Depletion-assisted multiplexed cell-free RNA sequencing reveals distinct human and microbial signatures in plasma versus extracellular vesicles.

BACKGROUND: Cell-free long RNAs in human plasma and extracellular vesicles (EVs) have shown promise as biomarkers in liquid biopsy, despite their fragmented nature. METHODS: To investigate these fragmented cell-free RNAs (cfRNAs), we developed a cost-effective cfRNA sequencing method called DETECTOR-seq (depletion-assisted multiplexed cell-free total RNA sequencing). DETECTOR-seq utilised a meticulously tailored set of customised guide RNAs to remove large amounts of unwanted RNAs (i.e., fragmented ribosomal and mitochondrial RNAs) in human plasma. Early barcoding strategy was implemented to reduce costs and minimise plasma requirements. RESULTS: Using DETECTOR-seq, we conducted a comprehensive analysis of cell-free transcriptomes in both whole human plasma and EVs. Our analysis revealed discernible distributions of RNA types in plasma and EVs. Plasma exhibited pronounced enrichment in structured circular RNAs, tRNAs, Y RNAs and viral RNAs, while EVs showed enrichment in messenger RNAs (mRNAs) and signal recognition particle RNAs (srpRNAs). Functional pathway analysis highlighted RNA splicing-related ribonucleoproteins (RNPs) and antimicrobial humoral response genes in plasma, while EVs demonstrated enrichment in transcriptional activity, cell migration and antigen receptor-mediated immune signals. Our study indicates the comparable potential of cfRNAs from whole plasma and EVs in distinguishing cancer patients (i.e., colorectal and lung cancer) from healthy donors. And microbial cfRNAs in plasma showed potential in classifying specific cancer types. CONCLUSIONS: Our comprehensive analysis of total and EV cfRNAs in paired plasma samples provides valuable insights for determining the need for EV purification in cfRNA-based studies. We envision the cost effectiveness and efficiency of DETECTOR-seq will empower transcriptome-wide investigations in the fields of cfRNAs and liquid biopsy. KEYPOINTS: DETECTOR-seq (depletion-assisted multiplexed cell-free total RNA sequencing) enabled efficient and specific depletion of sequences derived from fragmented ribosomal and mitochondrial RNAs in plasma. Distinct human and microbial cell-free RNA (cfRNA) signatures in whole Plasma versus extracellular vesicles (EVs) were revealed. Both Plasma and EV cfRNAs were capable of distinguishing cancer patients from normal individuals, while microbial RNAs in Plasma cfRNAs enabled better classification of cancer types than EV cfRNAs.

Four Lanthanide(III) Metal-Organic Frameworks Fabricated by Bithiophene Dicarboxylate for High Inherent Proton Conduction.

Currently, it is still a challenge to directly achieve highly stable metal-organic frameworks (MOFs) with superior proton conductivity solely through the exquisite design of ligands and the attentive selection of metal nodes. Inspired by this, we are intrigued by a multifunctional dicarboxylate ligand including dithiophene groups, 3,4-dimethylthieno[2,3-b]thiophene-2,5-dicarboxylic acid (H2DTD), and lanthanide ions with distinct coordination topologies. Successfully, four isostructural three-dimensional lanthanide(III)-based MOFs, [Ln2(DTD)3(DEF)4]·DEF·6H2O [LnIII = TbIII (Tb-MOF), EuIII (Eu-MOF), SmIII (Sm-MOF), and DyIII (Dy-MOF)], were solvothermally prepared, in which the effective proton transport will be provided by the coordinated or free solvent molecules, the crystalline water molecules, and the framework components, as well as a large number of highly electronegative S and O atoms. As expected, the four Ln-MOFs demonstrated the highest proton conductivities (σ) being 0.54 × 10-3, 3.75 × 10-3, 1.28 × 10-3, and 1.92 × 10-3 S·cm-1 for the four MOFs, respectively, at 100 °C/98% relative humidity (RH). Excitingly, Dy-MOF demonstrated an extraordinary ultrahigh σ of 1 × 10-3 S·cm-1 at 30 °C/98% RH. Additionally, the plausible proton transport mechanisms were emphasized.

Combination of clinical information and radiomics models for the differentiation of acute simple appendicitis and non simple appendicitis on CT images.

To investigate the radiomics models for the differentiation of simple and non-simple acute appendicitis. This study retrospectively included 334 appendectomy cases (76 simple and 258 non-simple cases) for acute appendicitis. These cases were divided into training (n = 106) and test cohorts (n = 228). A radiomics model was developed using the radiomic features of the appendix area on CT images as the input variables. A CT model was developed using the clinical and CT features as the input variables. A combined model was developed by combining the radiomics model and clinical information. These models were tested, and their performance was evaluated by receiver operating characteristic curves and decision curve analysis (DCA). The variables independently associated with non-simple appendicitis in the combined model were body temperature, age, percentage of neutrophils and Rad-score. The AUC of the combined model was significantly higher than that of the CT model (P = 0.041). The AUC of the radiomics model was also higher than that of the CT model but did not reach a level of statistical significance (P = 0.053). DCA showed that all three models had a higher net benefit (NB) than the default strategies, and the combined model presented the highest NB. A nomogram of the combined model was developed as the graphical representation of the final model. It is feasible to use the combined information of clinical and CT radiomics models for the differentiation of simple and non-simple acute appendicitis.

Cell-free multi-omics analysis reveals potential biomarkers in gastrointestinal cancer patients' blood.

During cancer progression, tumorigenic and immune signals are spread through circulating molecules, such as cell-free DNA (cfDNA) and cell-free RNA (cfRNA) in the blood. So far, they have not been comprehensively investigated in gastrointestinal cancers. Here, we profile 4 categories of cell-free omics data from patients with colorectal cancer and patients with stomach adenocarcinoma and then assay 15 types of genomic, epigenomic, and transcriptomic variations. We find that multi-omics data are more appropriate for detection of cancer genes compared with single-omics data. In particular, cfRNAs are more sensitive and informative than cfDNAs in terms of detection rate, enriched functional pathways, etc. Moreover, we identify several peripheral immune signatures that are suppressed in patients with cancer. Specifically, we establish a γδ-T cell score and a cancer-associated-fibroblast (CAF) score, providing insights into clinical statuses like cancer stage and survival. Overall, we reveal a cell-free multi-molecular landscape that is useful for blood monitoring in personalized cancer treatment.

Preparation, Modification, and Application of Biochar in the Printing Field: A Review.

Biochar is a solid material enriched with carbon produced by the thermal transformation of organic raw materials under anoxic or anaerobic conditions. It not only has various environmental benefits including reducing greenhouse gas emissions, improving soil fertility, and sequestering atmospheric carbon, but also has the advantages of abundant precursors, low cost, and wide potential applications, thus gaining widespread attention. In recent years, researchers have been exploring new biomass precursors, improving and developing new preparation methods, and searching for more high-value and meaningful applications. Biochar has been extensively researched and utilized in many fields, and recently, it has also shown good industrial application prospects and potential application value in the printing field. In such a context, this article summarizes the typical preparation and modification methods of biochar, and also reviews its application in the printing field, to provide a reference for future work.

The Clinical Characteristics and Prognostic Factors of Primary Extramammary Paget's Disease Treated with Surgery in Anogenital Regions: A Large Population Study from the SEER Database and Our Centre.

BACKGROUND: Extramammary Paget's disease (EMPD) is a rare malignant cutaneous tumour that is commonly located in anogenital regions. The diagnosis of the disease is always delayed, and treatment is usually troublesome. This study aims to summarise the clinicopathological characteristics and the risk factors of prognosis for EMPD in anogenital regions, potentially providing evidence for the diagnosis and treatment of anogenital EMPD. METHODS: 688 patients were sourced from the Surveillance, Epidemiology and End Results (SEER) program between 1992 and 2021. In total, 176 participants from our centre from between 2011 and 2021 were included to investigate the characteristics and prognosis for EMPD in anogenital regions. RESULTS: From the SEER program data, patient age of 65 years or older, metastasis of lymph nodes, Spanish-Hispanic-Latino race, diameter exceeding 10cm and lesions located anally were revealed as independent risk factors for shorter cancer-specific survival (CSS). However, the data from our centre highlighted that metastasis of lymph nodes and tumours extending through the epidermis are independent risk factors of shortened progression-free survival (PFS) and CSS of anogenital EMPD. CONCLUSION: This synthesised study revealed that some characteristics are regarded as risk factors for poor clinical prognosis, which have potential value in formulating more normative and effective strategies for patients with EMPD in anogenital regions.

Heterogeneous Fenton oxidation of 2,4-dichlorophenol catalyzed by PEGylated nanoscale zero-valent iron supported by biochar.

The excessive use of herbicides and fungicides containing 2,4-dichlorophenol (2,4-DCP) has led to serious environmental water pollution; 2,4-DCP is chemically stable and difficult to be degraded effectively by biological and physical methods. And the degradation of 2,4-DCP using advanced oxidation techniques has been a hot topic. Biochar, polyethylene glycol, ferrous sulfate, and sodium borohydride were used to synthesize the heterogeneous catalyst PEGylated nanoscale zero-valent iron supported by biochar (PEG-nZVI@BC). The catalyst was characterized using scanning electron microscope (SEM) and other means to determine its physicochemical properties. Catalytic performance and mechanism of this catalyst with hydrogen peroxide for the oxidation of 2,4-DCP were investigated. The results showed that PEG-nZVI@BC had good dispersibility, stability, and inoxidizability; the degradation efficiency of 50 mg/L 2,4-DCP by PEG-nZVI@BC/H2O2 system 92.94%, 1.68 times higher than that of nZVI/H2O2 system; there are both free radical and non-free radical pathways in PEG-nZVI@BC/H2O2 system; the degradation process of 2,4-DCP includes hydroxylation, dechlorination, and ring-opening. Overall, PEG-nZVI@BC is a promising heterogeneous catalyst for the degradation of 2,4-DCP.

Hydrogen Sulfide Creates a Favorable Immune Microenvironment for Colon Cancer.

Immunotherapy can elicit robust anticancer responses in the clinic. However, a large proportion of patients with colorectal cancer do not benefit from treatment. Although previous studies have shown that hydrogen sulfide (H2S) is involved in colorectal cancer development and immune escape, further insights into the mechanisms and related molecules are needed to identify approaches to reverse the tumor-supportive functions of H2S. Here, we observed significantly increased H2S levels in colorectal cancer tissues. Decreasing H2S levels by using CBS+/- mice or feeding mice a sulfur amino acid-restricted diet (SARD) led to a marked decrease in differentiated CD4+CD25+Foxp3+ Tregs and an increase in the CD8+ T-cell/Treg ratio. Endogenous or exogenous H2S depletion enhanced the efficacy of anti-PD-L1 and anti-CTLA4 treatment. H2S promoted Treg activation through the persulfidation of ENO1 at cysteine 119. Furthermore, H2S inhibited the migration of CD8+ T cells by increasing the expression of AAK-1 via ELK4 persulfidation at cysteine 25. Overall, reducing H2S levels engenders a favorable immune microenvironment in colorectal cancer by decreasing the persulfidation of ENO1 in Tregs and ELK4 in CD8+ T cells. SARD represents a potential dietary approach to promote responses to immunotherapies in colorectal cancer. SIGNIFICANCE: H2S depletion increases the CD8+ T-cell/Treg ratio and enhances the efficacy of anti-PD-L1 and anti-CTLA4 treatment in colon cancer, identifying H2S as an anticancer immunotherapy target.

Bioremediation of petroleum hydrocarbon contaminated soil by microorganisms immobilized on sludge modified by non-ionic surfactant.

The immobilization of microorganisms on high-quality and inexpensive carriers to remediate oil-contaminated soil is an effective strategy for contaminated soil remediation. Due to the abundance in nutrients, large specific surface area, and fewer pathogens, the composting sludge is considered a high-quality immobilized material. Herein, two non-ionic surfactants, TW-80 and sophorolipid, were used to modify composted sludge. High-efficiency petroleum hydrocarbon-degrading bacteria groups selected in the laboratory were fixed on the modified composting sludge under optimal conditions. The immobilized material was placed in the soil contaminated by petroleum hydrocarbons at an additive amount of 2wt/%, and a simulated remediation experiment was performed for 90 days. Both soil properties and microbial structure were characterized. Surfactant-modified compost sludge enhances the adsorption capacity to petroleum hydrocarbon. The immobilized microorganisms in the modified compost sludge showed a good effect on the remediation of soil contaminated by petroleum hydrocarbons. In addition, immobilized materials also increase the diversity of the microbial community structure in the soil. High-efficiency petroleum hydrocarbon-degrading bacteria immobilized on surfactant-modified compost can effectively promote the degradation of petroleum hydrocarbons in the soil and increase the abundance of microorganisms in the soil. It shows the feasibility of eco-friendly remediation of hydrocarbon-contaminated soil.

TikTok and YouTube as sources of information on anal fissure: A comparative analysis.

Introduction: Anal fissure is a common colorectal disease impacting patients' life quality with high incidence. Social media platforms are becoming a kind of health information source nowadays. This study aims to evaluate and compare the quality of anal fissure-related videos on TikTok and YouTube. Materials and methods: One hundred videos were sourced from TikTok and YouTube, respectively and videos were screened further. The completeness of six types of content within the videos is assessed, including the definition of disease, symptoms, risk factors, evaluation, management and outcomes. Finally, the DISCERN instrument, Patient Education Materials Assessment Tool and Global Quality scale are used to assess video display quality and content. A correlation analysis is undertaken considering the video features, DISCERN, PEMAT and GQS scores. Results: Physicians and non-profit organizations contributed almost all video content among selected videos. A statistically significant correlation between DISCERN classification and duration, PEMAT understandability, PEMAT actionability and GQS scores is recorded. DISCERN total scores were significantly positively correlated with video duration, PEMAT understandability, PEMAT actionability and GQS scores. GQS scores were significantly positively correlated with duration, PEMAT understandability and PEMAT actionability scores. For content, the videos mainly described management and symptoms while containing limited information on the disease evaluation, and outcomes. Conclusions: The sources of uploaders on YouTube are more diverse than TikTok, and the quality of videos is also relatively higher on YouTube. Even so, the video quality of the two platforms still needs to be further improved. Health information without integrity, reliability and practicability impacts patients' disease perception and health-seeking behavior, leading to serious consequences. Much effort must be taken to improve the quality of videos regarding anal fissures on the two platforms, which will facilitate the development of public health education on this issue.

Cancer type classification using plasma cell-free RNAs derived from human and microbes.

The utility of cell-free nucleic acids in monitoring cancer has been recognized by both scientists and clinicians. In addition to human transcripts, a fraction of cell-free nucleic acids in human plasma were proven to be derived from microbes and reported to have relevance to cancer. To obtain a better understanding of plasma cell-free RNAs (cfRNAs) in cancer patients, we profiled cfRNAs in ~300 plasma samples of 5 cancer types (colorectal cancer, stomach cancer, liver cancer, lung cancer, and esophageal cancer) and healthy donors (HDs) with RNA-seq. Microbe-derived cfRNAs were consistently detected by different computational methods when potential contaminations were carefully filtered. Clinically relevant signals were identified from human and microbial reads, and enriched Kyoto Encyclopedia of Genes and Genomes pathways of downregulated human genes and higher prevalence torque teno viruses both suggest that a fraction of cancer patients were immunosuppressed. Our data support the diagnostic value of human and microbe-derived plasma cfRNAs for cancer detection, as an area under the ROC curve of approximately 0.9 for distinguishing cancer patients from HDs was achieved. Moreover, human and microbial cfRNAs both have cancer type specificity, and combining two types of features could distinguish tumors of five different primary locations with an average recall of 60.4%. Compared to using human features alone, adding microbial features improved the average recall by approximately 8%. In summary, this work provides evidence for the clinical relevance of human and microbe-derived plasma cfRNAs and their potential utilities in cancer detection as well as the determination of tumor sites.

Appendico-vesicocolonic fistula: A case report and review of literature.

BACKGROUND: Appendico-vesicocolonic fistulas and appendiceal-colonic fistulas are two kinds of intestinal and bladder diseases that are rarely seen in the clinic. To our knowledge, no more than 4 cases of appendico-vesicocolonic fistulas have been publicly reported throughout the world, and no more than 100 cases of appendiceal-colonic fistulas have been reported. Although the overall incidence is low, an early diagnosis is difficult due to their atypical initial symptoms, but these diseases still require our attention. CASE SUMMARY: Here, we report a case of a 77-year-old male patient diagnosed with an appendico-vesicocolonic fistula combined with an appendiceal-colonic fistula. The main manifestations were diarrhea and urine that contained fecal material. The diagnosis was confirmed by multiple laboratory and imaging examinations. A routine urinalysis showed red blood cells and white blood cells. Abdominal and pelvic computed tomography scans showed close adhesions between the bowels and the bladder, and fistulas could be seen. Colonoscopy and cystoscopy and some other imaging examinations clearly showed fistulas. The preoperative diagnoses were a colovesical fistula and an appendiceal-colonic fistula. The fistulas were repaired by laparoscopic surgical treatment. The diseased bowel and part of the bladder wall were removed, followed by a protective ileostomy. The postoperative diagnosis was an appendico-vesicocolonic fistula combined with an appendiceal-colonic fistula, and the pathology suggested inflammatory changes. The patient recovered well after surgery, and all his symptoms resolved. CONCLUSION: The final diagnosis in this case was a double fistula consisting of an appendico-vesicocolonic fistula combined with an appendiceal-colonic fistula.

Two Similar Signatures for Predicting the Prognosis and Immunotherapy Efficacy of Stomach Adenocarcinoma Patients.

BACKGROUND: Globally, stomach adenocarcinoma (STAD)'s high morbidity and mortality should arouse our urgent attention. How long can STAD patients survive after surgery and whether novel immunotherapy is effective are questions that our clinicians cannot escape. METHODS: Various R packages, GSEA software, Metascape, STRING, Cytoscape, Venn diagram, TIMER2.0 website, TCGA, and GEO databases were used in our study. RESULTS: In the TCGA and GEO, macrophage abundance of STAD tissues was significantly higher than that of adjacent tissues and was an independent prognostic factor, significantly related to the overall survival (OS) of STAD patients. Between the high- and low- macrophage abundance, we conducted differential expression, univariate and multivariate Cox analysis, and obtained 12 candidate genes, and finally constructed a 3-gene signature. Both low macrophage abundance group and group D had higher TMB and PD-L1 expression. Furthermore, top 5 common gene-mutated STAD tissues had lower macrophage abundance. Macrophage abundance and 3 key genes expression were also lower in the Epstein-Barr Virus (EBV) and HM-indel STAD subtypes and significantly correlated with the tumor microenvironment score. The functional enrichment and ssGSEA revealed 2 signatures were similar and closely related to BOQUEST_STEM_CELL_UP, including genes up-regulated in proliferative stromal stem cells. Hsa-miR-335-5p simultaneously regulated 3 key genes and significantly related to the expression of PD-L1, CD8A and PDCD1. CONCLUSION: macrophage abundance and 3-gene signature could simultaneously predict the OS and immunotherapy efficacy, and both 2 signatures had remarkable similarities. Hsa-miR-335-5p and BOQUEST_STEM_CELL_UP might be novel immunotherapy targets.

Nomogram for Predicting the Probability of Permanent Stoma after Laparoscopic Intersphincteric Resection.

PURPOSE: The purpose of this study was to determine the risk factors for the development of a permanent stoma in laparoscopic intersphincteric resection (LS-ISR) for ultralow rectal adenocarcinoma and to develop and validate a prediction model to predict the probability of permanent stoma after surgery. METHODS: A primary cohort consisting of 301 consecutive patients who underwent LS-ISR was enrolled in this study. Multivariable logistic regression analysis was used to identify risk factors and develop the nomogram. The performance of the nomogram was assessed with respect to its calibration, discrimination, and clinical usefulness. An independent validation cohort contained 91 consecutive patients from January 2012 to January 2019. RESULTS: The permanent stoma rate was 11.3% (34/301) in the primary cohort and 18.7% (17/91) in the validation cohort. Multivariable analysis revealed that nCRT (OR, 3.195; 95% CI, 1.169-8.733; P=0.024), ASA score of 3 (OR, 5.062; 95% CI, 1.877-13.646; P=0.001), distant metastasis (OR, 14.645; 95% CI, 3.186-67.315; P=0.001), and anastomotic leakage (OR, 11.308; 95% CI, 3.650-35.035; P<0.001) were independent risk factors for permanent stoma, and a nomogram was established. The AUCs of the nomogram were 0.842 and 0.858 in the primary and validation cohorts, respectively. The calibration curves showed good calibration in both cohorts. Decision curve analysis demonstrated that the nomogram was clinically useful. CONCLUSION: We developed and validated a nomogram for ultralow rectal adenocarcinoma patients who underwent LS-ISR, and the nomogram could help surgeons identify which patients are at a higher risk of a permanent stoma after surgery.

The aging-related risk signature in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer worldwide. The opening of the TCGA and GEO databases has promoted the progress of CRC prognostic assessment, while the aging-related risk signature has never been mentioned. METHODS: R software packages, GSEA software, Venn diagram, Metascape, STRING, Cytoscape, cBioPortal, TIMER and GeneMANIA website were used in this study. RESULTS: Aging-related gene sets, GO_AGING, GO_CELL_AGING and GO_CELLULAR_SENESCENCE, were activated significantly in CRC tissues. We constructed an aging-related risk signature using LASSO COX regression in training group TCGA and validated in testing group GSE39582. The risk score was significantly associated with the overall survival of CRC patients, whose stability was clarified by stratified survival analysis and accuracy was demonstrated using the ROC curve. The risk score was significantly increased in the advanced stage, T3-4, N1-3 and M1 and positively correlated with the richness of immune cell infiltration in the tumor microenvironment. We further investigated the molecular characteristics of 15 hub genes at the DNA and protein levels and performed GSEA between high- and low-risk groups. CONCLUSIONS: The aging-related signature is a reliable prognostic analysis model and can predict the severity and immune cell infiltration of CRC patients.

BCL2A1 and CCL18 Are Predictive Biomarkers of Cisplatin Chemotherapy and Immunotherapy in Colon Cancer Patients.

Background: Cisplatin enhances the antitumor T cell response, and the combination of PD-L1 blockade produces a synergistic therapeutic effect. However, the clinical correlation between cisplatin and immunotherapy in colon cancer (CC) is unknown. Methods: Using the "pRRophetic" package, we calculated the IC50 of cisplatin. The correlation between cisplatin IC50, cisplatin resistance-related genes (CCL18 and BCL2A1), and immunotherapy were preliminarily verified in TCGA and further validated in independent cohorts (GSE39582 and GSE17538), cisplatin-resistant CC cell line DLD1, and our own clinical specimens. Classification performance was evaluated using the AUC value of the ROC curve. Scores of immune signatures, autophagy, ferroptosis, and stemness were quantified using the ssGSEA algorithm. Results: Based on respective medians of three CC cohorts, patients were divided into high- and low-IC50 groups. Compared with the high IC50 group, the low-IC50 group had significantly higher tumor microenvironment (TME) scores and lower tumor purity. Most co-signaling molecules were upregulated in low IC50 group. CC patients with good immunotherapy efficacy (MSI, dMMR, and more TMB) were more attributable to the low-IC50 group. Among seven shared differentially expressed cisplatin resistance-related genes, CCL18 and BCL2A1 had the best predictive efficacy of the above immunotherapy biomarkers. For wet experimental verification, compared with cisplatin-resistant DLD1, similar to PD-L1, CCL18 and BCL2A1 were significantly upregulated in wild-type DLD1. In our own CC tissues, the mRNA expression of CCL18, BCL2A1, and PD-L1 in dMMR were significantly increased. The high group of CCL18 or BCL2A1 had a higher proportion of MSI, dMMR, and more TMB. IC50, CCL18, BCL2A1, and PD-L1 were closely related to scores of immune-related pathways, immune signatures, autophagy, ferroptosis, and stemness. The microRNA shared by BCL2A1 and PD-L1, hsa-miR-137, were significantly associated with CCL18, BCL2A1, and PD-L1, and downregulated in low-IC50 group. The activity of the TOLL-like receptor signaling pathway affected the sensitivity of CC patients to cisplatin and immunotherapy. For subtype analysis, immune C2, immune C6, HM-indel, HM-SNV, C18, and C20 were equally sensitive to cisplatin chemotherapy and immunotherapy. Conclusions: CC patients sensitive to cisplatin chemotherapy were also sensitive to immunotherapy. CCL18 and BCL2A1 were novel biomarkers for cisplatin and immunotherapy.

Aminooxyacetic acid (AOAA) sensitizes colon cancer cells to oxaliplatin via exaggerating apoptosis induced by ROS.

Background: As the third confirmed gaseous transmitter, the role of hydrogen sulfide (H2S) in the pathogenesis of multiple types of cancer has been attracting increasing attention. Increased expression of cystathionine ß-synthase (CBS) and H2S in colon cancer tissue samples has been validated and tumor-derived H2S, mainly produced by CBS, stimulates bioenergetics, cell proliferation, and angiogenesis in colon cancer. Recently, the therapeutic manipulation of H2S has been proposed as a promising anticancer approach. However, the effect of aminooxyacetic acid (AOAA), which has been widely used as an inhibitor of CBS dependent synthesis of H2S, on the chemotherapeutic effect of oxaliplatin (OXA) and the underlying mechanisms remain to be illustrated. Methods: We examined the expression of CBS in human colorectal cancer specimens and matched normal mucosa by immunohistochemistry. The effect of AOAA on the sensitivity of colon cancer cells to OXA and the level of apoptosis induced by caspase cascade was investigated in both HCT116 and HT29 cell lines utilizing CCK-8 assays, flow cytometry analysis and western blot analysis. The endogenous levels of reactive oxygen species (ROS) were detected fluorescently by DCF-DA, and glutathione (GSH) levels were measured by a Total GSH Detection Kit. Tumor bearing xenograft mouse models and in vivo imaging systems were further used to investigate the effect of AOAA in vivo and immunohistochemistry (IHC) and TUNEL analysis were performed. Results: In the current study, we confirmed CBS, the main target of AOAA, is overexpressed in human colorectal cancer by immunohistochemistry. The inhibitory effect of AOAA on the synthesis of H2S was validated utilizing fluorescent probe and specific electrode. AOAA significantly reduced the IC50 values of OXA in both colon cancer cell lines. Co-incubation with AOAA elicited increased apoptosis induced by OXA, featured by increased activation of caspase cascade. Besides, AOAA further increased the levels of ROS induced by OXA and attenuated the synthesis of glutathione (GSH), which is a vital antioxidant. Besides, the results of in vivo imaging and following IHC and TUNEL analysis were in accordance with cellular experiments, indicating that AOAA sensitizes colon cancer cells to OXA via exaggerating intrinsic apoptosis. Conclusion: The results suggested that CBS is overexpressed in colorectal cancer tissues and AOAA sensitizes colon cancer cells to OXA via exaggerating apoptosis both in vitro and in vivo. Decreasing the endogenous level of GSH and consequently impaired detoxification of ROS might be one of the mechanisms underlying the effect of AOAA.

HLA Polymorphisms And TKI-Induced Liver Injury in Patients with Cancer: A Meta-analysis.

Background: Tyrosine kinase inhibitors (TKIs) are widely used for patients with cancer, although liver injury has been observed in a small proportion of these patients. The aim of this study was to investigate the mechanisms underlying TKI-induced liver injury according to HLA polymorphisms. Methods: We systematically searched three electronic databases (PubMed, PMC, EmBase, and the Cochrane library) to identify studies that evaluated the impact of HLA polymorphisms on the incidence of TKI-induced liver injury in cancer patients as of November 2018. The summary odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using a random-effects model. Further, sensitivity analysis and publication bias assessments were also performed. Results: In the final analysis, four studies that involved a total of 12,181 patients were included. Three of the studies included patients who received lapatinib, and the other study included patients who received pazopanib. Overall, carriers of HLA-DQA1*02:01 were associated with an increased risk of liver injury (OR: 6.85; 95%CI: 2.34-20.02; P<0.001). Furthermore, HLA-DQB1*02:02 was correlated with a greater risk of liver injury (OR: 5.61; 95%CI: 2.80-11.25; P<0.001). Finally, HLA-DRB1*07:01 was significantly correlated with a greater risk of liver injury (OR: 4.06; 95%CI: 2.33-7.09; P<0.001). Conclusions: The findings of this meta-analysis confirmed that three polymorphisms of HLA were significantly associated with an increased risk of TKI-induced liver injury. Further work will be required to determine these relationships in patients with specific characteristics.