicated that upregulation of chemokine (CC motif) ligand-2 (CCL2) expression and the presence of an inflammatory tumor microenvironment significantly contribute to the migratory and invasive properties of oral squamous cell carcinoma, specifically oral tongue squamous cell carcinoma (OTSCC). However, the precise epigenetic mechanism responsible for enhanced CCL2 expression in response to the inflammatory mediator tumor necrosis factor alpha (TNF-α) in OTSCC remains inadequately elucidated. We have demonstrated that the production of CCL2 can be induced by TNF-α, and this induction is mediated by the chromatin remodel protein BRG1. Through the use of a chromatin immunoprecipitation (ChIP) assay, we have found that BRG1 was involved in the recruitment of acetylated histones H3 and H4 at the CCL2 promoter, thereby activating TNF-α-induced CCL2 transcription. Furthermore, we have observed that recruitment of NF-κB p65 to the CCL2 promoter was increased following BRG1 overexpression and decreased after BRG1 knockdown in OTSCC cells. Our Re-ChIP assay has shown that BRG1 knockdown completely inhibits the recruitment of both acetylated histone H3 or H4 and NF-κB to the CCL2 promoter. In summary, the findings of our study demonstrate that BRG1 plays a significant role in mediating the production of CCL2 in OTSCC cells in response to TNF-α stimulation. This process involves the cooperative action of acetylated histone and NF-κB recruitment to the CCL2 promoter site. Our data suggest that BRG1 serves as a critical epigenetic mediator in the regulation of TNF-α-induced CCL2 transcription in OTSCC cells.

Efficient sequencing data compression and FPGA acceleration based on a two-step framework.

With the increasing throughput of modern sequencing instruments, the cost of storing and transmitting sequencing data has also increased dramatically. Although many tools have been developed to compress sequencing data, there is still a need to develop a compressor with a higher compression ratio. We present a two-step framework for compressing sequencing data in this paper. The first step is to repack original data into a binary stream, while the second step is to compress the stream with a LZMA encoder. We develop a new strategy to encode the original file into a LZMA highly compressed stream. In addition an FPGA-accelerated of LZMA was implemented to speedup the second step. As a demonstration, we present repaq as a lossless non-reference compressor of FASTQ format files. We introduced a multifile redundancy elimination method, which is very useful for compressing paired-end sequencing data. According to our test results, the compression ratio of repaq is much higher than other FASTQ compressors. For some deep sequencing data, the compression ratio of repaq can be higher than 25, almost four times of Gzip. The framework presented in this paper can also be applied to develop new tools for compressing other sequencing data. The open-source code of repaq is available at: https://github.com/OpenGene/repaq.

LERMS: A Low-Latency and Reliable Downlink Packet-Level Encoding Transmission Method in Untrusted 5GA Edge Network.

The increasing demand for end-to-end low-latency and high-reliability transmissions between edge computing nodes and user elements in 5G Advance edge networks has brought new challenges to the transmission of data. In response, this paper proposes LERMS, a packet-level encoding transmission scheme designed for untrusted 5GA edge networks that may encounter malicious transmission situations such as data tampering, discarding, and eavesdropping. LERMS achieves resiliency against such attacks by using 5GA Protocol data unit (PDU) coded Concurrent Multipath Transfer (CMT) based on Lagrangian interpolation and Raptor's two-layer coding, which provides redundancy to eliminate the impact of an attacker's malicious behavior. To mitigate the increased queuing delay resulting from encoding in data blocks, LERMS is queue-aware with variable block length. Its strategy is modeled as a Markov chain and optimized using a matrix method. Numerical results demonstrate that LERMS achieves the optimal trade-off between delay and reliability while providing resiliency against untrusted edge networks.

Transcriptomics-based investigation of manganese dioxide nanoparticle toxicity in rats' choroid plexus.

Manganese dioxide nanoparticles (MnO2-NPs) have a wide range of applications in biomedicine. Given this widespread usage, it is worth noting that MnO2-NPs are definitely toxic, especially to the brain. However, the damage caused by MnO2-NPs to the choroid plexus (CP) and to the brain after crossing CP epithelial cells has not been elucidated. Therefore, this study aims to investigate these effects and elucidate potential underlying mechanisms through transcriptomics analysis. To achieve this objective, eighteen SD rats were randomly divided into three groups: the control group (control), low-dose exposure group (low-dose) and high-dose exposure group (high-dose). Animals in the two treated groups were administered with two concentrations of MnO2-NPs (200 mg kg-1 BW and 400 mg kg-1 BW) using a noninvasive intratracheal injection method once a week for three months. Finally, the neural behavior of all the animals was tested using a hot plate tester, open-field test and Y-type electric maze. The morphological characteristics of the CP and hippocampus were observed by H&E stain, and the transcriptome of CP tissues was analysed by transcriptome sequencing. The representative differentially expressed genes were quantified by qRT-PCR. We found that treatment with MnO2-NPs could induce learning capacity and memory faculty decline and destroy the structure of hippocampal and CP cells in rats. High doses of MnO2-NPs had a more obvious destructive capacity. For transcriptomic analysis, we found that there were significant differences in the numbers and types of differential genes in CP between the low- and high-dose groups compared to the control. Through GO terms and KEGG analysis, high-dose MnO2-NPs significantly affected the expression of transporters, ion channel proteins, and ribosomal proteins. There were 17 common differentially expressed genes. Most of them were transporter and binding genes on the cell membrane, and some of them had kinase activity. Three genes, Brinp, Synpr and Crmp1, were selected for qRT-PCR to confirm their expression differences among the three groups. In conclusion, high-dose MnO2-NPs exposure induced abnormal neurobehaviour, impaired memory function, destroyed the structure of the CP and changed its transcriptome in rats. The most significant DEGs in the CP were within the transport system.

MiR-199a-5p-Regulated SMARCA4 Promotes Oral Squamous Cell Carcinoma Tumorigenesis.

SWI/SNF related, matrix associated, actin-dependent regulator of chromatin, subfamily a, member 4 (SMARCA4, also known as BRG1), an ATPase subunit of the switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex, plays an important regulatory role in many cytogenetic and cytological processes during cancer development. However, the biological function and mechanism of SMARCA4 in oral squamous cell carcinoma (OSCC) remain unclear. The present study aimed to investigate the role of SMARCA4 in OSCC and its potential mechanism. Using a tissue microarray, SMARCA4 expression was found to be highly upregulated in OSCC tissues. In addition, SMARCA4 upregulate expression led to increased migration and invasion of OSCC cells in vitro, as well as tumor growth and invasion in vivo. These events were associated with the promotion of epithelial-mesenchymal transition (EMT). Bioinformatic analysis and luciferase reporter assay confirmed that SMARCA4 is a target gene of microRNA miR-199a-5p. Further mechanistic studies showed that the miR-199a-5p regulated SMARCA4 can promote the invasion and metastasis of tumor cells through EMT. These findings indicate that the miR-199a-5p- SMARCA4 axis plays a role in tumorigenesis by promoting OSCC cell invasion and metastasis through EMT regulation. Our findings provide insights into the role of SMARCA4 in OSCC and the mechanism involved, which may have important implications for therapeutic purposes.

Serum Response Factor-Regulated IDO1/Kyn-Ahr Pathway Promotes Tumorigenesis of Oral Squamous Cell Carcinoma.

Serum response factor (SRF) regulates pro-carcinogenic genes in various cancers, but its role in oral squamous cell carcinoma (OSCC) remains unclear. SRF expression in 70 OSCC samples was detected via immunohistochemistry. Abundant SRF expressed in OSCC tissues was closely associated with tumor metastasis. SRF-overexpressing OSCC cells were constructed to evaluate how SRF affects OSCC cell tumorigenesis and epithelial-to-mesenchymal transition (EMT) in vitro and in vivo. Overexpressed SRF increased OSCC cell migration and invasion in vitro and tumor growth and invasion in vivo. This promoted EMT, characterized by decreased and increased expression of E- and N-cadherin, respectively. Furthermore, an analysis of RNA sequences of transcriptional targets of SRF showed that SRF transactivated the indoleamine 2, 3-dioxygenase 1 (IDO1)/kynurenine-aryl hydrocarbon receptor (Kyn-AhR) signaling pathway in OSCC cell lines. Direct SRF binding to the IDO1 gene promoter upregulated transcription, which was detected through chromatin immunoprecipitation and dual luciferase reporter assays. Inhibiting IDO1 or AhR impaired SRF-induced migration and invasion and prevented EMT in OSCC cells. Our results demonstrated that SRF is a critical regulator of the IDO1/Kyn-AhR signaling pathway. This in turn increases OSCC cell migration and invasion by modulating EMT, which, consequently, favors OSCC cell growth and metastasis. We revealed a novel molecular mechanism through which SRF modulates OSCC metastasis. This should provide potential targets or biomarkers for OSCC diagnosis and treatment.

FOXO1 inhibits FSL-1 regulation of integrin ß6 by blocking STAT3 binding to the integrin ß6 gene promoter.

Integrin ß6 (ITGB6), an epithelial-specific receptor, is downregulated in the gingival epithelium of periodontitis and is associated with inflammation response and periodontitis development. However, the transcriptional regulatory mechanism of ITGB6 downregulation in the human gingival epithelium remains unclear. Fibroblast-stimulating lipopeptide-1 (FSL-1), an oral biofilm component, promotes an epithelial cell-driven proinflammatory response in periodontitis partially by suppressing ITGB6 expression. The aim of the current study was to investigate the transcriptional regulatory mechanism of ITGB6 inhibition by FSL-1 in human epithelial cells (HaCaT and primary human gingival epithelial cells), and to delineate the transcriptional mechanism of ITGB6 suppression in periodontitis. We found that FSL-1 inhibited ITGB6 transcription through increasing forkhead box protein O1 (FOXO1) expression and inhibiting signal transducer and activator of transcription 3 (STAT3) activation. Furthermore, FOXO1 bound to STAT3 directly, leading to decreased STAT3 phosphorylation induced by FSL-1. Consequently, the binding of phosphorylated STAT3 to the ITGB6 promoter was decreased, and ITGB6 transcription was therefore downregulated following FSL-1 stimulation. The reciprocal action of STAT3 and FOXO1 on ITGB6 downregulation was also confirmed by the immunostaining of the inflammatory epithelium associated with periodontitis. Our findings suggest that the interaction of FOXO1-STAT3 may be a useful signal target for the treatment of periodontitis.

Comprehensive profiling of 1015 patients' exomes reveals genomic-clinical associations in colorectal cancer.

The genetic basis of colorectal cancer (CRC) and its clinical associations remain poorly understood due to limited samples or targeted genes in current studies. Here, we perform ultradeep whole-exome sequencing on 1015 patients with CRC as part of the ChangKang Project. We identify 46 high-confident significantly mutated genes, 8 of which mutate in 14.9% of patients: LYST, DAPK1, CR2, KIF16B, NPIPB15, SYTL2, ZNF91, and KIAA0586. With an unsupervised clustering algorithm, we propose a subtyping strategy that classisfies CRC patients into four genomic subtypes with distinct clinical characteristics, including hypermutated, chromosome instability with high risk, chromosome instability with low risk, and genome stability. Analysis of immunogenicity uncover the association of immunogenicity reduction with genomic subtypes and poor prognosis in CRC. Moreover, we find that mitochondrial DNA copy number is an independent factor for predicting the survival outcome of CRCs. Overall, our results provide CRC-related molecular features for clinical practice and a valuable resource for translational research.

Genomic temporal heterogeneity of circulating tumour DNA in unresectable metastatic colorectal cancer under first-line treatment.

OBJECTIVE: Circulating tumour DNA (ctDNA) sequencing is increasingly used in the clinical management of patients with colorectal cancer. However, the genomic heterogeneity in ctDNA during treatments and its impact on clinical outcomes remain largely unknown. DESIGN: We conducted a prospective cohort study (NCT04228614) of 171 patients with unresectable metastatic colorectal cancer (mCRC) who underwent first-line treatment and prospectively collected blood samples with or without tumour samples from patients at baseline and sequentially until disease progression or last follow-up. RESULTS: The RAS/BRAF alterations in paired baseline tissue and plasma samples from 63 patients displayed a favourable concordance (81.0%, 51/63). After a period of first-line treatment (median time between baseline and last liquid biopsy, 4.67 months), 42.6% (26/61) of RAS-mutant patients showed RAS clearance and 50.0% (5/10) of BRAF-mutant patients showed BRAF clearance, while 3.6% (3/84) and 0.7% (1/135) of patients showed new RAS or BRAF mutations in ctDNA. Patients with plasma RAS/BRAF clearance showed similar progression-free survival (PFS) and overall survival (OS) with patients who remained RAS/BRAF wild-type, while much better outcomes than those who remained RAS/BRAF mutant. Patients who gained new RAS/BRAF mutations showed similar prognosis as those who maintained RAS/BRAF mutations, and shorter PFS and OS than those who remained RAS/BRAF wild-type. CONCLUSION: This prospective, serial and large-scale ctDNA profiling study reveals the temporal heterogeneity of mCRC-related somatic variants, which should be given special attention in clinical practice, as evidenced by the finding that the shift in plasma RAS/BRAF mutational status can yield a drastic change in survival outcomes.

A nonlinear associations of metabolic score for insulin resistance index with incident diabetes: A retrospective Chinese cohort study.

Background: The Metabolic score of insulin resistance (METS-IR) has recently been accepted as a reliable alternative to insulin resistance (IR), which was demonstrated to be consistent with the hyperinsulinemic-euglycemic clamp. Few pieces of research have focused on the relationship between METS-IR and diabetes in Chinese. The purpose of this research was to explore the effect of METS-IR on new-onset diabetes in a large multicenter Chinese study. Methods: At the baseline of this retrospective longitudinal research, 116855 participators were included in the Chinese cohort study administered from 2010 to 2016. The subjects were stratified by quartiles of METS-IR. To assess the effect of METS-IR on incident diabetes, the Cox regression model was constructed in this study. Stratification analysis and interaction tests were applied to detect the potential effect of METS-IR and incident diabetes among multiple subgroups. To verify whether there was a dose-response relationship between METS-IR and diabetes, a smooth curve fitting was performed. In addition, to further determine the performance of METS -IR in predicting incident diabetes, the receiver operating characteristic curve (ROC) was conducted. Results: The average age of the research participators was 44.08 ± 12.93 years, and 62868 (53.8%) were men. METS-IR were significant relationship with new-onset diabetes after adjusting for possible variables (Hazard ratio [HR]: 1.077; 95% confidence interval [CI]: 1.073-1.082, P < 0.0001), the onset risk for diabetes in Quartile 4 group was 6.261-fold higher than those in Quartile 1 group. Moreover, stratified analyses and interaction tests showed that interaction was detected in the subgroup of age, body mass index, systolic blood pressure, diastolic blood pressure, and fasting plasma glucose, there was no significant interaction between males and females. Furthermore, a dose-response correlation was detected between METS-IR and incident diabetes, the nonlinear relationship was revealed and the inflection point of METS-IR was calculated to be 44.43. When METS-IR≥44.43, compared with METS-IR < 44.43, the trend was gradually saturated, with log-likelihood ratio test P < 0.001. Additionally, the area under receiver operating characteristic of the METS-IR in predicting incident diabetes was 0.729, 0.718, and 0.720 at 3, 4, and 5 years, respectively. Conclusions: METS-IR was correlated with incident diabetes significantly, and showed a nonlinear relationship. This study also found that METS-IR had good discrimination of diabetes.

Intra-Tumor Heterogeneity of Colorectal Cancer Necessitates the Multi-Regional Sequencing for Comprehensive Mutational Profiling.

BACKGROUND: The panorama and details of quantitative intratumor heterogeneity have not been fully investigated in colorectal cancer (CRC) patients with solitary lesion without distal metastasis, and its influences on sequencing interpretation and therapeutic strategies have not been explored. METHODS: Cancer tissues and matched blood from 70 sporadic CRC patients were collected and were divided into two cohorts. Four individual tissue biopsies were obtained from each of the 47 patients (multi-sample cohort). One random cancer tissue biopsy was obtained from each of the rest 23 patients (single-sample cohort). A 10 mL of blood was collected from all patients and the circulating cell-free DNA (cfDNA) was extracted. A 605-gene panel was used for targeted sequencing with tissue and paired blood. RESULTS: Mutational landscape revealed significantly higher mutational frequency in APC, CARD11 and CSMD3 in multi-sample cohort than single-sample cohort (P<0.05). The number of mutations and the ratio of trunk, shared and branch mutations showed extensive heterogeneity in multi-sample cohort, and the percentage of trunk mutations in major driver genes, including APC, TP53 and KRAS, was higher than 70%. A total of 929 mutations were detected in tissue/blood in multi-sample group, with 921(99.1%) from tissue and 472(50.8%) from blood (464 common mutations,49.9%). In contrast, 394 mutations were detected in tissue/blood in single-sample group, with 231 (58.6%) from tissue and 219 (55.6%) from blood (56 common mutations, 11.9%). The number of mutations of major driver genes detected in tissue was higher than that in blood in the multi-sample cohort, while it was similar in the single-sample group. Quantification analysis revealed differential correlation between tissue and blood VAF in trunk, shared and branch mutations. Meanwhile, VAF of trunk mutations was significantly higher than shared mutations and branch mutations. VAF exhibited significant differences among distinct stages, locations, differentiation and sex status. CONCLUSION: Characteristic extensive heterogeneity was revealed for solitary CRC without distal metastasis. Multi-regional biopsy was necessary for comprehensive mutation detection in CRC.

Genomic and transcriptional alterations in first-line chemotherapy exert a potentially unfavorable influence on subsequent immunotherapy in NSCLC.

Background: Recent studies in non-small cell lung cancer (NSCLC) patients have demonstrated that first-line immunotherapy is associated with better therapeutic response than second-line treatment. So far, the mechanisms need to be explored. It prompted us to evaluate the association between first-line chemotherapy and subsequent immunotherapy in NSCLC as well as its underlying mechanisms at the genomic and transcriptomic level. Methods: We launched a prospective, observational clinical study, paired tumor biopsies before and after chemotherapy were collected from NSCLC patients without tyrosine kinase inhibitor (TKI)-related driver gene mutations. The analyses included genomic and transcriptional changes performed by next-generation sequencing (NGS)-based whole-exome sequencing (WES) and messager ribonucleic acid (mRNA) sequencing. Characteristic mutational alterations in 1574 genes were investigated based on mutational status, clinicopathological factors, and chemotherapy responses. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, neoantigen prediction and intratumoral heterogeneity evaluation were also performed. Results: Samples and information from 32 NSCLC patients without TKI-related driver gene mutations were obtained. We found that the total number of single nucleotide variants (SNV)/insertion-deletion (INDEL) mutations did not change significantly after chemotherapy. The tumor mutation burden (TMB) decreased significantly after chemotherapy in smoking patients and the decreased TMB correlated with a better survival of smoking patients. The change in copy number variations (CNVs) exhibited a decreasing trend during chemotherapy. Subsequent analysis at mRNA level revealed a significant decrease in the expression levels of genes related to antigen processing and presentation as well as other factors relevant for response to immunotherapy. Pathway enrichment analysis confirmed that the immune-related signaling pathways or biological processes were decreased after first-line chemotherapy. Conclusions: Our study presents an explanation for the unsatisfactory results of immunotherapy when given after chemotherapy, and suggests that first-line chemotherapy is able to influence the tumor microenvironment and decrease the efficacy of subsequent immunotherapy. The study was registered at ClinicalTrials.gov, number NCT03764917, and has completed enrolment; patients are still in follow-up.

Mutational Profile Evaluates Response and Survival to First-Line Chemotherapy in Lung Cancer.

Evaluating the therapeutic response and survival of lung cancer patients receiving first-line chemotherapy has always been difficult. Limited biomarkers for evaluation exist and as a result histology represents an empiric tool to guide therapeutic decision making. In this study, molecular signatures associated with response and long-term survival of lung cancer patients receiving first-line chemotherapy are discovered. Whole-exome sequencing is performed on pretherapeutic tissue samples of 186 patients [145 non-small cell lung cancer (NSCLC) and 41 small cell lung cancer (SCLC)]. On the basis of genomic alteration characteristics, NSCLC patients can be classified into four subtypes (C1-C4). The long-term survival is similar among different subtypes. SCLC patients are also divided into four subtypes and significant difference in their progression free survival is revealed (P < 0.001). NSCLC patients can be divided into three subtypes (S1-S3) based on TMB. A trend of worse survival associated with higher TMB in subtype S3 than in S1+S2 is found. In contrast, no significant correlations between molecular subtype and therapeutic response are observed. In conclusion, this study identifies several molecular signatures associated with response and survival to first-line chemotherapy in lung cancer.

The mutational landscape and prognostic indicators of pseudomyxoma peritonei originating from the ovary.

Pseudomyxoma peritonei (PMP) is a rare disorder with unique pathological and genetic changes. Although several studies have reported the clinical features and mutational changes of PMP that originates from the appendix, few studies on PMP originating from the ovary have been reported due to its extreme rarity. In order to characterize the somatic mutational landscape and to investigate the prognosis predicting factors of ovary-originating PMP, we examined 830 cases of PMP and identified 16 patients with PMP that originated from the ovary. Whole-exome sequencing (WES) was performed on 12 cases using formalin-fixed, paraffin-embedded (FFPE) tissue samples. We found that 25% (3/12) of the patients carried mutations in cancer driver genes, including TP53, ATM and SETD2, and 16.7% (2/12) of the patients carried mutations in cancer driver genes, including ATRX, EP300, FGFR2, KRAS, NOCR1 and RB1. The MUC16 (58.33%), BSN (41.67%), PCNT (41.67%), PPP2R5A (41.67%), PRSS36 (41.67%), PTPRK (41.67%) and SBF1 (41.67%) genes presented the highest mutational frequencies. The PI3K-Akt signaling pathway, human papillomavirus infection pathway, cell skeleton, cell adhesion, and extracellular matrix and membrane proteins were the major pathways or functions that were affected. Patients were followed up to 174 months (median: 48.26 months). The 5-year OS rate for all patients was 71.2% and the median OS was not reached. PTPRK mutations, presurgical CA199 level, completeness of cytoreduction (CCR) and peritoneal cancer index (PCI) were identified as potential predictive factors for patient survival. In conclusion, the mutational landscape for ovary-originating PMP was revealed and exhibited unique features distinct from appendix-originating PMP. PTPRK, CA199, CCR and PCI may predict patient survival.

Prognostic Factors of Colorectal Cancer: A Comparative Study on Patients With or Without Liver Metastasis.

BACKGROUND: Radical or palliative surgery with subsequent adjuvant therapy is the routine treatment for stage II/III colorectal cancer(CRC) and some stage IV CRC patients. This study aimed to clarify the prognostic clinicopathological and genetic factors for these patients. METHODS: Fifty-five stage II-IV CRC patients undergoing surgery and adjuvant therapy were recruited, including patients without liver metastasis(5 at stage II, 21 at stage III) and with liver metastasis(29 at stage IV). Genetic alterations of the primary cancer tissues were investigated by whole exome sequencing(WES). Patients were followed up to 1652 days(median at 788 days). RESULTS: The mutational landscape of primary CRC tissue of patients with or without liver metastasis was largely similar, although the mutational frequency of TRIM77 and TCF7L2 was significantly higher in patients with liver metastasis. Several main driver gene co-mutations, such as TP53-APC, APC-KRAS, APC-FRG1, and exclusive mutations, such as TP53-CREBBP, were found in patients with liver metastasis, but not in patients without liver metastasis. No significant difference was found between the two groups in aberrant pathways. If stage II-IV patients were studied altogether, relapse status, SUPT20HL1 mutations, Amp27_21q22.3 and Del8_10q23.2 were independent risk factors(P<0.05). If patients were divided into two groups by metastatic status, surgery types and Amp6_20q13.33 were independent risk factors for patients without liver metastasis(P<0.05), while TRIM77 mutations were the only independent risk factor for patients with liver metastasis(P<0.05). CONCLUSIONS: Surgery types and Amp6_20q13.33 were independent risk factors for CRC patients without liver metastasis, and TRIM77 mutations were the independent risk factor for CRC patients with liver metastasis.

Metastatic Low-Grade Sarcoma with CARS-ALK Fusion Dramatically Responded to Multiple ALK Tyrosine Kinase Inhibitors: A Case Report with Comprehensive Genomic Analysis.

This article reports a case of advanced metastatic low-grade sarcoma. The patient was diagnosed with an inoperable large (14 × 12 cm) lesion on his neck in September 2015 and underwent two ineffective chemotherapies in the following 4 months. Interestingly, although several pathologists could not agree on the histopathological diagnosis, the precise molecular pathological diagnosis was obtained using next-generation sequencing (NGS) and finally brought excellent therapeutic effects. The patient was detected to have CARS-ALK fusion by NGS and then was successfully treated with crizotinib orally. He received surgical resection of primary and metastatic lesions after tumor shrinkage. The combined treatment brought a durable response for 40 months. Although the tumor recurred in July 2019, the patient has been responding well to the second-line ALK tyrosine kinase inhibitor alectinib to date. We performed whole genome sequencing on the patient's primary, metastatic, and recurrent tumors and did comprehensive genomic analysis. Furthermore, our analysis results revealed that a whole genome duplication event might have happened during tumorigenesis of this case. KEY POINTS: To our best knowledge, this is the first report of a very successful treatment with first- and second-line ALK tyrosine kinase inhibitors for CARS-ALK fusion-positive metastatic low-grade sarcoma. Molecular pathological result can guide precision treatment for sarcoma, even when the exact histopathology cannot be obtained. Multiple samples from this patient were analyzed using whole genome sequencing. Results provided detailed genomic characteristics and showed tumor evolution of this low-grade sarcoma case. A whole genome duplication event might have happened during tumorigenesis of this low-grade sarcoma case.