Survival mechanisms of circulating tumor cells and their implications for cancer treatment.

Metastasis remains the principal trigger for relapse and mortality across diverse cancer types. Circulating tumor cells (CTCs), which originate from the primary tumor or its metastatic sites, traverse the vascular system, serving as precursors in cancer recurrence and metastasis. Nevertheless, before CTCs can establish themselves in the distant parenchyma, they must overcome significant challenges present within the circulatory system, including hydrodynamic shear stress (HSS), oxidative damage, anoikis, and immune surveillance. Recently, there has been a growing body of compelling evidence suggesting that a specific subset of CTCs can persist within the bloodstream, but the precise mechanisms of their survival remain largely elusive. This review aims to present an outline of the survival challenges encountered by CTCs and to summarize the recent advancements in understanding the underlying survival mechanisms, suggesting their implications for cancer treatment.

PKM2 compensates for proteasome dysfunction by mediating the formation of the CHIP-HSP70-BAG3 complex and the aggregation of ubiquitinated proteins.

Protein aggregation and degradation via autophagy (aggrephagy) are major strategies adopted by cells to remove misfolded polypeptides when there is proteasome dysfunction. The functional protein complex consisting of heat shock protein 70 (Hsp70), cochaperone ubiquitin ligase carboxyl-terminal of Hsp70/Hsp90 interacting protein (CHIP), and co-chaperone Bcl-2-associated athanogene 3 (BAG3) has been associated with the activation of protein aggregation. However, data on the mechanisms of action of the complex in the protein degradation remains scant. Here, we report that upon proteasome stress, the M2 isoform of pyruvate kinase (PKM2) promotes the aggregation of ubiquitinated proteins and its knockout or knockdown aggravates the sensitivity of cells to proteasome inhibitors. Besides, following proteasome inhibition, PKM2 promotes the interaction of BAG3 with CHIP and HSP70. Interestingly, re-expression of loss-of-function mutants in PKM2-knockout cells showed that the regulatory function of PKM2 in this progress does not depend on the activity of glycolytic enzymes or protein kinases. Taken together, these findings demonstrate that PKM2 mediates the formation of the CHIP-HSP70-BAG3 protein complex and promotes the aggregation of ubiquitinated misfolded proteins, thus compensating for proteasome stress in cells.

Identification and characterization of inhibitory nanobody against p38δ.

p38δ is a member of p38 mitogen-activated protein kinases (MAPKs) family that displays cell- and tissue-specific expression patterns. Recent studies demonstrate that p38δ is centrally involved in several pathologic events, such as diabetes, neurodegeneration diseases, inflammatory diseases, and cancer, and suggest that it may be a potential target for diagnosis and therapy of specific diseases. A nanobody is a new type of antibody that exhibits high antigen-binding activity, solubility, stability, and easy production. This study utilized phage display to isolate nanobodies specifically against p38δ from a fully synthetic nanobody library. Two of them, nanobodies Nb13-6 and Nb13-1, display high binding activity to p38δ, less cross-reactivity with other p38 MAPKs, and high thermal and pH stabilities. Modeling and docking analysis indicated that Nb13-6 is mostly linked to the activation loop of p38δ. Furthermore, detailed studies revealed that Nb13-6 inhibited the protein kinase activity of p38δ and the growth of cancer cells. Therefore, this study provides p38δ-specific nanobodies that are promisingly exploited for diagnosing and treating p38δ-associated diseases.

Sertraline inhibits stress-induced tumor growth through regulating CD8 + T cell-mediated anti-tumor immunity.

Chronic stress has been reported to be associated with tumor initiation and progression. But the underlying mechanism and the specific role of tumor immunity in this process are still unknown. Herein, we applied the repeated restrain stress model in C57BL/6J mice and found that the tumor growth in stressed mice was accelerated compared with that in control mice. In addition, serotonin, also called 5-hydroxytryptamine (5-HT), in the serum of stressed mice was also elevated. Sertraline, a selective serotonin reuptake inhibitor used in the clinic, can restore the serum 5-HT level in stressed mice and restrain tumor growth. We further explored the distribution of major immune cells, including B lymphocytes cells, T lymphocytes, natural killer cells, dendritic cells, tumor-associated macrophages (TAM) and regulatory T cells (Treg). We found that the infiltration of CD8 + T cells in the tumor microenvironment (TME) decreased significantly in stressed mice. And the extra 5-HT treatment could further decrease the infiltration of CD8 + T cells in the TME. The expression of IFN-γ and Granular enzyme B (GzmB) in CD8 + T cells were also dropped in the stressed mice group, whereas the expression of programmed cell death protein 1 (PD-1) on CD8 + T cells was increased. The T cell deficiency induced by stress can be reversed by sertraline, indicating its promising role in strengthening the efficacy of anti-PDL1/PD-1 immunotherapy. The present study provides new mechanistic insights into the impact of chronic stress on antitumor immunity and implicates a novel combined immunotherapy strategy for cancer patients with chronic stress.

Role of oncogenic KRAS in the prognosis, diagnosis and treatment of colorectal cancer.

Colorectal cancer (CRC) is a heterogeneous disease at the cellular and molecular levels. Kirsten rat sarcoma (KRAS) is a commonly mutated oncogene in CRC, with mutations in approximately 40% of all CRC cases; its mutations result in constitutive activation of the KRAS protein, which acts as a molecular switch to persistently stimulate downstream signaling pathways, including cell proliferation and survival, thereby leading to tumorigenesis. Patients whose CRC harbors KRAS mutations have a dismal prognosis. Currently, KRAS mutation testing is a routine clinical practice before treating metastatic cases, and the approaches developed to detect KRAS mutations have exhibited favorable sensitivity and accuracy. Due to the presence of KRAS mutations, this group of CRC patients requires more precise therapies. However, KRAS was historically thought to be an undruggable target until the development of KRASG12C allele-specific inhibitors. These promising inhibitors may provide novel strategies to treat KRAS-mutant CRC. Here, we provide an overview of the role of KRAS in the prognosis, diagnosis and treatment of CRC.

Casp8 acts through A20 to inhibit PD-L1 expression: The mechanism and its implication in immunotherapy.

Immunotherapy targeting the PD-L1/PD-1 pathway is a novel type of clinical cancer treatment, but only small subsets of patients can benefit from it because of multiple factors. PD-L1/PD-1 expression is a biomarker for predicting the efficacy of anti-PD-L1/PD-1 therapy, which highlights the importance of understanding the regulatory mechanisms of PD-L1 expression in cancer cells. Casp8 is an apical caspase protease involved in mediating cell apoptosis, but it also has multiple nonapoptotic functions. Casp8 mutations are associated with increased risks of cancer, and low expression of Casp8 is closely connected with poor prognosis in patients with cancer. In addition, mutations of Casp8 in lymphocytes also lead to human immunodeficiency, thereby causing dysfunction of the innate immune system, but the roles of Casp8 in antitumor immunity remain unclear. Here, we found that knocking down Casp8 in mouse melanoma cells promoted tumor progression in an immune system-dependent manner. Mechanistically, Casp8 induced PD-L1 degradation by upregulating TNFAIP3 (A20) expression, a ubiquitin-editing enzyme that results in PD-L1 ubiquitination. In addition, compared with Casp8fl/fl mice, mice with conditional deletion of Casp8 in natural killer (NK) cells (Ncr1iCre/+ Casp8fl/fl mice) showed a decreased frequency of IFN-γ+ and CD107a+ NK cells but an increased frequency of PD-1+ and CTLA-4+ NK cells. Melanoma cells with Casp8 knocked down exhibited sensitivity to anti-PD-1 or anti-CTLA-4 antibody treatments, particularly in Ncr1iCre/+Casp8fl/fl mice. Together, the results indicate that Casp8 induces PD-L1 degradation by upregulating A20 expression and that decreased Casp8 expression is a potential biomarker for predicting the sensitivity to anti-PD-L1/PD-1 immunotherapy.

An epithelial-mesenchymal transition-related 5-gene signature predicting the prognosis of hepatocellular carcinoma patients.

BACKGROUND: Tumor metastasis is one of the leading reasons of the dismal prognosis of hepatocellular carcinoma (HCC). Epithelial-mesenchymal transition (EMT) is closely associated with tumor metastasis including HCC. The purpose of this study is to construct and validate an EMT-related gene signature for predicting the prognosis of HCC patients. METHODS: Gene expression data of HCC patients was downloaded from The Cancer Genome Atlas (TCGA) database. Gene set enrichment analysis (GSEA) was performed to found the EMT-related gene sets which were obviously distinct between normal samples and paired HCC samples. Cox regression analysis was used to develop an EMT-related prognostic signature, and the performance of the signature was evaluated by Kaplan-Meier curves and time-dependent receiver operating characteristic (ROC) curves. A nomogram incorporating the independent predictors was established. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression levels of the hub genes in HCC cell lines, and the role of PDCD6 in the metastasis of HCC was determined by functional experiments. RESULTS: An EMT-related 5-gene signature (PDCD6, TCOF1, TRIM28, EZH2 and FAM83D) was constructed using univariate and multivariate Cox regression analysis. Based on the signature, the HCC patients were classified into high- and low-risk groups, and patients in high-risk group had a poor prognosis. Time-dependent ROC and Cox regression analyses suggested that the signature could predict HCC prognosis exactly and independently. The predictive capacity of the signature was also validated in two external cohorts. GSEA results showed that many cancer-related signaling pathways such as PI3K/Akt/mTOR pathway and TGF-ß/SMAD pathway were enriched in high-risk group. The result of qRT-PCR revealed that PDCD6, TCOF1 and FAM83D were highly expressed in HCC cancer cells. Among them, PDCD6 were found to promote cell migration and invasion. CONCLUSION: The EMT-related 5-gene signature can serve as a promising prognostic biomarker for HCC patients and may provide a novel mechanism of HCC metastasis.

The selective serotonin reuptake inhibitors enhance the cytotoxicity of sorafenib in hepatocellular carcinoma cells.

Sertraline and fluoxetine are the two most commonly used selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression. Accumulating evidence has revealed that SSRIs can reduce the risk of hepatocellular carcinoma (HCC), but their therapeutic effects in HCC have not yet been elucidated. Previous studies have reported that sertraline and fluoxetine can suppress the growth of gastric carcinoma, melanoma and nonsmall cell lung cancers by inhibiting the mammalian target rapamycin (mTOR) activity. In this study, we found that sertraline and fluoxetine blocked the protein kinase B (AKT)/mTOR pathway and suppressed the growth of HCC cells in vitro, in xenografts and in diethylnitrosamine/carbon tetrachloride (DEN/CCL4)-induced primary liver mouse model. Sertraline and fluoxetine can synergize with sorafenib, the first approved standard therapy for advanced HCC, to inhibit the viability of HCC cells in vitro and in vivo. In addition, the combination of sorafenib and SSRIs synergistically inhibited the effects of the AKT/mTOR pathway. These results reveal novel therapeutic effects of a combination of SSRIs and sorafenib in HCC.

Effect of lead exposure from electronic waste on haemoglobin synthesis in children.

BACKGROUND: Primitive electronic waste (e-waste) recycling is ongoing in Guiyu, so toxic heavy metals may continue to threaten the health of children in the area. OBJECTIVE: This study primarily aimed to evaluate the effect of e-waste exposure on haemoglobin (Hb) synthesis in preschool children. METHODS: Medical examinations were conducted with the permission of children's guardians and the approval of the Ethics Committee of the Medical College of Shantou University. This study recruited 224 children (aged 3-6 years, exposed group) who lived in Guiyu and 204 children (aged 3-6 years, control group) who lived in a town free of e-waste pollution. Blood levels of lead, Hb, ferritin, folate and vitamin B12 were tested in all children. Furthermore, all children were assessed for thalassemia, and their parents were asked to fill in questionnaires. RESULTS: There were no significant differences in the level of ferritin, folate, or vitamin B12 between the exposed and control groups (P > 0.05). No children were identified as having thalassemia in all study participants. Blood lead level (BLL) and the risk of children with BLL ≥ 10 µg/dL in the exposed group were significantly higher than those in the control group (all P < 0.01). Three subgroups of each group were created according to BLL (Group A: < 5.0 µg/dL; Group B: 5.0-9.9 µg/dL; Group C: ≥ 10.0 µg/dL). Hb level decreased with elevated BLL in the exposed group (P = 0.03), but not in the control group (P = 0.14). Hb levels in group B and group C were also significantly lower in the exposed group than in the control group (Group B: 122.6 ± 9.5 g/L versus 125.8 ± 8.2 g/L, P = 0.01; Group C: 120.3 ± 7.3 g/L versus 123.6 ± 8.3 g/L, P = 0.03). In addition, the prevalence of anaemia associated with BLLs above 10 µg/dL and between 5.0 and 9.9 µg/dL were both significantly higher in the exposed group than in the control group (4.0% vs. 0.5%, 5.4% vs. 1.5%, respectively, both P < 0.05). CONCLUSION: Lead exposure more significantly inhibits Hb synthesis in children who live in e-waste dismantling areas than in those who live in non-e-waste dismantling areas. Other toxins released from e-waste may also contribute to the inhibition of Hb synthesis and may lead to anaemia in local children. Further investigations are needed to provide evidence for the development of relevant protective measures.

[Comprehensive analysis of the aberrantly expressed profiles of lncRNAs, miRNAs and the regulation network of the associated ceRNAs in clear cell renal cell carcinoma].

To evaluate the differential expression profiles of the lncRNAs, miRNAs, mRNAs and ceRNAs, and their implication in the prognosis in clear cell renal cell carcinoma (CCRCC), the large sample genomics analysis technologies were used in this study. The RNA and miRNA sequencing data of CCRCC were obtained from The Cancer Genome Atlas (TCGA) database, and R software was used for gene expression analysis and survival analysis. Cytoscape software was used to construct the ceRNA network. The results showed that a total of 1 570 lncRNAs, 54 miRNAs, and 17 mRNAs were differentially expressed in CCRCC, and most of their expression levels were up-regulated (false discovery rate < 0.01 and absolute log fold change > 2). The ceRNA regulatory network showed the interaction between 89 differentially expressed lncRNAs and 9 differentially expressed miRNAs. Further survival analysis revealed that 38 lncRNAs (including COL18A1-AS1, TCL6, LINC00475, UCA1, WT1-AS, HOTTIP, PVT1, etc.) and 2 miRNAs (including miR-21 and miR-155) were correlated with the overall survival time of CCRCC ( P < 0.05). Together, this study provided us several new evidences for the targeted therapy and prognosis assessment of CCRCC.

[A ß-catenin/IQGAP1 regulatory feedback loop and its effects on the proliferation of colon cancer cells].

The aim of this article is to study the regulatory feedback loop between ß-catenin and IQ motif containing GTPase activating protein 1 (IQGAP1), as well as the effect of this regulation loop in colon cancer cell proliferation. Western blot was used to detect the expression of IQGAP1 and ß-catenin after changing their expression respectively by transfection in SW1116 cells. CCK-8 cell proliferation assay was used to detect the effect of IQGAP1 involved in the proliferation of SW1116 cells promoted by ß-catenin. The results of Western blot indicated that ß-catenin could positively regulate IQGAP1, while IQGAP1 silencing could up-regulate ß-catenin, forming a negative feedback loop. The results of CCK-8 showed that IQGAP1 silencing inhibited ß-catenin-mediated proliferation in SW1116 cells. In conclusion, our research reveals a negative regulatory feedback loop between ß-catenin and IQGAP1 which has a remarkable effect on the proliferation ability of colon cancer cells.

Quantitative assessment of atrial regional function using motion estimation computed tomography.

OBJECTIVES: We validated a novel image-based motion estimation computed tomographic (CT) technique (iME) to quantify atrial regional function in swine in vivo. MATERIALS AND METHODS: Domestic swine (n = 8) underwent CT scan with intravenous contrast before and after median sternotomy where 15 to 30 glass beads were sutured to the atria to calculate the motion estimation error. Four-dimensional motion vector field was estimated using iME. Area change ratio (%AC) was calculated over the atrial endocardium to assess the surface deformation. RESULTS: The error between the measured and the calculated coordinates based on motion vector field was 0.76 ± 0.43 mm. The %AC was regionally heterogeneous. The %AC time course was significantly different between the right and the left atriums (P < 0.001) as well as between the right atrial appendage and the right atrial chamber (P = 0.004). CONCLUSIONS: Quantitative assessment of atrial regional function using iME is highly accurate. Image-based motion estimation computed tomographic (CT) technique can quantify subtle regional dysfunction that is not apparent in global functional indices such as ejection fraction.

Targeting RAF dimers in RAS mutant tumors: From biology to clinic.

RAS mutations occur in approximately 30% of tumors worldwide and have a poor prognosis due to limited therapies. Covalent targeting of KRAS G12C has achieved significant success in recent years, but there is still a lack of efficient therapeutic approaches for tumors with non-G12C KRAS mutations. A highly promising approach is to target the MAPK pathway downstream of RAS, with a particular focus on RAF kinases. First-generation RAF inhibitors have been authorized to treat BRAF mutant tumors for over a decade. However, their use in RAS-mutated tumors is not recommended due to the paradoxical ERK activation mainly caused by RAF dimerization. To address the issue of RAF dimerization, type II RAF inhibitors have emerged as leading candidates. Recent clinical studies have shown the initial effectiveness of these agents against RAS mutant tumors. Promisingly, type II RAF inhibitors in combination with MEK or ERK inhibitors have demonstrated impressive efficacy in RAS mutant tumors. This review aims to clarify the importance of RAF dimerization in cellular signaling and resistance to treatment in tumors with RAS mutations, as well as recent progress in therapeutic approaches to address the problem of RAF dimerization in RAS mutant tumors.

Endogenous Coriobacteriaceae enriched by a high-fat diet promotes colorectal tumorigenesis through the CPT1A-ERK axis.

A high-fat diet (HFD) may be linked to an increased colorectal cancer (CRC) risk. Stem cell proliferation and adipokine release under inflammatory and obese conditions are the main factors regulating CRC progression. Furthermore, alterations in intestinal flora have been linked to tumorigenesis and tumour progression. However, whether a HFD can promote CRC occurrence by altering intestinal flora remains unclear. The objective of this study was to identify bacterial strains enriched by a HFD and investigate the association and mechanism by which a HFD and bacterial enrichment promote CRC occurrence and development. In this study, the intestinal microbiota of mice was assessed using 16S rRNA and metagenomic sequencing. Serum metabolites of HFD-fed mice were assessed using tandem liquid chromatography-mass spectrometry. CRC cell lines and organoids were co-cultured with Coriobacteriaceae to evaluate the effect of these bacteria on the CPT1A-ERK signalling pathway. We found that Coriobacteriaceae were enriched in the colons of HFD-fed mice. An endogenous Coriobacteriaceae strain, designated as Cori.ST1911, was successfully isolated and cultured from the stools of HFD-fed mice, and the tumorigenic potential of Cori.ST1911 in CRC was validated in several CRC mouse models. Furthermore, Cori.ST1911 increased acylcarnitine levels by activating CPT1A, demonstrating the involvement of the CPT1A-ERK axis. We also found that the endogenous Lactobacillus strain La.mu730 can interfere with Cori.ST1911 colonisation and restore gut barrier function. In conclusion, we identified a novel endogenous intestinal Coriobacteriaceae, Cori.ST1911, which might lead to a new gut microbiota intervention strategy for the prevention and treatment of CRC.

Targeting the MHC-I endosomal-lysosomal trafficking pathway in cancer: From mechanism to immunotherapy.

Immune checkpoint blockade (ICB) therapy has achieved broad applicability and durable clinical responses across cancer types. However, the overall response rate remains suboptimal because some patients do not respond or develop drug resistance. The low infiltration of CD8+ cytotoxic T cells (CTLs) in the tumor microenvironment due to insufficient antigen presentation is closely related to the innate resistance to ICB. The duration and spatial distribution of major histocompatibility complex class I (MHC-I) expression on the cell surface is critical for the efficient presentation of endogenous tumor antigens and subsequent recognition and clearance by CTLs. Tumor cells reduce the surface expression of MHC-I via multiple mechanisms to impair antigen presentation pathways and evade immunity and/or develop resistance to ICB therapy. As an increasing number of studies have focused on membrane MHC-I trafficking and degradation in tumor cells, which may impact the effectiveness of tumor immunotherapy. It is necessary to summarize the mechanism regulating membrane MHC-I translocation into the cytoplasm and degradation via the lysosome. We reviewed recent advances in the understanding of endosomal-lysosomal MHC-I transport and highlighted the means exploited by tumor cells to evade detection and clearance by CTLs. We also summarized new therapeutic strategies targeting these pathways to enhance classical ICB treatment and provide new avenues for optimizing cancer immunotherapy.

[The effect of eukaryotic expression plasmid ARHI on gastric cancer].

OBJECTIVE: To study the effect of expressed aplasia ras homolog member I (ARHI) on the malignant biological behaviors of gastric cancer including the proliferation, migration and invasion of the cell. METHODS: The eukaryotic expression plasmid of ARHI was constructed and transfected into MKN-28 cell with lipofectamine 2000 as pEGFP-ARHI group, transfected with pEGFP-N1 as pEGFP-N1 group, and untreated MKN-28 as control group. The expression of ARHI was detected by Western blotting and fluorescence microscope. CCK-8 assay was used to analyze the cell proliferation, the wound-healing assay and transwell assay were performed to investigate the effects on migration and invasion. RESULTS: Compared with the pEGFP-N1 group and control group, proliferation, invasion and migration of the pEGFP-ARHI group were depressed (P < 0.05). CONCLUSION: Recombination eukaryotic expression pEGFP-ARHI could partially reverse the malignant phenotypes of gastric cancer cell MKN-28.

The micro and macro interactions in acute autoimmune encephalitis: a study of resting-state EEG.

Objective: Early recognition of autoimmune encephalitis (AIE) is often difficult and time-consuming. Understanding how the micro-level (antibodies) and macro-level (EEG) couple with each other may help rapidly diagnose and appropriately treat AIE. However, limited studies focused on brain oscillations involving micro- and macro-interactions in AIE from a neuro-electrophysiological perspective. Here, we investigated brain network oscillations in AIE using Graph theoretical analysis of resting state EEG. Methods: AIE Patients (n = 67) were enrolled from June 2018 to June 2022. Each participant underwent a ca.2-hour 19-channel EEG examination. Five 10-second resting state EEG epochs with eyes closed were extracted for each participant. The functional networks based on the channels and Graph theory analysis were carried out. Results: Compared with the HC group, significantly decreased FC across whole brain regions at alpha and beta bands were found in AIE patients. In addition, the local efficiency and clustering coefficient of the delta band was higher in AIE patients than in the HC group (P < 0.05). AIE patients had a smaller world index (P < 0.05) and higher shortest path length (P < 0.001) in the alpha band than those of the control group. Also, the AIE patients' global efficiency, local efficiency, and clustering coefficients decreased in the alpha band (P < 0.001). Different types of antibodies (antibodies against ion channels, antibodies against synaptic excitatory receptors, antibodies against synaptic inhibitory receptors, and multiple antibodies positive) showed distinct graph parameters. Moreover, the graph parameters differed in the subgroups by intracranial pressure. Correlation analysis revealed that magnetic resonance imaging abnormalities were related to global efficiency, local efficiency, and clustering coefficients in the theta, alpha, and beta bands, but negatively related to the shortest path length. Conclusion: These findings add to our understanding of how brain FC and graph parameters change and how the micro- (antibodies) scales interact with the macro- (scalp EEG) scale in acute AIE. The clinical traits and subtypes of AIE may be suggested by graph properties. Further longitudinal cohort studies are needed to explore the associations between these graph parameters and recovery status, and their possible applications in AIE rehabilitation.

A fully four-dimensional, iterative motion estimation and compensation method for cardiac CT.

PURPOSE: To develop a new fully four-dimensional (4D), iterative image reconstruction algorithm for cardiac CT that alternates the following two methods: estimation of a time-dependent motion vector field (MVF) of the heart from image data and reconstruction of images using the estimated MVF and projection data. METHODS: Volumetric image data at different cardiac phase points were obtained using electrocardiogram-gated CT. Motion estimation (ME) and motion-compensated image reconstruction (MCR) were performed alternately until convergence was achieved. The ME method estimated the cardiac MVF using 4D nonrigid image registration between a cardiac reference phase and all the other phases. The nonrigid deformation of the heart was modeled using cubic B-splines. The cost function consisted of a sum of squared weighted differences and spatial and temporal regularization terms. A nested conjugate gradient optimization algorithm was applied to minimize the cost function and estimate the MVFs. Cardiac images were reconstructed using a motion-tracking algorithm that utilized the MVFs estimated by the ME method. The reconstructed images supplied the input to the ME of the next iteration. The performance of the proposed method was evaluated using four patient data sets acquired with a 64-slice CT scanner. The heart rates of the patients ranged from 52 to 71 beats/min. RESULTS: Motion artifacts were significantly reduced, and the image quality increased with the number of iterations. Without MCR, the right coronary artery (RCA) was deformed into an arc in axial images of rapid phases. With the proposed method the RCA appeared sharper and was reconstructed similar in shape to the reconstruction at the quiescent phase at mid-diastole. The boundary between the interventricular septum and the right ventricle was also clearer and sharper using the proposed algorithm. The steepness of the transition range at a rapid phase (35% R-R) was increased from 6.8 HU∕pixel to 11.5 HU∕pixel. The ME-MCR algorithm converged in just four iterations. CONCLUSION: We developed a fully 4D image reconstruction method that alternates ME and MCR algorithms in an iterative fashion. Performance tests using clinical patient data resulted in reduced motion artifacts.

Chemotherapy and radiotherapy downregulate the activity and expression of DNA methyltransferase and enhance Bcl-2/E1B-19-kDa interacting protein-3-induced apoptosis in human colorectal cancer cells.

Bcl-2/E1B 19-kDa interacting protein 3 (BNIP3) is a proapoptotic protein whose expression level is often low in colorectal cancer (CRC) cells due to the BNIP3 gene promoter DNA methylation by DNA methyltransferase (DNMT). It is known that chemotherapy and radiotherapy suppress CRC through inducing tumor apoptosis. However, the molecular mechanisms underlying chemotherapy and radiotherapy-induced apoptosis of CRC cells are not well defined. In this study, we observed that the expression level of BNIP3 in colon cancer cells was significantly increased by treatment with therapeutic agents and radiation in vitro. The BNIP3 protein level in CRC tissues from patients who received preoperative concurrent chemotherapy was significantly higher than in those who received surgery alone. Furthermore, treatment with chemotherapeutic agents and radiation significantly decreased the DNMT1 expression level and enzymatic activity. Both expression level and activity of DNMT1 were inversely correlated with the expression level of BNIP3 in colon carcinoma cells after treatment with chemotherapeutic agents and radiation. Consistent with increased BNIP3 expression, chemotherapeutic agents and radiation induced colon carcinoma cell apoptosis in a dose-dependent manner. Based on these observations, we conclude that chemotherapy and radiotherapy inhibit DNMT1 expression to upregulate BNIP3 expression to promote CRC cell apoptosis. And, BNIP3 may play a role in the caspase-dependent apoptosis pathways, mainly during treatment with chemotherapy and radiotherapy.

[Corrigendum] miR­200b/c targets the expression of RhoE and inhibits the proliferation and invasion of non­small cell lung cancer cells.

Subsequently to the publication of the above article, an interested reader drew to the authors' attention that the miR­200c and Si­RhoE data panels in Fig. 5B on p. 1739 appeared to contain an overlap of the data, such that the data would have been derived from the same original source where the different panels were intended to show the results from differently performed experiments. The authors have re­examined their data, and realize that these data panels were inadvertently selected incorrectly; specifically, the data panel showing the results of the migration activities of A549 following transfection with Si­RhoE in Fig. 5B was incorporated incorrectly during the process of assembling this figure, and this panel contained the overlap with the miR­200c group. The revised version of Fig. 5, showing all the correct data for Fig. 5B, is presented on the next page. The authors confirm that the errors made in the presentation of Fig. 5 did not adversely affect the conclusions reported in this paper, and they are grateful to the Editor of International Journal of Oncology for granting them this opportunity to publish a Corrigendum. All the authors agree to the publication of this Corrigendum, and they also apologize to the readership for any inconvenience caused. [International Journal of Oncology 53: 1732­1742, 2018; DOI: 10.3892/ijo.2018.4493].