Transcriptomic and immunophenotypic profiling reveals molecular and immunological hallmarks of colorectal cancer tumourigenesis.

OBJECTIVE: Biological insights into the stepwise development and progression of colorectal cancer (CRC) are imperative to develop tailored approaches for early detection and optimal clinical management of this disease. Here, we aimed to dissect the transcriptional and immunologic alterations that accompany malignant transformation in CRC and to identify clinically relevant biomarkers through spatial profiling of pT1 CRC samples. DESIGN: We employed digital spatial profiling (GeoMx) on eight pT1 CRCs to study gene expression in the epithelial and stromal segments across regions of distinct histology, including normal mucosa, low-grade and high-grade dysplasia and cancer. Consecutive histology sections were profiled by imaging mass cytometry to reveal immune contextures. Finally, publicly available single-cell RNA-sequencing data was analysed to determine the cellular origin of relevant transcripts. RESULTS: Comparison of gene expression between regions within pT1 CRC samples identified differentially expressed genes in the epithelium (n=1394 genes) and the stromal segments (n=1145 genes) across distinct histologies. Pathway analysis identified an early onset of inflammatory responses during malignant transformation, typified by upregulation of gene signatures such as innate immune sensing. We detected increased infiltration of myeloid cells and a shift in macrophage populations from pro-inflammatory HLA-DR+CD204- macrophages to HLA-DR-CD204+ immune-suppressive subsets from normal tissue through dysplasia to cancer, accompanied by the upregulation of the CD47/SIRPα 'don't eat me signal'. CONCLUSION: Spatial profiling revealed the molecular and immunological landscape of CRC tumourigenesis at early disease stage. We identified biomarkers with strong association with disease progression as well as targetable immune processes that are exploitable in a clinical setting.

Low risk of local recurrence after a successful en bloc endoscopic submucosal dissection for noninvasive colorectal lesions with positive horizontal resection margins (R-ESD study).

BACKGROUND : During endoscopic submucosal dissection (ESD), the normal mucosa is cut under constant optical control. We studied whether a positive horizontal resection margin after a complete en bloc ESD predicts local recurrence. METHODS: In this European multicenter cohort study, patients with a complete en bloc colorectal ESD were selected from prospective registries. Cases were defined by a horizontal resection margin that was positive or indeterminate for dysplasia (HM1), whereas controls had a free resection margin (HM0). Low risk lesions with submucosal invasion (T1) and margins free of carcinoma were analyzed separately. The main outcome was local recurrence. RESULTS: From 928 consecutive ESDs (2011-2020), 354 patients (40 % female; mean age 67 years, median follow-up 23.6 months), with 308 noninvasive lesions and 46 T1 lesions, were included. The recurrence rate for noninvasive lesions was 1/212 (0.5 %; 95 %CI 0.02 %-2.6 %) for HM0 vs. 2/96 (2.1 %; 95 %CI 0.57 %-7.3 %) for HM1. The recurrence rate for T1 lesions was 1/38 (2.6 %; 95 %CI 0.14 %-13.5 %) for HM0 vs. 2/8 (25 %; 95 %CI 7.2 %-59.1 %) for HM1. CONCLUSION: A positive horizontal resection margin after an en bloc ESD for noninvasive lesions is associated with a marginal nonsignificant increase in the local recurrence rate, equal to an ESD with clear horizontal margins. This could not be confirmed for T1 lesions.

Triazine-based covalent-organic framework embedded with cuprous oxide as the bioplatform for photoelectrochemical aptasensing Escherichia coli.

A superior photoelectrochemical (PEC) aptasensor was manufactured for the detection of Escherichia coli (E. coli) based on a hybrid of triazine-based covalent-organic framework (COF) and cuprous oxide (Cu2O). The COF synthesized using 1,3,5-tris(4-aminophenyl)-benzene (TAPB) and 1,3,5-triformylphloroglucinol (Tp) as building blocks acted as a scaffold for encapsulated Cu2O nanoparticles (denoted as Cu2O@TAPB-Tp-COF), which then was employed as the bioplatform for anchoring E. coli-targeted aptamer. Cu2O@Cu@TAPB-Tp-COF demonstrated enhanced separation of the photogenerated carriers and photoabsorption ability and boosted photoelectric conversion efficiency. The developed Cu2O@TAPB-Tp-COF-based PEC aptasensor exhibited a lower detection limit of 2.5 CFU mL-1 toward E. coli within a wider range of 10 CFU mL-1 to 1 × 104 CFU mL-1 than most of reported aptasensors for determining foodborne bacteria, together with high selectivity, good stability, and superior ability and reproducibility. The recoveries of E. coli spiked into milk and bread samples ranged within 95.3-103.6% and 96.6-102.8%, accompanying with low RSDs of 1.37-4.48% and 1.74-3.66%, respectively. The present study shows a promising alternative for the sensitive detection of foodborne bacteria from complex foodstuffs and pathogenic bacteria-polluted environment.

Risk and Time Pattern of Recurrences After Local Endoscopic Resection of T1 Colorectal Cancer: A Meta-analysis.

BACKGROUND & AIMS: Growing numbers of patients with T1 CRC are being treated with local endoscopic resection only and as a result, the need for optimization of surveillance strategies for these patients also increases. We aimed to estimate the cumulative incidence and time pattern of CRC recurrences for endoscopically treated patients with T1 CRC. METHODS: Using a systematic literature search in PubMed, EMBASE, Web of Science and Cochrane Library (from inception till 15 May 2020), we identified and extracted data from studies describing the cumulative incidence of local or distant CRC recurrence for patients with T1 CRC treated with local endoscopic resection only. Pooled estimates were calculated using mixed-effect logistic regression models. RESULTS: Seventy-one studies with 5167 unique, endoscopically treated patients with T1 CRC were included. The pooled cumulative incidence of any CRC recurrence was 3.3% (209 events; 95% CI, 2.6%-4.3%; I2 = 54.9%), with local and distant recurrences being found at comparable rates (pooled incidences 1.9% and 1.6%, respectively). CRC-related mortality was observed in 42 out of 2519 patients (35 studies; pooled incidence 1.7%, 95% CI, 1.2%-2.2%; I2 = 0%), and the CRC-related mortality rate among patients with recurrence was 40.8% (42/103 patients). The vast majority of recurrences (95.6%) occurred within 72 months of follow-up. Pooled incidences of any CRC recurrence were 7.0% for high-risk T1 CRCs (28 studies; 95% CI, 4.9%-9.9%; I2 = 48.1%) and 0.7% (36 studies; 95% CI, 0.4%-1.2%; I2 = 0%) for low-risk T1 CRCs. CONCLUSIONS: Our meta-analysis provides quantitative outcome measures which are relevant to guidelines on surveillance after local endoscopic resection of T1 CRC.

Risk of recurrence after local resection of T1 rectal cancer: a meta-analysis with meta-regression.

BACKGROUND: T1 rectal cancer (RC) patients are increasingly being treated by local resection alone but uniform surveillance strategies thereafter are lacking. To determine whether different local resection techniques influence the risk of recurrence and cancer-related mortality, a meta-analysis was performed. METHODS: A systematic search was conducted for T1RC patients treated with local surgical resection. The primary outcome was the risk of RC recurrence and RC-related mortality. Pooled estimates were calculated using mixed-effect logistic regression. We also systematically searched and evaluated endoscopically treated T1RC patients in a similar manner. RESULTS: In 2585 unique T1RC patients (86 studies) undergoing local surgical resection, the overall pooled cumulative incidence of recurrence was 9.1% (302 events, 95% CI 7.3-11.4%; I2 = 68.3%). In meta-regression, the recurrence risk was associated with histological risk status (p < 0.005; low-risk 6.6%, 95% CI 4.4-9.7% vs. high-risk 28.2%, 95% CI 19-39.7%) and local surgical resection technique (p < 0.005; TEM/TAMIS 7.7%, 95% CI 5.3-11.0% vs. other local surgical excisions 10.8%, 95% CI 6.7-16.8%). In 641 unique T1RC patients treated with flexible endoscopic excision (16 studies), the risk of recurrence (7.7%, 95% CI 5.2-11.2%), cancer-related mortality (2.3%, 95% CI 1.1-4.9), and cancer-related mortality among patients with recurrence (30.0%, 95% CI 14.7-49.4%) were comparable to outcomes after TEM/TAMIS (risk of recurrence 7.7%, 95% CI 5.3-11.0%, cancer-related mortality 2.8%, 95% CI 1.2-6.2% and among patients with recurrence 35.6%, 95% CI 21.9-51.2%). CONCLUSIONS: Patients with T1 rectal cancer may have a significantly lower recurrence risk after TEM/TAMIS compared to other local surgical resection techniques. After TEM/TAMIS and endoscopic resection the recurrence risk, cancer-related mortality and cancer-related mortality among patients with recurrence were comparable. Recurrence was mainly dependent on histological risk status.

Long noncoding RNA CCAT2 promotes hepatocellular carcinoma proliferation and metastasis through up-regulation of NDRG1.

BACKGROUND: Emerging studies demonstrate that long noncoding RNAs (lncRNAs) play crucial roles in hepatocarcinogenesis through various mechanisms. LncRNA CCAT2 was a newly discovered lncRNA and amplified in several cancers. However, the mechanisms involved in function of CCAT2 in hepatocellular carcinoma (HCC) remain to be explored. METHODS: CCAT2 expressions in HCC tissues and cell lines were measured by RT-qPCR. MTS assay, colony formation assay, wound-healing assay and transwell assay were used to explore the biological functions of CCAT2 on HCC cells proliferation and metastasis. Experiments in vivo were carried out to confirm these effects. The underlying mechanisms were analyzed by western blot and dual-luciferase reporter assay. RESULTS: In this study, we found that CCAT2 were significantly elevated in HCC tissues and cell lines, and it promoted HCC cells proliferation and metastasis both in vitro and in vivo. Additionally, we identified that NDRG1 was a downstream target of CCAT2. Meanwhile, depletion of CCAT2 inhibited cellular proliferation and metastasis behaviors induced by NDRG1- overexpression. Analysis of mechanism underlying these effects revealed that CCAT2 increased the expression of NDRG1 by enhancing its promoter activity. Furthermore, the active region between CCAT2 and NDRG1 promoter was confirmed by dual-luciferase reporter assay. CONCLUSIONS: All these observations demonstrate that CCAT2 acts as an oncogene by up-regulating NDRG1, which may have the potential to be used as a promising prognostic biomarker and therapeutic target for HCC.

LINC00628 suppresses migration and invasion of hepatocellular carcinoma by its conserved region interacting with the promoter of VEGFA.

Accumulated evidence revealed that numerous long noncoding RNAs (lncRNAs) have been found to be involved in the development and progression of hepatocellular carcinoma (HCC). LINC00628, a member of lncRNAs, has been reported to act as a tumor suppressor in gastric cancer and breast cancer. However, its potential role in HCC still remains unknown. Herein, we characterized the function of LINC00628 in HCC. Our investigation has revealed that LINC00628 were dramatically decreased in HCC tissues and cells, and inhibited the migration and invasion of HCC cells in vitro and in vivo. Moreover, LINC00628 exerted its tumor suppressive function by repressing the vascular endothelial growth factor A (VEGFA) promoter activity. A highly conserved region element in LINC00628 was identified by a cross-species comparative analysis, which is required for LINC00628 exerted its function. Dual-luciferase reporter assay showed that the conserved sequence mediated the interaction with a specific region of VEGFA promoter, resulting in a decrease of VEGFA expression. In conclusion, our results demonstrated that LINC00628 could function as a tumor suppressor in HCC via its conserved sequence elements interacting with a particular region of VEGFA promoter, suggesting that LINC00628 may serve as a novel promising target for diagnosis and therapy in HCC.

Quality of life and fear of cancer recurrence in T1 colorectal cancer patients treated with endoscopic or surgical tumor resection.

BACKGROUND AND AIMS: To optimize therapeutic decision-making in early invasive colorectal cancer (T1 CRC) patients, it is important to elicit the patient's perspective next to considering medical outcome. Because empirical data on patient-reported impact of different treatment options are lacking, we evaluated patients' quality of life, perceived time to recovery, and fear of cancer recurrence after endoscopic or surgical treatment for T1 CRC. METHODS: In this cross-sectional study, we selected patients with histologically confirmed T1 CRC who participated in the Dutch Bowel Cancer Screening Programme and received endoscopic or surgical treatment between January 2014 and July 2017. Quality of life was measured using the European Organization for Research and Treatment 30-item Core Quality of Life Questionnaire and the 5-level EuroQoL 5-dimension questionnaire. We used the Cancer Worry Scale (CWS) to evaluate patients' fear of cancer recurrence. A question on perceived time to recovery after treatment was also included in the set of questionnaires sent to patients. RESULTS: Of all 119 eligible patients, 92.4% responded to the questionnaire (endoscopy group, 55/62; surgery group, 55/57). Compared with the surgery group, perceived time to recovery was on average 3 months shorter in endoscopically treated patients after adjustment for confounders (19.9 days vs 111.3 days; P = .001). The 2 treatment groups were comparable with regard to global quality of life, functioning domains, and symptom severity scores. Moreover, patients in the endoscopy group did not report more fear of cancer recurrence than those in the surgery group (CWS score, 0-40; endoscopy 7.6 vs surgery 9.7; P = .140). CONCLUSIONS: From the patient's perspective, endoscopic treatment provides a quicker recovery than surgery, without provoking more fear of cancer recurrence or any deterioration in quality of life. These results contribute to the shared therapeutic decision-making process of clinicians and T1 CRC patients.

[Correlations of 18F-Fluorodeoxyglucose Positron Emission Tomography/Magnetic Resonance Imaging Parameters with the Pathological Differentiation of Head and Neck Squamous Cell Carcinoma and Their Diagnostic Efficiencies].

Objective To evaluate the correlation of the positron emission tomography/magnetic resonance imaging (PET/MR) parameters with the pathological differentiation of head and neck squamous cell carcinoma(HNSCC) and the diagnostic efficiencies of PET/MR parameters. Methods Patients with clinical suspicion of HNSCC were included and underwent PET/MR scan. HNSCC was pathologically confirmed in all these patients. The PET/MR examination included PET and MR sequences of diffusion-weighted imaging (DWI) and T2-and T1-weighted imaging. The multiple parameters of PET/MR included the mean values of apparent diffusion coefficient(ADCmean) and the maximum and mean values of standardized uptake value (SUVmax and SUVmean) were measured and estimated. The correlations of all the parameters and distribution between the different tumor differentiation groups were analyzed. Logistic regression was utilized to build the model as the PET/MR combined parameter for predicting the differentiation by multiple parameters of PET/MR. The receiver operating characteristic curve was calculated for each parameter and the combination. Results Totally 23 patients were included in this study:9 patients (9 males and 0 female) had well-differentiated tumor,with an average age of (61.0±6.8)years;14 cases had moderately-differentiated (n=10) or poorly-differentiated tumors (n=4),with an average age of (62.0±9.1) years. All the patients were males. There was statistical correlation between SUVmean and SUVmax (P<0.001);however,ADCmean showed no statistical correlation with SUVmax and with SUVmean (P=0.42,P=0.13). ADCmean and SUVmean showed significant difference between well-differentiated group and moderately-poorly-differentiated group (P=0.005,P=0.007). Compared with the individual parameters,the combination of PET/MR parameters with SUVmean and ADCmean had higher efficacy in predicting tumor differentiation,with an area under curve of 0.84. Conclusions The distributions of ADCmean,SUVmax and SUVmean differ among HNSCC with different pathological differentiation. Compared with the individual parameters,the combination of the PET/MR parameters has higher efficiency in predicting tumor differentiation.

Elemental Mercury Oxidation over Fe-Ti-Mn Spinel: Performance, Mechanism, and Reaction Kinetics.

The design of a high-performance catalyst for Hg0 oxidation and predicting the extent of Hg0 oxidation are both extremely limited due to the uncertainties of the reaction mechanism and the reaction kinetics. In this work, Fe-Ti-Mn spinel was developed as a high-performance catalyst for Hg0 oxidation, and the reaction mechanism and the reaction kinetics of Hg0 oxidation over Fe-Ti-Mn spinel were studied. The reaction orders of Hg0 oxidation over Fe-Ti-Mn spinel with respect to gaseous Hg0 concentration and gaseous HCl concentration were approximately 1 and 0, respectively. Therefore, Hg0 oxidation over Fe-Ti-Mn spinel mainly followed the Eley-Rideal mechanism (i.e., the reaction of gaseous Hg0 with adsorbed HCl), and the rate of Hg0 oxidation mainly depended on Cl• concentration on the surface. As H2O, SO2, and NO not only inhibited Cl• formation on the surface but also interfered with the interface reaction between gaseous Hg0 and Cl• on the surface, Hg0 oxidation over Fe-Ti-Mn spinel was obviously inhibited in the presence of H2O, SO2, and NO. Furthermore, the extent of Hg0 oxidation over Fe-Ti-Mn spinel can be predicted according to the kinetic parameter kE-R, and the predicted result was consistent with the experimental result.

Recyclable Naturally Derived Magnetic Pyrrhotite for Elemental Mercury Recovery from Flue Gas.

Magnetic pyrrhotite, derived from the thermal treatment of natural pyrite, was developed as a recyclable sorbent to recover elemental mercury (Hg0) from the flue gas as a cobenefit of wet electrostatic precipitators (WESP). The performance of naturally derived pyrrhotite for Hg0 capture from the flue gas was much better than those of other reported magnetic sorbents, for example Mn-Fe spinel and Mn-Fe-Ti spinel. The rate of pyrrhotite for gaseous Hg0 capture at 60 °C was 0.28 µg g min-1 and its capacity was 0.22 mg g-1 with the breakthrough threshold of 4%. After the magnetic separation from the mixture collected by the WESP, the spent pyrrhotite can be thermally regenerated for recycle. The experiment of 5 cycles of Hg0 capture and regeneration demonstrated that both the adsorption efficiency and the magnetization were not notably degraded. Meanwhile, the ultralow concentration of gaseous Hg0 in the flue gas was concentrated to high concentrations of gaseous Hg0 and Hg2+ during the regeneration process, which facilitated the centralized control of mercury pollution. Therefore, the control of Hg0 emission from coal-fired plants by the recyclable pyrrhotite was cost-effective and did not have secondary pollution.

LX loaded nanoliposomes synthesis, characterization and cellular uptake studies in H2O2 stressed SH-SY5Y cells.

In this study, we report the cellular uptake studies of novel LX loaded nanoliposomes in H2O2 stress SH-SY5Y Cells synthesized by thin film evaporation method. We have isolated the smallest size nanoliposomes after 90 min ultrasonification, keeping Polydisperse Index as 0.259. The morphology, size, zepta potential and drug efficiency of prepared nanoliposomes are characterized by using Transmission Electron Microscope (TEM), particle size analyzer and High Pressure Liquid Chromatography (HPLC). The particle size analyzer have confirmed the particle size of nanoluposomes measured in range of 100-250 nm, whereas the shape of these nanoliposomes is almost spherical. The zeta potential of small size nanoliposomes was measured as -49.62 and encapsulation efficiency of the LX loaded nanoliposomes was 87%. The oxidative stress response in SH-SY5Y Cells for various doses of drug with and without nanoliposomes has affectively improved the cell-stress response up to 20% after 24 h of incubation at 37 degrees C. The results indicated that LX loaded nanoliposomes were taken by the cells effectively which ultimately improved the cell-stress response. Thus, this study confirmed that synthesized nanoliposomes are not only effective drug carriers but could be potentially used for delivery of genes, antibodies, and proteins in future.

Management after non-curative endoscopic resection of T1 rectal cancer.

Since the introduction of population-based screening, increasing numbers of T1 rectal cancers are detected and removed by local endoscopic resection. Patients can be cured with endoscopic resection alone, but there is a possibility of residual tumor cells remaining after the initial resection. These can be located intraluminally at the resection site or extraluminally in the form of (lymph node) metastases. To decrease the risk of residual cells progressing towards more advanced disease, additional treatment is usually needed. However, with the currently available risk stratification models, it remains challenging to determine who should and should not be further treated after non-curative endoscopic resection. In this review, the different management strategies for patients with non-curatively treated T1 rectal cancers are discussed, along with the available evidence for each strategy and relevant considerations for clinical decision making. Furthermore, we provide practical guidance on the management and surveillance following non-curative endoscopic resection of T1 rectal cancer.

Application and Development Prospect of Nanoscale Iron Based Metal-Organic Frameworks in Biomedicine.

Metal-organic frameworks (MOFs) are coordination polymers that comprise metal ions/clusters and organic ligands. MOFs have been extensively employed in different fields (eg, gas adsorption, energy storage, chemical separation, catalysis, and sensing) for their versatility, high porosity, and adjustable geometry. To be specific, Fe2+/Fe3+ exhibits unique redox chemistry, photochemical and electrical properties, as well as catalytic activity. Fe-based MOFs have been widely investigated in numerous biomedical fields over the past few years. In this study, the key index requirements of Fe-MOF materials in the biomedical field are summarized, and a conclusion is drawn in terms of the latest application progress, development prospects, and future challenges of Fe-based MOFs as drug delivery systems, antibacterial therapeutics, biocatalysts, imaging agents, and biosensors in the biomedical field.

Endoscopic adventitial dissection of a rectal GI stromal cell tumor.

Video 1Demonstration of endoscopic adventitial dissection.

The role and mechanism of NADPH oxidase in the development and progression of thyroid carcinoma.

Thyroid cancer is the fastest increasing cancer in both men and women and is the most common endocrine cancer. Researchers have gradually intensified their research on the mechanism of thyroid cancer development. Within this realm, Oxidative stress is often believed to play a causal and contributory role in thyroid cancer development. NADPH oxidase is one of the important sources of reactive oxygen species for tumor cell growth and is involved in the biological processes of thyroid tumor cell proliferation, migration, invasion and epithelial-to-mesenchymal transition. However, the mechanism of NADPH oxidase in the pathogenesis of thyroid cancer is still not very clear at present. Clarifying the role and mechanism of NADPH oxidase in the pathogenesis of thyroid cancer will help to develop new strategies for the prevention and treatment of thyroid cancer as early as possible, and improve the survival rates of thyroid tumor patients. This article reviews the research progress on the mechanism of NADPH oxidase in thyroid cancer.

Patient educational videos on T1 colorectal cancer.

Video 1Colorectal cancer: how does it develop and how can you detect it? Video 2A polyp suspected to be colorectal cancer: what now? Video 3Early-stage colon cancer with unfavorable features: what now?

In-silico identification and characterization of O-methyltransferase gene family in peanut (Arachis hypogaea L.) reveals their putative roles in development and stress tolerance.

Cultivated peanut (Arachis hypogaea) is a leading protein and oil-providing crop and food source in many countries. At the same time, it is affected by a number of biotic and abiotic stresses. O-methyltransferases (OMTs) play important roles in secondary metabolism, biotic and abiotic stress tolerance. However, the OMT genes have not been comprehensively analyzed in peanut. In this study, we performed a genome-wide investigation of A. hypogaea OMT genes (AhOMTs). Gene structure, motifs distribution, phylogenetic history, genome collinearity and duplication of AhOMTs were studied in detail. Promoter cis-elements, protein-protein interactions, and micro-RNAs targeting AhOMTs were also predicted. We also comprehensively studied their expression in different tissues and under different stresses. We identified 116 OMT genes in the genome of cultivated peanut. Phylogenetically, AhOMTs were divided into three groups. Tandem and segmental duplication events played a role in the evolution of AhOMTs, and purifying selection pressure drove the duplication process. AhOMT promoters were enriched in several key cis-elements involved in growth and development, hormones, light, and defense-related activities. Micro-RNAs from 12 different families targeted 35 AhOMTs. GO enrichment analysis indicated that AhOMTs are highly enriched in transferase and catalytic activities, cellular metabolic and biosynthesis processes. Transcriptome datasets revealed that AhOMTs possessed varying expression levels in different tissues and under hormones, water, and temperature stress. Expression profiling based on qRT-PCR results also supported the transcriptome results. This study provides the theoretical basis for further work on the biological roles of AhOMT genes for developmental and stress responses.