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Background: Breast cancer, one of the most prevalent malignancies among women worldwide, has rising incidence rates. Physical activity, particularly exercise, has emerged as a significant modifier of cancer prognosis, influencing both tumor biology and patient outcomes. Methods: In this study, we utilized a murine breast cancer model, dividing mice into a control group and an exercise group; the latter underwent 21 days of voluntary running. We conducted RNA sequencing, bioinformatics analysis, pan-cancer analysis, and cellular experiments to investigate the underlying mechanisms influenced by exercise. Results: Exercise led to a significant reduction in tumor size and weight. Post-exercise mRNA sequencing indicated a notable upregulation of THSD7B in the exercised mice, with significant alterations observed in pathways such as MicroRNAs in cancers and the Calcium signaling pathway. In a broader cancer context, THSD7B showed considerable expression variability, being significantly downregulated in several cancers, correlating with positive prognostic outcomes in PRAD, LAML, KIRC, and GBM and highlighting its potential role as a prognostic marker and therapeutic target. THSD7B expression was also negatively associated with processes of breast cancer cell proliferation, migration, and invasion. Conclusion: This study underscores the dual role of exercise in modulating gene expression relevant to tumor growth and highlights the potential of THSD7B as a therapeutic target in cancer. Future research should further explore the specific mechanisms by which exercise and THSD7B influence cancer progression and develop immunotherapy-enhanced strategies to change patient outcomes in clinical settings.
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Condicionamento Físico Animal , Animais , Camundongos , Feminino , Prognóstico , Humanos , Regulação Neoplásica da Expressão Gênica , Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Neoplasias da Mama/imunologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Proliferação de Células , Linhagem Celular Tumoral , Biomarcadores Tumorais/genéticaRESUMO
N6-Methyladenosine (m6A) is a important process regulating gene expression post-transcriptionally. Programmed death ligand 1 (PD-L1) is a major immune inhibitive checkpoint that facilitates immune evasion and is expressed in tumor cells. In this research we discovered that Wilms' tumor 1-associated protein (WTAP) degradation caused by ubiquitin-mediated cleavage in cancer cells (colorectal cancer, CRC) under hypoxia was inhibited by Pumilio homolog 1 (PUM1) directly bound to WTAP. WTAP enhanced PD-L1 expression in a way that was m6A-dependent. m6A "reader," Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) identified methylated PD-L1 transcripts and subsequently fixed its mRNA. Additionally, we found that T-cell proliferation and its cancer cell-killing effects were prevented by overexpression of WTAP in vitro and in vivo. Overexpression prevented T cells from proliferating and killing CRC by maintaining the expression of PD-L1. Further evidence supporting the WTAP-PD-L1 regulatory axis was found in human CRC and organoid tissues. Tumors with high WTAP levels appeared more responsive to anti-PD1 immunotherapy, when analyzing samples from patients undergoing treatment. Overall, our findings demonstrated a novel PD-L1 regulatory mechanism by WTAP-induced mRNA epigenetic regulation and the possible application of targeting WTAP as immunotherapy for tumor hypoxia.
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Adenosina , Antígeno B7-H1 , Neoplasias Colorretais , Humanos , Adenosina/análogos & derivados , Adenosina/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Animais , Camundongos , Linhagem Celular Tumoral , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Fatores de Processamento de RNA/genética , Fatores de Processamento de RNA/metabolismo , Feminino , Hipóxia Tumoral/genética , Proteínas de Ciclo CelularRESUMO
Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS) and multiple types of B cell malignancies. Emerging evidence demonstrates that KSHV reprograms host-cell central carbon metabolic pathways, which contributes to viral persistence and tumorigenesis. However, the mechanisms underlying KSHV-mediated metabolic reprogramming remain poorly understood. Carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase (CAD) is a key enzyme of the de novo pyrimidine synthesis, and was recently identified to deamidate the NF-κB subunit RelA to promote aerobic glycolysis and cell proliferation. Here we report that KSHV infection exploits CAD for nucleotide synthesis and glycolysis. Mechanistically, KSHV vCyclin binds to and hijacks cyclin-dependent kinase CDK6 to phosphorylate Ser-1900 on CAD, thereby activating CAD-mediated pyrimidine synthesis and RelA-deamidation-mediated glycolytic reprogramming. Correspondingly, genetic depletion or pharmacological inhibition of CDK6 and CAD potently impeded KSHV lytic replication and thwarted tumorigenesis of primary effusion lymphoma (PEL) cells in vitro and in vivo. Altogether, our work defines a viral metabolic reprogramming mechanism underpinning KSHV oncogenesis, which may spur the development of new strategies to treat KSHV-associated malignancies and other diseases.
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Herpesvirus Humano 8 , Sarcoma de Kaposi , Humanos , Herpesvirus Humano 8/metabolismo , Glicólise , Carcinogênese , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Nucleotídeos/metabolismoRESUMO
OBJECTIVE: The study aimed to validate the role of 3D-endorectal ultrasonography in prognosis and recurrence for patients with T3-stage rectal cancer by evaluating the preoperative extramural depth of tumor invasion. METHODS: In this study, we investigated the medical records of rectal cancer patients who were admitted to Changhai Hospital's Colorectal Surgery Division. The sample group was categorized into three subgroups (T3a, T3b, and T3c) based on the extent of tumor progression (<5 mm, 5-10 mm, and >10 mm) to assess the endorectal ultrasonography diagnostic performance. The 5-year disease-free survival and overall survival were assessed using the Kaplan-Meier method and a log rank test. Cox regression analysis verified the tumor invasion depth's significance as a prognostic predictor, and it was also utilized to evaluate other independent risk variables for recurrence after surgery. RESULTS: The study included 72 individuals with low and middle rectal cancer from January 2014 to November 2019. Twenty-two individuals had stage T3a, 22 had stage T3b, and 28 had stage T3c based on preoperative endorectal ultrasonography. Endorectal ultrasonography had 88.0%, 86.8%, and 76.2% overall accuracy for stratifying subgroups, respectively. According to the Kaplan-Meier curve, 5-year OS was 100%, 83.5%, and 92.9% for T3a, T3b, and T3c (p = 0.172), and 5-year disease-free survival was 100%, 80.8%, and 72.9% for T3a, T3b, and T3c, respectively (p = 0.014). A distinct risk factor for 5-year disease-free survival was the degree of tumor infiltration (p = 0.039). CONCLUSION: Preoperative T3 stage subdivision allows for categorization of prognosis and survival. Endorectal ultrasonography reports should make explicit declarations of T3a, T3b, and T3c scales.
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Neoplasias Retais , Humanos , Estadiamento de Neoplasias , Prognóstico , Neoplasias Retais/diagnóstico por imagem , Neoplasias Retais/cirurgia , Neoplasias Retais/patologia , UltrassonografiaRESUMO
The chemotherapeutic doxorubicin (DOX) detrimentally impacts the heart during cancer treatment. This necessitates development of non-cardiotoxic delivery systems that retain DOX anticancer efficacy. We used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), endothelial cells (hiPSC-ECs), cardiac fibroblasts (hiPSC-CFs), multi-lineage cardiac spheroids (hiPSC-CSs), patient-specific hiPSCs, and multiple human cancer cell lines to compare the anticancer efficacy and reduced cardiotoxicity of single protein encapsulated DOX (SPEDOX-6), to standard unformulated (UF) DOX. Cell viability assays and immunostaining in human cancer cells, hiPSC-ECs, and hiPSC-CFs revealed robust uptake of SPEDOX-6 and efficacy in killing these proliferative cell types. In contrast, hiPSC-CMs and hiPSC-CSs exhibited substantially lower cytotoxicity during SPEDOX-6 treatment compared with UF DOX. SPEDOX-6-treated hiPSC-CMs and hiPSC-CSs maintained their functionality, as indicated by sarcomere contractility assessment, calcium imaging, multielectrode arrays, and RNA sequencing. This study demonstrates the potential of SPEDOX-6 to alleviate cardiotoxic side effects associated with UF DOX, while maintaining its anticancer potency.
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Células-Tronco Pluripotentes Induzidas , Miócitos Cardíacos , Humanos , Cardiotoxicidade , Células-Tronco Pluripotentes Induzidas/metabolismo , Células Endoteliais , Células Cultivadas , Doxorrubicina/efeitos adversosRESUMO
Background: Colorectal cancer (CRC) is the third most common cancer and the fourth most common cause of cancer-related death worldwide. Advanced stage CRC, during the recent past, had a dismal prognosis and only a few available treatments. Pumilio homologous protein 1 (PUM1) is reportedly aberrant in human malignancies, including CRC. However, the role of PUM1 in the regulation of tumor-initiating cells (T-ICs) remains unknown. Methods: The levels of messenger RNAs (mRNAs) were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunoblot analyses. Statistical analyses were performed to determine the associations between the levels of PUM1 and tumor features and patient outcomes. Whether PUM1 is a downstream target of miR-218-5p was verified by bioinformatics target gene prediction and qRT-PCR. Results: Herein, it was found that T-ICs, chemoresistance, and recurrent CRC samples all manifest increased PUM1 expression. Functional investigations have shown that PUM1 increased the self-renewal, tumorigenicity, malignant proliferation, and chemoresistance of colorectal cells. PUM1 activates the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) signaling pathway biochemically. Furthermore, it was discovered that miR-218-5p specifically targets T-ICs' PUM1 3'-untranslated region (3'-UTR). More importantly, the PUM1/PI3K/AKT axis regulates CRC cells' responses to treatment with cetuximab, and PUM1 overexpression increased cetuximab resistance. More evidence points to the possibility that low PUM1 may predict cetuximab benefits in CRC patients after analysis of the patient cohort, patient-derived tumor organoids, and patient-derived xenografts (PDXs). Conclusions: Taken together, the result of this work points to the critical function of the miR-218-5p/PUM1/PI3K/AKT regulatory circuit in regulating T-ICs characteristics and thus suggests possible therapeutic targets for CRC.
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[This corrects the article DOI: 10.7150/jca.42731.].
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BACKGROUND: Strawberries are an important economic fruit crop world-wide. In strawberry cultivation, continuous cropping (CC) can seriously threaten yield and quality. However, our understanding of the gene expression changes in response to CC and during subsequent defense processes is limited. In this study, we analyzed the impact of CC on the transcriptome of strawberry roots using RNA-Seq technology to elucidate the effect of CC and the subsequent molecular changes. RESULTS: We found that CC significantly affects the growth of strawberry plants. The transcriptome analysis identified 136 differentially expressed genes (DEGs), including 49 up-regulated and 87 down-regulated DEGs. A Gene Ontology (GO) analysis indicated that the up-regulated DEGs were mainly assigned to defense-related GO terms, and most down-regulated DEGs were assigned to nutrient-related GO terms. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that the responsive DEGs were classified in a large number of important biological pathways, such as phenylalanine metabolism, starch and sucrose metabolism, phenylpropanoid biosynthesis, glutathione metabolism and plant-pathogen interaction. We also found that four WRKY transcription factors and three peroxidase genes involved in plant defense pathways were up-regulated in the roots of strawberry plants subjected to CC. CONCLUSION: Several unigenes involved in plant defense processes, such as CNGCs, WRKY transcription factors, PR1, and peroxidase genes with highly variable expression levels between non-CC and CC treatments may be involved in the regulation of CC in strawberry. These results indicate that strawberry roots reallocate development resources to defense mechanisms in response to CC. This study will further deepen our understanding of the fundamental regulatory mechanisms of strawberry resource reallocation in response to CC.
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Fragaria , Fragaria/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Glutationa/metabolismo , Peroxidases/metabolismo , Fenilalanina/genética , Fenilalanina/metabolismo , Amido/metabolismo , Sacarose , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , TranscriptomaRESUMO
Rationale: Triple-negative breast cancer (TNBC) does not respond to anti-estrogen and anti-HER2 therapies and is commonly treated by chemotherapy. TNBC has a high recurrence rate, particularly within the first 3 years. Thus, there is an urgent clinical need to develop more effective therapies for TNBC. Topoisomerase I (TOP1) inhibitors cause DNA damage, making these drugs desirable for TNBC treatment since DNA repair machinery is defective in this subtype of breast cancer. Among the main molecular subtypes of breast cancer, the TNBC cell lines exhibited the highest TOP1 inhibition sensitivity. However, clinically used TOP1 inhibitors, such as topotecan and irinotecan, have shown limited clinical applications and the reasons remain unclear. Understanding the mechanism of differential responses to TOP1 blockade and identifying the predictive markers for cancer cell sensitivity will help further TOP1-targeted therapy for TNBC treatment and improve the clinical use of TOP1 inhibitors. Methods: Viability assays were used to evaluate breast cancer cell sensitivity to topotecan and other TOP1 inhibitors as well as TOP2 inhibitors. An in vitro-derived topotecan-resistant TNBC cell model and TNBC xenograft models were employed to confirm cancer cell response to TOP1 blockade. RNA-seq was used to identify potential predictive markers for TNBC cell response to TOP1 blockade. Western blotting and qRT-PCR were performed to measure the protein levels and RNA expression. ATAC-seq and luciferase reporter assays were used to examine MYC transcriptional regulations. The effects of MYC and JNK in cancer cell response to TOP1 inhibition were validated via loss-of-function and gain-of-function experiments. Results: We observed two distinct and diverging cancer cell responses - sensitive versus resistant to TOP1 inhibition, which was confirmed by TNBC xenograft mouse models treated by topotecan. TNBC cells exhibited bifurcated temporal patterns of ATR pathway activation upon TOP1 inhibitor treatment. The sensitive TNBC cells showed an "up then down" dynamic pattern of ATR/Chk1 signaling, while the resistant TNBC cells exhibited a "persistently up" profile. On the contrary, opposite temporal patterns of induced expression of MYC, a key regulator and effector of DNA damage, were found in TNBC cells treated by TOP1 inhibitors. Mechanistically, we showed that TOP1-induced JNK signaling upregulated MYC expression. Furthermore, pharmacological inhibition of ATR reversed TNBC cell resistance to topotecan, whereas MYC knockdown and JNK inhibition reduced cancer cell sensitivity. Conclusions: Dynamic temporal profiles of induced ATR/Chk1 and JNK activation as well as MYC expression, may predict cancer cell response to TOP1 inhibitors. JNK activation-mediated constitutive elevation of MYC expression may represent a novel mechanism governing cancer cell sensitivity to TOP1-targeting therapy. Our results may provide implications for identifying TNBC patients who might benefit from the treatment with TOP1 inhibitors.
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DNA Topoisomerases Tipo I , Neoplasias de Mama Triplo Negativas , Animais , Linhagem Celular Tumoral , Proliferação de Células , DNA Topoisomerases Tipo I/metabolismo , DNA Topoisomerases Tipo I/farmacologia , DNA Topoisomerases Tipo I/uso terapêutico , Humanos , Camundongos , Proteínas Proto-Oncogênicas c-myc/genética , Transdução de Sinais/genética , Topotecan/farmacologia , Topotecan/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismoRESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolves rapidly under the pressure of host immunity, as evidenced by waves of emerging variants despite effective vaccinations, highlighting the need for complementing antivirals. We report that targeting a pyrimidine synthesis enzyme restores inflammatory response and depletes the nucleotide pool to impede SARS-CoV-2 infection. SARS-CoV-2 deploys Nsp9 to activate carbamoyl-phosphate synthetase, aspartate transcarbamoylase, and dihydroorotase (CAD) that catalyzes the rate-limiting steps of the de novo pyrimidine synthesis. Activated CAD not only fuels de novo nucleotide synthesis but also deamidates RelA. While RelA deamidation shuts down NF-κB activation and subsequent inflammatory response, it up-regulates key glycolytic enzymes to promote aerobic glycolysis that provides metabolites for de novo nucleotide synthesis. A newly synthesized small-molecule inhibitor of CAD restores antiviral inflammatory response and depletes the pyrimidine pool, thus effectively impeding SARS-CoV-2 replication. Targeting an essential cellular metabolic enzyme thus offers an antiviral strategy that would be more refractory to SARS-CoV-2 genetic changes.
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Antivirais , Aspartato Carbamoiltransferase , Tratamento Farmacológico da COVID-19 , Carbamoil Fosfato Sintase (Glutamina-Hidrolizante) , Di-Hidro-Orotase , Inibidores Enzimáticos , Pirimidinas , SARS-CoV-2 , Replicação Viral , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Aspartato Carbamoiltransferase/antagonistas & inibidores , Carbamoil Fosfato Sintase (Glutamina-Hidrolizante)/antagonistas & inibidores , Di-Hidro-Orotase/antagonistas & inibidores , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Inflamação/tratamento farmacológico , Camundongos , Pirimidinas/antagonistas & inibidores , Pirimidinas/biossíntese , Proteínas de Ligação a RNA/metabolismo , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/fisiologia , Fator de Transcrição RelA/metabolismo , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacosRESUMO
BACKGROUND: Improved patient satisfaction in endoscopy is worthy of study as it is an invasive and potentially uncomfortable procedure. There is growing literature on patient satisfaction assessment in endoscopy as part of improving quality assurance. This study aimed to determine whether virtual reality (VR) technology can decrease patients' pain and nervousness during colonoscopies. METHODS: Patients enrolled without sedation were randomly categorised into groups that watched VR (VR group; n=58) and those that did not watch VR (control group; n=59). The primary outcomes were pain score and skin conductance. Secondary endpoints included heart rate, systolic and diastolic arterial pressures, overall patient satisfaction, willingness to repeat the procedure, the difficulty of the procedure, the procedure duration, and bowel preparation. RESULTS: The median (interquartile range (IQR)) pain scores were 7 (6-8) and 5 (4-6) in the control and VR groups, respectively (p<0.001). The median (IQR) skin conductance values after colonoscope insertion were 0.660 (0.490-0.840) and 0.390 (0.280-0.600) in the control and VR groups, respectively (p<0.001). Overall, patient satisfaction was significantly improved with the use of VR, along with a significant reduction in the difficulty perceived by the endoscopist. CONCLUSION: VR technology helped to reduce patients' pain and nervousness and to improve patients' satisfaction during colonoscopies.
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Realidade Virtual , Ansiedade , Colonoscopia , Humanos , Dor , Estudos Prospectivos , TecnologiaRESUMO
INTRODUCTION AND IMPORTANCE: A protective loop ileostomy is recommended in ultra-low rectal cancer to reduce the complications associated with anastomotic leakage (AL), but there are few studies on the complications after AL. The purpose of this study was to outline our experience in the successful treatment of severe abdominal infection after AL in rectal cancer patients with the protective loop ileostomy. CASE PRESENTATION: In this report, we describe three cases of AL after standard total mesorectal excision with the protective loop ileostomy. Severe abdominal infection occurred postoperatively. The patients were successfully treated by surgical reintervention and had an uneventful recovery. No recurrence was observed after 2 years. CLINICAL DISCUSSION: We consider that pelvic floor reconstruction and extending the extubation time should be performed in patients with a high risk of AL. Moreover, when severe abdominal infection and early infectious shock occur after AL, immediate reoperation should be performed to minimize the complication. CONCLUSION: Protective loop ileostomy can't decrease the re-operation rate for patients with AL. We should take preventive measures during and after the operation, as well as early detection and early treatment.
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BACKGROUND: Cetuximab is an effective antibody to treat colorectal cancer (CRC) by targeting the epidermal growth factor receptor (EGFR). However, the mechanisms of acquired resistance to cetuximab therapy, especially in patients without identifiable gene mutations, are not fully understood. METHODS: Our study investigated the role of pumilio RNA-binding family member 1 (PUM1) in cetuximab resistance. We established cetuximab-resistant colon cancer cell lines SW480R and Caco-2R and knocked out PUM1 and DEAD-box helicase 5 (DDX5) with the clustered regularly interspaced short palindromic repeats (CRISPR)-caspase 9 (Cas9) system. To check cell proliferation, we used Cell Counting Kit-8. We performed qPCR and immunoblot to examine the levels of mRNAs and proteins for each cell line. RESULTS: Our data showed that PUM1 was upregulated in SW480R and Caco-2R cells with increased protein levels and cell proliferation, and PUM1 knockout reduced cell viability in the presence of cetuximab. We also found that PUM1 interacted with DDX5 in 3' untranslated region (UTR) and positively regulated its mRNA expression. Furthermore, suppression of DDX5 also decreased the proliferation of SW480R and Caco-2R cells. CONCLUSION: Our study suggests that PUM1 positively regulates DDX5 and acts as a promoter in cetuximab-resistant colon cancer cells.
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BACKGROUND: Anastomotic leakage (AL) is one of the commonest and most serious complications after rectal cancer surgery. The previous analyses on predictors for AL included small-scale patients, and their prediction models performed unsatisfactorily. METHODS: Clinical data of 5,220 patients who underwent anterior resection for rectal cancer were scrutinized to create a prediction model via random forest classifier. Additionally, data of 836 patients served as the test dataset. Patients diagnosed with AL within 6 months' follow-up were recorded. A total of 20 candidate factors were included. Receiver operating characteristic (ROC) curve was conducted to determine the clinical efficacy of our model, and compare the predictive performance of different models. RESULTS: The incidence of AL was 6.2% (326/5,220). A multivariate logistic regression analysis and the random forest classifier indicated that sex, distance of tumor from the anal verge, bowel stenosis or obstruction, preoperative hemoglobin, surgeon volume, diabetes, neoadjuvant chemoradiotherapy, and surgical approach were significantly associated with AL. After propensity score matching, the temporary stoma was not identified as a protective factor for AL (P=0.58). Contrastingly, the first year of performing laparoscopic surgery was a predictor (P=0.009). We created a predictive random forest classifier based on the above predictors that demonstrated satisfactory prediction efficacy. The area under the curve (AUC) showed that the random forest had higher efficiency (AUC =0.87) than the nomogram (AUC =0.724). CONCLUSIONS: Our findings suggest that eight factors may affect the incidence of AL. Our random forest classifier is an innovative and practical model to effectively predict AL, and could provide rational advice on whether to perform a temporary stoma, which might reduce the rate of stoma and avoid the ensuing complications.
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INTRODUCTION AND IMPORTANCE: Hemoclips have been used to protect leakage after endoscopic resection of large colorectal polyps or early-staged rectal cancer, or for perforation of the sigmoid colon during colonoscopy. However, endoscopic clips were seldom used to manage anastomotic leakage after low anterior resection of rectal cancer. CASE PRESENTATION: A patient with postoperative anastomotic leakage after low anterior resection for rectal cancer was successfully treated by endoscopic hemoclips under colonoscopic vision after failure of conservative treatment. Postoperative course was uncomplicated and the patient was discharged from the hospital seven days later. CLINICAL DISCUSSION AND CONCLUSION: Endoscopic hemoclips should be considered as an alternative option for the treatment of an anastomotic leakage in cases where conservative treatment has failed. As they are safe and effective for closure, however good bowel preparation and strict inclusion criteria are required.
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Correlation between blood inflammatory parameters and acute appendicitis (AA) remains controversial. This meta-analysis aims to evaluate whether platelet (PLT) indices including mean platelet volume (MPV), PLT count, and platelet distribution width (PDW) are associated with AA. Pubmed, Embase, and Cochrane Library databases were searched for observational studies published from inception through April 2020 by two independent investigators. Studies reporting associations between platelet indices and AA were selected for inclusion. Standardized mean difference (SMD) and 95% confidence interval (CI) were estimated for continuous outcomes using a DerSimonian-Laird random-effects model. Of 842 records identified, 17 studies with a total of 6793 subjects met our inclusion criteria. Meta-analysis indicated that compared with those in healthy controls, significant decrease in MPV levels was observed in subjects with AA (SMD - 0.34; 95% CI - 0.56 to - 0.12; P = 0.003). Subgroup analyses represented a significant reduction of MPV levels in patients aged ≥ 30 years and non-complicated/non-perforated AA. Due to the small number of studies and patients included in each subgroup, these subgroup analyses need to be interpreted with caution. However, none of the levels of PLT (SMD - 0.13; 95% CI - 0.28-0.012; P = 0.071) or PDW (SMD 0.30; 95% CI - 0.22-0.83; P = 0.257) was seen decrease or increase in subjects with AA. This meta-analysis indicates a significant decrease in MPV levels in patients with AA, which makes MPV have the potential of serving as a biomarker for AA. The associations of other PLT indices with AA need to be further examined.
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Apendicite , Doença Aguda , Idoso , Apendicite/cirurgia , Biomarcadores , Humanos , Volume Plaquetário Médio , Contagem de PlaquetasRESUMO
BACKGROUND: MicroRNAs (miRNAs) play an important regulatory role in carcinogenesis and cancer progression. MiR-95-3p has been reported to be an oncogene in hepatocellular carcinoma. However, the role of miR-95-3p in colorectal carcinoma (CRC) remains unclear. METHODS: miR-95-3p was validated in an independent validation sample cohort of 215 CRC tissues. Functional assays, Cell proliferation (MTT) assay colony formation, wound healing, transwell and animal xenograft assays were used to determine the oppressor role of miR-95-3p in human CRC progression. Furthermore, Bioinformatics analysis, western blotting and dual-luciferase reporter assay were used to determine the mechanism by which miR-95-3p suppresses progression of CRC cells. RESULTS: In this study, we found that miR-95-3p was downregulated in CRC tissues. The low level of miR-95-3p in CRC tumors was correlated with aggressive clinicopathological characteristics, and it predicted poor prognosis in CRC patients. The overexpression of miR-95-3p significantly inhibited CRC cell proliferation, colony formation and metastasis in vitro and in vivo. Bioinformatic analysis further identified hepatoma-derived growth factor (HDGF) as a novel target of miR-95-3p in CRC cells. These findings suggest that miR-95-3p regulates CRC cell survival, partially through the downregulation of HDGF. CONCLUSIONS: Therefore, the miR-95-3p/HDGF axis might serve as a novel therapeutic target in patients with CRC.
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Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , MicroRNAs/genética , Adulto , Idoso , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Camundongos Nus , Pessoa de Meia-IdadeRESUMO
Purpose: MicroRNAs (miRNAs) are key regulators of the growth and development of a wide range of cancer types such as colorectal cancer (CRC). A number of previously studies have observed that the levels of miR-365a-3p expression are dysregulated in many cancers, but the specific role of this miRNA in CRC and its association with patient prognosis remains unclear. Methods: The expression of miR-365a-3p in CRC tissues and cell lines was detected by Real-time Quantitative polymerase chain reaction (RT-qPCR), while the relationship between miR-365a-3p expression and clinicopathological characteristics was further analyzed. After increasing the expression of miR-365a-3p by plasmid transfection in CRC cells, we further investigated the cell proliferation, invasion and migration by cell counting kit-8 (CCK-8), and Transwell assays. Epithelial-mesenchymal transition (EMT) pathway was also measured by western blotting. In addition, the relationship among miR-365a-3p, ADAM10 and JAK in CRC, was explored by luciferase reporter assay. Results: In the present study, we determined that CRC cells and clinical samples exhibited decreased miR-365a-3p expression, and this was associated with larger tumor size, lymph node metastasis, and local invasion. Patients with lower expression of miR-365a-3p had significantly decreased recurrence-free survival (RFS) and overall survival (OS) relative to those with higher levels of this miRNA. In a multivariate analysis, we confirmed that reduced miR-365a-3p levels were independently predictive of poorer CRC patient outcomes. In a functional study, we determined that elevated miR-365a-3p expression inhibited the ability of CRC cells to proliferate and metastasize in vitro and in vivo. We further identified ADAM10 as a direct miR-365a-3p target, resulting in the suppression of ADAM10 expression in cells expressing this miRNA and ADAM10 levels were in turn closely linked to JAK/STAT signaling. Conclusion: Our study suggested the ability of miR-365a-3p to inhibit the progression of CRC at least in part via suppressing ADAM10 expression and associated JAK/STAT signaling, thus identifying this signaling axis as a possible prognostic and therapeutic target in CRC.
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BACKGROUND: Altered expression profile of microRNAs (miRNAs) was reported to be associated with colorectal cancer (CRC). The aims of this study are to identify the changed miRNAs in the plasma of CRC patients and explore the underlying mechanism of these miRNAs during tumorigenesis. METHODS: Plasma miRNA expression profiles were compared between healthy people and CRC patients. MiRNA expression was measured using quantitative real-time PCR. Colony formation and MTT assays were used to test cell proliferation. Luciferase assay, immunohistochemistry and Western blotting were employed to explore the molecular mechanism. RESULTS: MiR-142-3p level was found as the most significantly repressed miRNA in CRC patients. Overexpression of miR-142-3p dramatically repressed colony formation and cell proliferation of both HT29 and HCT116 cells while inhibition of miR-142-3p promoted those of the cells. Interestingly, overexpression of miR-142-3p reduced the level and nuclear accumulation of ß-catenin. We further observed that miR-142-3p remarkably inhibited the transcriptional activity of ß-catenin gene (CTNNB1). However, mutations in the predicted binding sites blocked this inhibition, suggesting that miR-142-3p may directly bind to the mRNA of ß-catenin. CONCLUSION: In conclusion, we identified miR-142-3p exerts its function as a tumor suppressor through blocking the activation of Wnt signaling by directly targeting to CTNNB1.