Application of Circulating Tumor DNA in Precision Diagnosis and Treatment of Colorectal Cancer

Colorectal cancer (CRC) is one of the most common malignant tumors recorded worldwide. This condition has high morbidity and mortality and seriously endangers people's health. Traditional diagnostic models fail to meet people's current needs for real-time monitoring of tumors. Compared with traditional detection methods, ctDNA detection is not only noninvasive but can also attain real-time detection of comprehensive genomic information of tumors. The advancement of detection technology has gradually highlighted the potential of ctDNA detection in the clinical treatment of CRC. This article reviews the advancements on the clinical application of ctDNA in early screening, minimal residual disease detection, and guidance on individualized treatment of CRC patients

Senescent Stromal Cells in the Tumor Microenvironment: Victims or Accomplices?

Cellular senescence is a unique cellular state. Senescent cells enter a non-proliferative phase, and the cell cycle is arrested. However, senescence is essentially an active cellular phenotype, with senescent cells affecting themselves and neighboring cells via autocrine and paracrine patterns. A growing body of research suggests that the dysregulation of senescent stromal cells in the microenvironment is tightly associated with the development of a variety of complex cancers. The role of senescent stromal cells in impacting the cancer cell and tumor microenvironment has also attracted the attention of researchers. In this review, we summarize the generation of senescent stromal cells in the tumor microenvironment and their specific biological functions. By concluding the signaling pathways and regulatory mechanisms by which senescent stromal cells promote tumor progression, distant metastasis, immune infiltration, and therapy resistance, this paper suggests that senescent stromal cells may serve as potential targets for drug therapy, thus providing new clues for future related research

Simultaneous Removal of Nitrate and Tetracycline by an Up-Flow Immobilized Biofilter

The removal of nitrate (NO3−-N) and antibiotics in aquaculture tail water is urgent and necessary. A lab-scale up-flow immobilized biofilter (I-BF) filled with polyurethane foam (PUF) carriers and a microbial consortium was developed for simultaneous removal of nitrate and tetracycline (TC). The denitrification and TC removal performance of the I-BF reactor was investigated under different TC concentrations (0, 10, 50, 100 mg·L−1), carbon/nitrogen (C/N) ratio (2, 4, 5, 6) and hydraulic retention times (HRT) (4, 8, 12 h). Simultaneous removal of nitrogen and TC was achieved by the I-BF reactor. Low TC concentration (≤50 mg·L−1) had little effect on nitrogen removal. The denitrification performance of the I-BF reactor was inhibited at high TC load, which may be attributed to the damage of cell membranes and the inhibition of the intracellular denitrification enzymes’ activities. The optimal C/N ratio and HRT were 5 h and 8 h with almost complete denitrification and high TC removal efficiency (73.46%) at influent NO3−-N and TC concentrations of 100 mg·L−1 and 50 mg·L−1, respectively. The I-BF reactor proposed in this study has promising applications such as the treatment of piggery wastewater, aquaculture tail water and pharmaceutical wastewater co-contaminated with nitrate and antibiotics

Characterizing patent big data upon IPC: a survey of triadic patent families and PCT applications

Abstract Research objective Triadic patent (TP) families and Patent Cooperation Treaty (PCT) applications are often used as datasets to measure innovation capability or R&D internationalization, but their concordance is unclear, which is the main issue in this study. Methods We collect the global TP and PCT data from the Derwent Innovations Index (DII), and a total of 1,589,172 TP families and 4,067,389 PCT applications are retrieved. Based on International Patent Classification (IPC) codes, we compare these two big datasets in three parts: IPC distribution, IPC co-occurrence network, and nation-IPC co-occurrence network. In order to understand the overall similarities and differences between TP and PCT, we make the basic statistics of the global data and w-core defined based on the w-index. Furthermore, the w-cores are visualized and the global similarities are calculated for the detailed concordance and differences. Findings The result shows that the w-core is suitable to select the core part of big data and TP and PCT get high concordance. Meanwhile, in technological convergence, some specific technical fields (e.g. chemistry, medicine, electronic communication, and lighting technology) and countries/regions (e.g. Germany, Japan, China, and Korea), there are a few differences. Practical implications TP families are very similar to PCT applications in terms of reflecting innovation capability or R&D internationalization at a macro level, but when it comes to technological convergence, specific research topics, and countries/regions, the choice may depend on the purpose of the research

Microsatellite instability in mismatch repair proficient colorectal cancer: clinical features and underlying molecular mechanismsResearch in context

Summary: Background: Both defects in mismatch repair (dMMR) and high microsatellite instability (MSI-H) have been recognised as crucial biomarkers that guide treatment strategies and disease management in colorectal cancer (CRC). As MMR and MSI tests are being widely conducted, an increasing number of MSI-H tumours have been identified in CRCs with mismatch repair proficiency (pMMR). The objective of this study was to assess the clinical features of patients with pMMR/MSI-H CRC and elucidate the underlying molecular mechanism in these cases. Methods: From January 2015 to December 2018, 1684 cases of pMMR and 401 dMMR CRCs were enrolled. Of those patients, 93 pMMR/MSI-H were identified. The clinical phenotypes and prognosis were analysed. Frozen and paraffin-embedded tissue were available in 35 patients with pMMR/MSI-H, for which comprehensive genomic and transcriptomic analyses were performed. Findings: In comparison to pMMR/MSS CRCs, pMMR/MSI-H CRCs exhibited significantly less tumour progression and better long-term prognosis. The pMMR/MSI-H cohorts displayed a higher presence of CD8+ T cells and NK cells when compared to the pMMR/MSS group. Mutational signature analysis revealed that nearly all samples exhibited deficiencies in MMR genes, and we also identified deleterious mutations in MSH3-K383fs. Interpretation: This study revealed pMMR/MSI-H CRC as a distinct subgroup within CRC, which manifests diverse clinicopathological features and long-term prognostic outcomes. Distinct features in the tumour immune-microenvironment were observed in pMMR/MSI-H CRCs. Pathogenic deleterious mutations in MSH3-K383fs were frequently detected, suggesting another potential biomarker for identifying MSI-H. Funding: This work was supported by the Science and Technology Commission of Shanghai Municipality (20DZ1100101)

The Largest Chinese Cohort Study Indicates Homologous Recombination Pathway Gene Mutations as Another Major Genetic Risk Factor for Colorectal Cancer with Heterogeneous Clinical Phenotypes

While genetic factors were associated with over 30% of colorectal cancer (CRC) patients, mutations in CRC-susceptibility genes were identified in only 5% to 10% of these patients. Besides, previous studies on hereditary CRC were largely designed to analyze germline mutations in patients with single genetic high-risk factor, which limited understanding of the association between genotype and phenotypes. From January 2015 to December 2018, we retrospectively enrolled 2,181 patients from 8,270 consecutive CRC cases, covering 5 categories of genetic high-risk factors. Leukocyte genomic DNA was analyzed for germline mutations in cancer predisposition genes. The germline mutations under each category were detected and analyzed in association with CRC susceptibility, clinical phenotypes, and prognoses. A total of 462 pathogenic variants were detected in 19.3% of enrolled CRC patients. Mismatch repair gene mutation was identified in 9.1% of patients, most prevalent across all high-risk groups. Homologous recombination (HR) gene mutations were detected in 6.5% of cases, penetrated in early-onset and extra-colonic cancer risk groups. Mutations in HR genes, including BARD1, RAD50, and ATM, were found to increase CRC risk with odds ratios of 2.8-, 3.1-, and 3.1-fold, respectively. CRC patients with distinct germline mutations manifested heterogeneous phenotypes in clinicopathology and long-term prognoses. Thus, germline mutation screenings should be performed for CRC patients with any of those genetic risk factors. This study also reveals that HR gene mutations may be another major driver for increased CRC risk

Frequent mutations of genes encoding ubiquitin-mediated proteolysis pathway components in clear cell renal cell carcinoma

We sequenced whole exomes of ten clear cell renal cell carcinomas (ccRCCs) and performed a screen of similar to 1,100 genes in 88 additional ccRCCs, from which we discovered 12 previously unidentified genes mutated at elevated frequencies in ccRCC. Notably, we detected frequent mutations in the ubiquitin-mediated proteolysis pathway (UMPP), and alterations in the UMPP were significantly associated with overexpression of HIF1 alpha and HIF2 alpha in the tumors (P = 0.01 and 0.04, respectively). Our findings highlight the potential contribution of UMPP to ccRCC tumorigenesis through the activation of the hypoxia regulatory network