Modulación por Passiflora edulis de triglicéridos y colesterol intracelulares en líneas celulares de cáncer colorrectal SW480 y sus derivadas metastásicas (SW620) / Modulation by Passiflora edulis of intracellular triglycerides and cholesterol in SW480 col orectal cancer cell lines and their metastatic derivatives (SW620)

Cancer cells modify lipid metabolism to proliferate, Passiflora edulis ( P. edulis ) fruit juice (ZuFru) has antitumor activity, but whether a mechanism is through modulation of cell lipids is unknown. T o establish if ZuFru modifies cholesterol and triglycerides in SW480 and SW620. ZuFru composition was studied by phytochemical march; antiproliferative activity by sulforhodamine B, cholesterol , and triglycerides by Folch method. Z ufru contains anthocyanins, flavonoids, alkaloids , and tannins. Cell lines showed differences in their growth rate ( p =0.049). At 39.6 µg/m L of ZuFru, cell viability was decreased: SW480 (45.6%) and SW620 (45.1%). In SW480, cholesterol (44.6%) and triglycerides (46.5%) decreased; In SW620, cholesterol decreased 14.8% and triglycerides increased 7%, with significant differences for both lines. A ntiproliferative activity of ZuFru could be associated with the inhibition of intracellular biosynthesis of cholesterol and triglycerides in SW480. Action mechanisms need to be further investigated.

Las células cancerosas modifican el metabolismo lipídico para proliferar; el zumo de fruta (ZuFru) de Passiflora edulis ( P. edulis ) tiene activida d antitumoral, sin embargo, se desconoce si se involucran los lípidos celulares. E stablecer si ZuFru modifica colesterol y triglicéridos en células SW480 y SW620. C omposición del ZuFru, actividad antiproliferativa, colesterol y triglicéridos. Se encontraro n antocianinas, flavonoides, alcaloides y taninos. Las líneas celulares mostraron diferencias en su tasa de crecimiento ( p =0 . 049); ZuFru 39,6 µg/ml se disminuyó la viabilidad celular; SW480 (45,6%) y SW620 (45,1%); en SW480 colesterol (44,6%) y triglicérid os (46,5%) en SW620, colesterol (14,8%) y los triglicéridos aumentaron 7%, con diferencias significativas para ambas líneas. La actividad antiproliferativa del ZuFru podría estar asociada a la inhibición de la biosíntesis intracelular de colesterol y de tr iglicéridos en SW480, pero no en SW620. Estos mecanismos de acción deben ser fuertemente investigados.

Prótesis colónicas en el tratamiento paliativo del cáncer colónico. Nuestra evaluación tras 10 años de experiencia / Self-expanding metal stents in the palliative treatmentof coloncancer. Results of 10 years of experience

Introducción: la colocación de prótesis metálicas autoexpansibles (PAE) por vía endoscópica surge como opción terapéutica para la obstrucción colónica neoplásica en dos situaciones: como tratamiento paliativo y como puente a la cirugía curativa. Este procedimiento evita cirugías en dos tiempos y disminuye la probabilidad de colostomía definitiva y sus complicaciones con el consecuente deterioro de la calidad de vida. Objetivo: comunicar nuestra experiencia en la colocación de PAE para el tratamiento paliativo de la obstrucción colorrectal neoplásica. Diseño: retrospectivo, longitudinal, descriptivo y observacional. Material y métodos: se incluyeron todos los pacientes a quienes el mismo grupo de endoscopistas les colocó PAE con intención paliativa por cáncer colorrectal avanzado entre agosto de 2008 y diciembre de 2019. Fueron analizadas las variables demográficas y clínicas, el éxito técnico y clínico, las complicaciones tempranas y tardías y la supervivencia. Resultados: se colocó PAE en 54 pacientes. La media de edad fue 71 años. El 85% de las lesiones se localizó en el colon izquierdo. En el 57% de los pacientes se realizó en forma ambulatoria. El éxito técnico y clínico fue del 92 y 90%, respectivamente y la supervivencia media de 209 días. La tasa de complicaciones fue del 29,6%, incluyendo un 14,8% de obstrucción y un 5,6% de migración. La mortalidad tardía atribuible al procedimiento fue del 5,6%, ocasionada por 3 perforaciones tardías: 2 abiertas y 1 microperforación con formación de absceso localizado. Conclusiones: la colocación de PAE como tratamiento paliativo de la obstrucción neoplásica colónica es factible, eficaz y segura. Permitió el manejo ambulatorio o con internación breve y la realimentación temprana, mejorando las condiciones para afrontar un eventual tratamiento quimioterápico paliativo. Las mayoría de las complicaciones fueron tardías y resueltas endoscópicamente en forma ambulatoria. (AU)

Introduction: endoscopic placement of self-expanding metal stents (SEMS) emerges as a therapeutic option for neoplastic obstruction of the colon in two situations: as palliative treatment and as a bridge to curative surgery. This procedure avoids two-stage surgeries and reduces the probability of permanent colostomy and its complications with the consequent deterioration in quality of life. Objective: to report our experience in the placement of SEMS as palliative treatment in neoplastic colorectal obstruction. Design: retrospective, longitudinal, descriptive and observational study. Methods: all patients in whom the same group of endoscopists performed SEMS placement with palliative intent for advanced colorectal cancer between August 2008 and December 2019 were analyzed. Data collected were demographic and clinical variables, technical and clinical success, early and late complications, and survival. Results: SEMS were placed in 54 patients. The average age was 71 years. Eighty-five percent were left-sided tumors. In 57% of the patients the procedure was performed on an outpatient basis. Technical and clinical success was 92 and 90%, respectively, and median survival was 209 days. The complication rate was 29.6%, including 14.8% obstruction and 5.6% migration. Late mortality attributable to the procedure was 5.6%, caused by 3 late perforations: 2 open and 1 microperforation with localized abscess formation. Conclusions: The placement of SEMS as a palliative treatment for neoplastic colonic obstruction is feasible, effective and safe. It allowed outpa-tient management or brief hospitalization and early refeeding, improving the conditions to face an eventual palliative chemotherapy treatment. Most complications were late and resolved endoscopically on an outpatient basis. (AU)

Calidad asistencial y seguimiento de los pacientes operados por cáncer colorrectal en un Hospital de Paysandú, Uruguay / Quality of care and follow-up of patients operated on forcolorectal cancer at the Paysandú Hospital, Uruguay

Introducción: el cáncer colorrectal (CCR) es la segunda causa de muerte dentro de las enfermedades neoplásicas. El pronóstico individual está signado por el estadio de la enfermedad al momento del diagnóstico y la posibilidad de realizar un tratamiento curativo. Este también depende de la estratificación post quirúrgica y de la aparición de complicaciones ulteriores. El objetivo del seguimiento es diagnosticar la recidiva en un estadio potencialmente curable y detectar otros cánceres primarios. Objetivo: realizar una valoración de la calidad de la cirugía colorrectal y el seguimiento de los pacientes operados de CCR en nuestro hospital. Diseño: estudio descriptivo, observacional, retrospectivo. Material y métodos: se analizaron todos los pacientes con CCR operados en el servicio de cirugía del Hospital de Paysandú entre enero de 2017 y diciembre de 2020. Se describen diversas variables que influyen en la calidad quirúrgica y se analizan las relacionadas al seguimiento post operatorio dividiendo a los pacientes en 3 grupos, seguimiento completo, perdidos y sin datos de seguimiento. Resultados: se incluyeron 39 pacientes, con una edad media de 68 años. El 28% se diagnosticaron en estadio IV, con porcentajes bajos en estadios tempranos. Hubo 57% de cirugías de urgencia y 43% electivas. La causa más frecuente de urgencia fue la oclusión intestinal (36,6%). La tasa de dehiscencia anastomótica fue 16,6% y la de mortalidad 15,3%. Solo el 33% de los pacientes tuvieron seguimiento completo. Conclusión: existe un déficit en la atención y el seguimiento de los pacientes operados por CCR en nuestro hospital. Se impone la creación de un equipo específico en el área de coloproctología, así como un protocolo de seguimiento unificado para mejorar estos resultados. (AU)

Introduction: colorectal cancer (CRC) is the second cause of death among neoplastic diseases. The individual prognosis is determined by the stage of the disease at the time of diagnosis and the possibility of curative treatment. This also depends on the postsurgical stratification and the appearance of subsequent complications. The goal of follow-up is to diagnose recurrence at a potentially curable stage and detect other primary cancers. Objective: to carry out an evaluation of the quality of colorectal surgery and the follow-up of patients operated on for CRC in our hospital. Design: descriptive, retrospective observational study. Material and methods: all patients with CRC operated on in the surgery service of the Paysandú Hospital between January 2017 and December 2020 were analyzed. Variables that influence surgical quality are described and those related to postoperative follow-up are analyzed by dividing patients in 3 groups, complete follow-up, lost to follow-up and without follow-up data. Results: Thirty-nine patients were included, with a mean age of 68 years. Twenty-eight percent were diagnosed in stage IV, with low percentages in early stages. There were 57% emergency procedures and 43% elective proceduress. The most common cause of emergency was intestinal obstruction (36.6%). The anastomotic dehiscence rate was 16.6% and the mortality rate was 15.3%. Only 33% of patients had complete follow-up. Conclusion: there is a deficit in the care and follow-up of patients undergoing CRC surgery in our hospital. The creation of a specific team in the area of coloproctology is required, as well as a unified monitoring protocol to improve these results. (AU)

Influência da terapia neoadjuvante na razão de linfonodos / Influence of neoadjuvant therapy on the ratio of lymph nodes

ABSTRACT Background: To evaluate the relationship between the ratio of affected lymph nodes (LNR) and clinical and anatomopathological variables in patients with rectal adenocarcinoma submitted or not to neoadjuvant chemoradiotherapy. Methods: The LNR was determined by dividing the number of compromised LNR by the total number of LNR dissected in the surgical specimen. Patients were divided into two groups: with QRT and without QRT. In each group, the relationship between LNR and the following variables was evaluated: degree of cell differentiation, depth of invasion in the rectal wall, angiolymphatic /perineural invasion, degree of tumor regression and occurrence of metastases. The LNR was evaluated in patients with more than 1, LNR (LNR >12) or less (LNR<12) in the surgical specimen with overall survival (OS) and disease-free survival (DFS). The results were expressed as the mean with the respective standard deviation. Qualitative variables were analyzed using Fisher's exact test, while quantitative variables were analyzed using the Kruskal -Wallis and Mann-Whitney tests. The significance level was 5%. Results: We evaluated 282 patients with QRT and 114 without QRT, between 1995-2011. In the QRT Group, LNR showed a significant association with mucinous tumors (P=0.007) and degree of tumor regression (P=0.003). In both groups, LNR was associated with poorly differentiated tumors (P=0.001, P=0.02), presence of angiolymphatic invasion (P<0.0001 and P=0.01), perineural (P=0.0007, P=0.02), degree of rectal wall invasion (T3>T2; P<0.0001, P=0.02); Compromised LNR (P<0.0001, P<0.01), metastases (P<0.0001, P<0.01). In patients with QRT, LNR<12 was associated with DFS (5.889; 95%CI1.935-19.687; P=0.018) and LNR>12 with DFS and OS (17.984; 95%CI5.931-54.351; P<0.001 and 10.286; 95%CI 2.654-39.854; P=0.007, respectively). Conclusion: LNR was associated with histological aspects of poor prognosis, regardless of the use of QRT. In the occurrence of less than 12 evaluated LNR, the LNR was associated only with the DFS.

RESUMO Contexto: Avaliar a relação entre a razão de linfonodos (RLA) acometidos e variáveis clínicas e anatomopatológicas em portadores de adenocarcinoma de reto submetidos ou não à quimiorradioterapia neoadjuvante. Métodos: A RLA foi determinada dividindo-se o número total de linfonodos (LFNs) dissecados no espécime cirúrgico pelo número de comprometidos. Os doentes foram divididos em dois grupos: com QRT e sem QRT. Em cada grupo foi avaliada a relação entre a RLA e as seguintes variáveis: grau de diferenciação celular, profundidade de invasão na parede retal, invasão angiolinfática/perineural, grau de regressão tumoral e ocorrência de metástases. Avaliou-se a RLA em pacientes com mais do que 12 LFNs (RLA>12) ou menos (RLA<12) na peça cirúrgica com a sobrevida global (SG) e sobrevida livre de doença (SLD). Os resultados foram expressos pela média com o respectivo desvio padrão. As variáveis qualitativas foram analisadas utilizando-se o teste exato de Fisher, enquanto as quantitativas pelos testes de Kruskal-Wallis e Mann-Whitney. O nível de significância foi de 5%. Resultados: Foram avaliados 282 pacientes com QRT e 114 sem QRT, entre 1995-2011. No Grupo QRT, RLA mostrou associação significativa com os tumores mucinosos (P=0,007) e grau de regressão tumoral (P=0,003). Nos dois grupos, a RLA associou-se com tumores pouco diferenciados (P=0,001 e P=0,02), presença de invasão angiolinfática (P<0,0001 e P=0,01), perineural (P=0,0007 e P=0,02), grau de invasão da parede retal (T3>T2; P<0,0001 e P=0,02); LFNs comprometidos (P<0,0001 e P<0,01), metástases (P<0,0001 e P<0,01). Nos pacientes com QRT, a RLA <12 associou-se com a SLD (5,889; IC95%1,935-19,687; P=0,018) e a RLA >12 com SLD e SG (17,984; IC95%5,931-54,351; P<0,001 e 10,286; IC95%2,654-39,854; P=0,007, respectivamente). Conclusão: A RLA associou-se a aspectos histológicos de mau prognóstico, independentemente do emprego de QRT. Na ocorrência de menos de 12 LFNs avaliados, a RLA associou-se apenas com a SLD.

Caracterização dos estágios iniciais do câncer colorretal utilizando microscopia de autofluorescência 3D: um estudo preliminar / Early stages of colorectal cancer characterization by autofluorescence 3d microscopy: a preliminary study

ABSTRACT Background: Colorectal cancer is one of the most prevalent pathologies worldwide whose prognosis is linked to early detection. Colonoscopy is the gold standard for screening, and diagnosis is usually made histologically from biopsies. Aiming to reduce the inspection and diagnostic time as well as the biopsies and resources involved, other techniques are being promoted to conduct accurate in vivo colonoscopy assessments. Optical biopsy aims to detect normal and neoplastic tissues analysing the autofluorescence spectrum based on the changes in the distribution and concentration of autofluorescent molecules caused by colorectal cancer. Therefore, the autofluorescence contribution analysed by image processing techniques could be an approach to a faster characterization of the target tissue. Objective: Quantify intensity parameters through digital processing of two data sets of three-dimensional widefield autofluorescence microscopy images, acquired by fresh colon tissue samples from a colorectal cancer murine model. Additionally, analyse the autofluorescence data to provide a characterization over a volume of approximately 50 µm of the colon mucosa for each image, at second (2nd), fourth (4th) and eighth (8th) weeks after colorectal cancer induction. Methods: Development of a colorectal cancer murine model using azoxymethane/dextran sodium sulphate induction, and data sets acquisition of Z-stack images by widefield autofluorescence microscopy, from control and colorectal cancer induced animals. Pre-processing steps of intensity value adjustments followed by quantification and characterization procedures using image processing workflow automation by Fiji's macros, and statistical data analysis. Results: The effectiveness of the colorectal cancer induction model was corroborated by a histological assessment to correlate and validate the link between histological and autofluorescence changes. The image digital processing methodology proposed was then performed on the three-dimensional images from control mice and from the 2nd, 4th, and 8th weeks after colorectal cancer chemical induction, for each data set. Statistical analyses found significant differences in the mean, standard deviation, and minimum parameters between control samples and those of the 2nd week after induction with respect to the 4th week of the first experimental study. This suggests that the characteristics of colorectal cancer can be detected after the 2nd week post-induction. Conclusion: The use of autofluorescence still exhibits levels of variability that prevent greater systematization of the data obtained during the progression of colorectal cancer. However, these preliminary outcomes could be considered an approach to the three-dimensional characterization of the autofluorescence of colorectal tissue, describing the autofluorescence features of samples coming from dysplasia to colorectal cancer.

RESUMO Contexto: O câncer colorretal é uma das patologias mais prevalentes em todo o mundo, cujo prognóstico está ligado à detecção precoce. A colonoscopia é o padrão ouro para triagem, e o diagnóstico geralmente é feito histologicamente a partir de biópsias. Visando reduzir o tempo de inspeção e diagnóstico, bem como as biópsias e recursos envolvidos, outras técnicas estão sendo promovidas para realizar avaliações precisas de colonoscopia in vivo. A biópsia óptica visa detectar tecidos normais e neoplásicos analisando o espectro de autofluorescência com base nas mudanças na distribuição e concentração de moléculas autofluorescentes causadas pelo câncer colorretal. Portanto, a contribuição da autofluorescência analisada por técnicas de processamento de imagem poderia ser uma abordagem para uma caracterização mais rápida do tecido-alvo. Objetivo: Quantificar parâmetros de intensidade por meio do processamento digital de dois conjuntos de dados de imagens de microscopia de autofluorescência em campo amplo tridimensionais, adquiridas por amostras de tecido fresco de cólon de um modelo murino de câncer colorretal. Adicionalmente, analisar os dados de autofluorescência para fornecer uma caracterização em um volume de aproximadamente 50 µm da mucosa do cólon para cada imagem, na segunda (2ª), quarta (4ª) e oitava (8ª) semanas após a indução do câncer colorretal. Método: Desenvolvimento de um modelo murino de câncer colorretal usando indução de azoximetano/sulfato de sódio dextrano, e aquisição de conjuntos de dados de imagens Z-stack por microscopia de autofluorescência em campo amplo, de animais controle e induzidos ao câncer colorretal. Etapas de pré-processamento de ajustes de valores de intensidade seguidas por procedimentos de quantificação e caracterização usando automação de fluxo de trabalho de processamento de imagem por macros do Fiji, e análise estatística de dados. Resultados: A eficácia do modelo de indução de câncer colorretal foi corroborada por uma avaliação histológica para correlacionar e validar a ligação entre as mudanças histológicas e de autofluorescência. A metodologia de processamento digital de imagem proposta foi então realizada nas imagens tridimensionais de camundongos controle e das 2ª, 4ª e 8ª semanas após a indução química do câncer colorretal, para cada conjunto de dados. Análises estatísticas encontraram diferenças significativas nos parâmetros médios, desvio padrão e mínimos entre amostras de controle e aquelas da 2ª semana após a indução em relação à 4ª semana do primeiro estudo experimental. Isso sugere que as características do câncer colorretal podem ser detectadas após a 2ª semana pós-indução. Conclusão: O uso de autofluorescência ainda apresenta níveis de variabilidade que impedem uma maior sistematização dos dados obtidos durante a progressão do câncer colorretal. No entanto, esses resultados preliminares podem ser considerados uma abordagem para a caracterização tridimensional da autofluorescência do tecido colorretal, descrevendo as características de autofluorescência de amostras que vão da displasia ao câncer colorretal.

Monotropein Induced Apoptosis and Suppressed Cell Cycle Progression in Colorectal Cancer Cells / 中国结合医学杂志

OBJECTIVE@#To determine whether monotropein has an anticancer effect and explore its potential mechanisms against colorectal cancer (CRC) through network pharmacology and molecular docking combined with experimental verification.@*METHODS@#Network pharmacology and molecular docking were used to predict potential targets of monotropein against CRC. Cell counting kit assay, plate monoclonal assay and microscopic observation were used to investigate the antiproliferative effects of monotropein on CRC cells HCT116, HT29 and LoVo. Flow cytometry and scratch assay were used to analyze apoptosis and cell cycle, as well as cell migration, respectively in HCT116, HT29, and LoVo cells. Western blotting was used to detect the expression of proteins related to apoptosis, cell cycle, and cell migration, and the expression of proteins key to the Akt pathway.@*RESULTS@#The Gene Ontology and Reactome enrichment analyses indicated that the anticancer potential of monotropein against CRC might be involved in multiple cancer-related signaling pathways. Among these pathways, RAC-beta serine/threonine-protein kinase (Akt1, Akt2), cyclin-dependent kinase 6 (CDK6), matrix metalloproteinase-9 (MMP9), epidermal growth factor receptor (EGFR), cell division control protein 42 homolog (CDC42) were shown as the potential anticancer targets of monotropein against CRC. Molecular docking suggested that monotropein may interact with the 6 targets (Akt1, Akt2, CDK6, MMP9, EGFR, CDC42). Subsequently, cell activity of HCT116, HT29 and LoVo cell lines were significantly suppressed by monotropein (P<0.05). Furthermore, our research revealed that monotropein induced cell apoptosis by inhibiting Bcl-2 and increasing Bax, induced G1-S cycle arrest in colorectal cancer by decreasing the expressions of CyclinD1, CDK4 and CDK6, inhibited cell migration by suppressing the expressions of CDC42 and MMP9 (P<0.05), and might play an anticancer role through Akt signaling pathway.@*CONCLUSION@#Monotropein exerts its antitumor effects primarily by arresting the cell cycle, causing cell apoptosis, and inhibiting cell migration. This indicates a high potential for developing novel medication for treating CRC.

Application of Circulating Tumor DNA in Precision Diagnosis and Treatment of Colorectal Cancer / 肿瘤防治研究

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

Effects of gene polymorphism on efficacy and toxic effect of chemotherapy regimen containing oxaliplatin treatment in stage Ⅲ and Ⅳ colorectal cancer / 中国药房

OBJECTIVE To investigate the effects of GSTP1， XRCC1， ABCB1， MTHFR gene polymorphisms on efficacy and toxic effect of chemotherapy regimen containing oxaliplatin in patients with stage Ⅲ and Ⅳ colorectal cancer patients. METHODS Clinical data of 76 patients with stage Ⅲ and Ⅳ colorectal cancer who received chemotherapy regimen containing oxaliplatin （XELOX，FOLFOX） were collected from the Second Affiliated Hospital of Soochow University from September 2018 to March 2020. The correlation of genotypes with progression-free survival （PFS） and toxic effect was analyzed by using univariate and multivariate COX regression model. RESULTS Carriers of the ABCB1 3435T＞C locus C allele （TC/CC） had a significantly higher risk of progression compared to TT genotype patients [HR＝2.39， 95%CI （1.05，5.50）， P＝0.038]. The risk of progression in patients at stage Ⅳ was significantly higher than those at stage Ⅲ [HR＝8.11， 95%CI（3.39，19.40）， P＜0.001]. Chemotherapy regimen， Karnofsky performance status score and tumor site had no significant effect on disease progression （P＞0.05）. Mutations in gene loci were not correlated with adverse reactions （P＞0.05）. CONCLUSIONS Patients carrying ABCB1 TC/CC and receiving chemotherapy regimen containing oxaliplatin have a higher risk of disease progression， which may be associated with longer PFS in patients （TT genotype） with stage Ⅳ colorectal cancer receiving the chemotherapy， while GSTP1， XRCC1， and MTHFR gene polymorphisms have no significant impact.

Progressive Changes of Colitis Into Colorectal Cancer Associated With Changes in Neutrophil Lymphocyte Ratio, Serum, Micrornas and Infiltrate Neutrophils

@#Introduction: Understand the progression of colorectal cancer from the beginning until the advance stages is difficult and challenging. However, this could be overcome with a good animal model. Methods: In this study, a modified approach had been used to develop colorectal cancer model. The model was developed and monitored from colitis formation until the late stage of colorectal cancer. The changes of neutrophil lymphocyte ratio (NLR), serum microRNAs and infiltrate neutrophil in different stages of colorectal cancer were assessed in this study. Results: Results showed that the progression of the disease is correlated with NLR as early as the formation of colitis (r=0.121, p<0.026). Meanwhile, the size of the tumor at each stage is also associated with the NLR value (r=0.185, p<0.0012). In the serum microRNAs study, it was found microRNAs expression in blood serum change in different stages of colorectal cancer. In the early stage of colitis formation, miR223 (> 3 fold expression, p < 0.0025) were abundantly found in the blood serum. Meanwhile in others stage mild (miRNA345 > 2.5 fold, p<0.0011), moderate (miRNA347 & miR512 > 3 fold, p<0.002) and severe (miR31 & miR145 > 2 fold, p<0.0001) microRNAs were also found expressed differently. The quantities of infiltrate neutrophil were varied in different stages of the disease. Conclusion: This study provides an insight into the immunity and molecular level of colorectal cancer and it allows a progressive monitoring on the changes in the molecular, cellular and histological level.

Mechanism of Qingre Huayu Jianpi Prescription Inhibiting Development of Colitis-associated Colorectal Cancer in Mice / 中国实验方剂学杂志

ObjectiveTo explore the effect of Qingre Huayu Jianpi prescription （QHJ） on colitis-associated colorectal cancer （CAC） in mice， and its related mechanism. MethodC57BL/6 mice were randomly divided into four groups including the normal， model， QHJ low-dose （QHJ-L， 10 g·kg-1）， and QHJ high-dose （QHJ-H， 40 g·kg-1） groups. Azoxymethane （AOM） and dextran sodium sulfate （DSS） were combined to chemically build a CAC mouse model for 14 weeks. Each drug group was given intragastrically from the 5th week to the 14th week， once per day. An equal volume of water was fed to the normal and model groups. The mouse survival rate， colon length， weight， and pathological alterations were assessed. The protein expressions of Wnt-3a protein signaling （Wnt3a）， β-catenin， Non-phosphor-β-catenin （Non-p-β-catenin）， and cholesterol-binding glycoproteins 133 （CD133） were detected by Western blot. The localization and expression of the cluster of differentiation （CD） 80 and CD11 antigen-like family member B （CD11b） were detected by immunohistochemistry （IHC）. The colon organoids derived from CAC mice were isolated and cultured to detect the expression of Wnt signaling pathway-related proteins. ResultThe survival rate of the CAC mice was improved by QHJ treatment and the number of colon tumors was inhibited significantly. Compared with those in the normal group， the expression levels of Wnt3a， β-catenin， Non-p-β-catenin， and CD133 in colon tissues in the model group were significantly increased （P<0.05， P<0.01）. Compared with those in the model group， the levels of Wnt3a and β-catenin in the QHJ-L group were significantly decreased （P<0.01）， and the protein levels of Wnt3a， β-catenin， Non-p-β-catenin， and CD133 in the QHJ-H group were significantly decreased （P<0.05， P<0.01）. Meanwhile， the expression level of CD11b in the model group was significantly increased compared with that in the normal group while the CD80 level was significantly decreased （P<0.05， P<0.01）. Compared with those in the model group， CD11b in QHJ-L and QHJ-H groups was significantly decreased， and CD80 was significantly increased（P<0.05， P<0.01）. The expressions of Non-p-β-catenin and CD133 in colonic organoids of CAC model mice were significantly increased， while QHJ treatment could inhibit the expressions of Non-p-β-catenin and CD133 in colonic organoids （P<0.01）. ConclusionQHJ could inhibit the inflammation-cancer development in CAC mice， the mechanism of which might be related to regulating the microenvironment and inhibiting the over-activation of Wnt signaling.

Inhibitory effect and mechanism of total flavonoids from Melicope pteleifolia on transplanted tumor of colorectal cancer in nude mice / 中国药房

OBJECTIVE To study the inhibitory effect and mechanism of total flavonoids from Melicope pteleifolia （TF-MPL） on transplanted tumor of colorectal cancer in nude mice. METHODS The transplanted tumor model of colorectal cancer was induced by injecting 0.2 mL colorectal cancer cell LoVo subcutaneously via the right armpit of nude mice. After successful modeling， nude mice were randomly divided into model group， 5-fluorouracil group （positive control， 10 mg/kg）， TF-MPL high- dose and low-dose groups （25， 12.5 mg/kg）； a normal group （normal saline containing 0.3% carboxymethyl cellulose sodium） without modeling was additionally set up， with 6 mice in each group. Each group was intraperitoneally injected with the corresponding drug solution/solvent for 21 consecutive days. The inhibitory rate of the transplanted tumor， liver and spleen index， and the levels of tumor necrosis factor-α （TNF-α） and interleukin-6 （IL-6） in serum were detected after the last medication； the morphological changes of tumor tissue were observed； immunohistochemical staining was used to detect protein expressions of Toll- like receptor 4 （TLR4） and nuclear factor-κB subunit p65 （NF-κB p65） in tumor tissue of nude mice. Western blot assay was used to detect protein expressions of TLR4， myeloid differentiation factor 88 （MyD88）， TNF receptor-associated factor 6 （TRAF6）， interleukin-1 receptor-associated kinase 1 （IRAK-1）， NF-κB p65 and caspase-3 in tumor tissue of nude mice. RESULTS Compared with the model group， TF-MPL high-dose group showed a significant decrease in tumor weight （inhibitory rate of 36.91%）， liver and spleen index， serum levels of TNF-α and IL-6 and protein expressions of TLR4， MyD88， TRAF6，IRAK-1 and NF- κB p65 （P＜0.05 or P＜0.01）； the expression of caspase-3 protein was increased significantly （P＜0.05）， and more tumor cell shrinkage and deformation， nuclear pyknosis and fragmentation were observed. CONCLUSIONS TF-MPL can significantly inhibit the growth of transplanted tumor of colorectal cancer in nude mice， the mechanism of which may be associated with reducing inflammatory response， inhibiting TLR4/MyD88/NF-κB signaling pathway， and promoting apoptosis in colorectal cancer cells.

Research progress in liver transplantation for colorectal liver metastasis / 器官移植

Colorectal cancer is one of the common malignant tumors in China. Studies have shown that more than 50% of patients with colorectal cancer will experience metastasis. After systematic treatment, patients with resectable colorectal cancer could obtain favorable 5-year survival rate. However, patients with unresectable colorectal liver metastasis constantly obtain poor prognosis. In spite of the development of medical treatment, patients with unresectable colorectal liver metastasis can be treated by multiple approaches, such as interventional therapy combined with targeted therapy and immunotherapy, clinical efficacy is relatively low. Hence, clinicians divert extensive attention to liver transplantation. Liver transplantation, as an emerging treatment in recent years, is expected to improve clinical prognosis of patients with unresectable colorectal liver metastasis. In this article, research progress in liver transplantation for patients with unresectable colorectal liver metastasis was reviewed, mainly including the historical overview, recent results, prognostic factors, adaptation criteria, relationship with systemic treatment, liver source shortage and donor allocation, aiming to provide reference for liver transplantation for patients with colorectal liver metastasis.

Peranan RNA Bulat dalam Kanser Kolorektal / Jurnal Sains Kesihatan Malaysia

@#Circular RNAs (circRNAs) are a class of non-coding RNAs formed by covalently closed loops through backsplicing. From previous studies, RNA was found to be involved in the development and formation of colorectal cancer. By emphasizing on the true function of circRNAs through focusing on its biogenesis, roles in disease treatment and roles as biomarkers, we are able to utilize circRNAs as therapy for cancer. Cancer is a chronic disease that contributes to high mortality worldwide. Colorectal cancer is one of the most common cancer in the world and in Malaysia in general. The incidence and mortality rates of colorectal cancer worldwide show a drastic and alarming increase. Colorectal cancer occurs due to mutations from certain genes involved in proliferation regulation, cell survival and cell death. This article aims to discuss the role and importance of Circular RNA in colorectal cancer. By identifying the true function of circRNAs, it can help us to develop our understanding on the real biological roles of circRNAs in colorectal cancer.

Trend of Colorectal Cancer Burden in China from 1990 to 2019 / 肿瘤防治研究

Objective To quantitatively analyze the effects of population aging and other risk factors on the burden of colorectal cancer in China from 1990 to 2019. Methods The Global Burden of Disease Study 2019 was used to describe the temporal trend of the burden of colorectal cancer. A decomposition method established by Gupta was applied to quantify the burden related to population growth, aging, age-specific prevalence, and disease severity. Results The age-standardized disability adjusted life years (DALY) rates of colorectal cancer in China showed an overall upward trend from 1990 to 2019. The DALY in 2019 increased by 191.12% compared with that in 1990, with 34.54% of the increase attributed to population growth, 111.36% to population aging, and 77.56% to the rise of age-specific prevalence. Meanwhile, -32.54% benefited from the changes in disease severity. Diet low in milk was the primary risk factor for the disease burden of colorectal cancer in China in 2019, followed by diet low in whole grains and calcium. In the last 30 years, the corresponding risk factor of the most rapid increase in China was high BMI with an average annual percentage of change of 4.14%, and the corresponding risk factor of the most rapid decrease in China was diet low in fiber with an average annual percentage of change of -2.00%. Conclusion Aging population is mainly responsible for the considerable increase in the burden of colorectal cancer in China from 1990 to 2019. The health administrative authorities should take corresponding measures to address the adverse impacts associated with aging.

Mechanism of TFF3-dependent TWIST1 Upregulating TRIB3 to Promote Colorectal Cancer Metastasis / 肿瘤防治研究

Objective To investigate the effects of TFF3 overexpression on the proliferation, migration, and invasion ability of colorectal cancer HT29 cells and the mechanisms involved in cancer metastasis. Methods HT29 cells were transfected with pIRES2-TFF3, and the expression levels of mRNAs and proteins related to TFF3 gene, TWIST1/TRIB3 signaling pathway, and epithelial-mesenchymal transition (EMT) were detected by qRT-PCR and Western blot. The proliferation, migration, and invasion ability of HT29 cells were detected by the CCK-8, cell scratch, and Transwell assays. Changes in cell morphology after TFF3 overexpression were observed through transmission electron microscopy. Results After the HT29 cells were transfected with pIRES2-TFF3, the expression levels of TFF3 mRNA and protein significantly increased (P<0.01); cell proliferation, migration, and invasion were significantly enhanced (P<0.01); and the expression of related genes, such as TWIST1, TRIB3, Vimentin, and Snail were significantly upregulated. By contrast, the expression of E-cadherin significantly decreased (P<0.05). Various changes in cell morphology were observed after TFF3 overexpression, such as decrease in cell junctions, loss of cilia, formation of pseudopodia, and increase in fusiform cells. Conclusion TFF3 overexpression may promote EMT in colorectal cancer cells through the Twist1/TRIB3 signaling pathway, increase their metastatic potential, and accelerate the malignant progression of colorectal cancer.

Targeting FAPα-positive lymph node metastatic tumor cells suppresses colorectal cancer metastasis

Lymphatic metastasis is the main metastatic route for colorectal cancer, which increases the risk of cancer recurrence and distant metastasis. The properties of the lymph node metastatic colorectal cancer (LNM-CRC) cells are poorly understood, and effective therapies are still lacking. Here, we found that hypoxia-induced fibroblast activation protein alpha (FAPα) expression in LNM-CRC cells. Gain- or loss-function experiments demonstrated that FAPα enhanced tumor cell migration, invasion, epithelial-mesenchymal transition, stemness, and lymphangiogenesis via activation of the STAT3 pathway. In addition, FAPα in tumor cells induced extracellular matrix remodeling and established an immunosuppressive environment via recruiting regulatory T cells, to promote colorectal cancer lymph node metastasis (CRCLNM). Z-GP-DAVLBH, a FAPα-activated prodrug, inhibited CRCLNM by targeting FAPα-positive LNM-CRC cells. Our study highlights the role of FAPα in tumor cells in CRCLNM and provides a potential therapeutic target and promising strategy for CRCLNM.

A novel TNKS/USP25 inhibitor blocks the Wnt pathway to overcome multi-drug resistance in TNKS-overexpressing colorectal cancer

Modulating Tankyrases (TNKS), interactions with USP25 to promote TNKS degradation, rather than inhibiting their enzymatic activities, is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin pathway. Here, we identified UAT-B, a novel neoantimycin analog isolated from Streptomyces conglobatus, as a small-molecule inhibitor of TNKS-USP25 protein-protein interaction (PPI) to overcome multi-drug resistance in colorectal cancer (CRC). The disruption of TNKS-USP25 complex formation by UAT-B led to a significant decrease in TNKS levels, triggering cell apoptosis through modulation of the Wnt/β-catenin pathway. Importantly, UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels, as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts, as well as APCmin/+ spontaneous CRC models. Collectively, these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment, and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.

Exosome-Transmitted miR-224-5p Promotes Colorectal Cancer Cell Proliferation via Targeting ULK2 in p53-Dependent Manner / 生物医学与环境科学（英文）

OBJECTIVE@#To investigate the role and molecular mechanism of exosomal miR-224-5p in colorectal cancer (CRC).@*METHODS@#The miR-224-5p expression in CRC patient tissues and cell-derived exosomes was measured by laser capture microdissection and qRT-PCR, respectively. Dual-luciferase reporter gene assay was used to determine the target gene of miR-224-5p. The protein expressions of p53 and unc-51 like kinase 2 (ULK2) in CRC cells were detected by western blot. Flow cytometry was used to detect cell cycle and apoptosis. Cell proliferation was measured by CCK8 and EdU assay.@*RESULTS@#The miR-224-5p expression was upregulated in CRC tissues and increased progressively with the rise of CRC stage. CRC cells secreted extracellular miR-224-5p mainly in an exosome-dependent manner, and then miR-224-5p could be transferred to surrounding tumor cells to regulate cell proliferation in the form of autocrine or paracrine. Moreover, ULK2 was characterized as a direct target of miR-224-5p and was downregulated in CRC tissues. Interestingly, ULK2 inhibited CRC cell proliferation in a p53-dependent manner. Furthermore, exosome-derived miR-224-5p partially reversed the proliferation regulation of ULK2 on CRC cells.@*CONCLUSION@#Our findings demonstrate that exosome-transmitted miR-224-5p promotes p53-dependent cell proliferation by targeting ULK2 in CRC, which may offer promising targets for CRC prevention and therapy.

Biological Connotation of Pathogenesis of Colorectal Cancer Due to Damp-heat Accumulation Based on Immune Response-intestinal Microbial Axis / 中国实验方剂学杂志

Colorectal cancer （CRC） is a malignant tumor of the intestinal tract with changes in bowel habits， blood in the stool， and pain as the main clinical manifestations. With the change in lifestyle and diet structure in recent years， the incidence of CRC has been increasing year by year. The pathogenesis of CRC is closely related to abnormal immune response and chronic inflammation， intestinal microbial dysbiosis， and the production of oncogenic metabolites. There is a two-way communication between the intestinal microbiota and the body's immunity， which not only plays a key role in maintaining the body's health but also has a close relationship with the development of diseases. An increasing number of studies have shown that abnormal immune responses accelerate the disease process by producing inflammatory factors， causing chronic inflammation in the body， disrupting the intestinal mucosal barrier， and increasing mucosal permeability， thus resulting in dysbiosis of the intestinal microbial ecology and a large number of pathogenic microorganisms and their metabolites. In addition， dysbiosis of intestinal microbes， by suppressing the normal immune response， leads to the disruption of multiple metabolic pathways in the body， affecting the internal and external stress response of the intestine， inducing inflammation， and thus producing disease. Therefore， the complex crosstalk mechanism between the immune response and intestinal microbial axis is closely related to the development of CRC. Based on traditional Chinese medicine theory and clinical research， it was found that dietary factors are an important causative factor in the development of CRC. The deficiency of positive energy is the root cause of the disease， and damp-heat accumulation is the key pathogenesis. Through modern medical and biological research， it is believed that abnormal immune response is the microscopic manifestation of damp-heat entrapment， while intestinal microbial dysbiosis is the biological basis of toxic injection into the large intestine， and in the pathogenesis of CRC， the imbalance of immune response-intestinal microbial axis is compatible with damp-heat accumulation in traditional Chinese medicine. This study aims to explore the biological connotation of CRC due to damp-heat accumulation from the immune response-intestinal microbial axis， so as to interpret the pathogenesis of CRC due to damp-heat accumulation with objective data and provide new ideas and theoretical basis for the pathogenesis and treatment strategies of CRC due to damp-heat accumulation.

Knowledge, attitudes, and practices in colorectal cancer screening in the Philippines

Background and Objective@#Colorectal cancer (CRC) has the third highest incidence in the Philippines. Currently, there is a paucity in literature that is focused on the knowledge, attitudes, and perceptions of Filipinos regarding CRC screening. This is the first study in the Philippines that describes this. @*Methods@#This is a cross-sectional study that validated a 52-item Filipino questionnaire on the knowledge on colorectal cancer, willingness to undergo CRC screening, and perceived benefits and barriers to fecal occult blood test (FOBT) and colonoscopy. The study enrolled household heads more than 20 years of age residing in both urban and rural communities in the Philippines. @*Results@#The UP-PGH CRC KAP (University of the Philippines – Philippine General Hospital Colorectal Cancer Knowledge, Attitudes, and Practices) and Rawl Questionnaire’s validity and internal consistency were established in a pilot study of 30 respondents. A total of 288 respondents were then enrolled to the main study group with a median age of 54.0. Knowledge scores for prognosis and utility of CRC screening were modest (6.3/12 and 8.4/20, respectively). Perceived benefit scores to FOBT and colonoscopy were high (9.9/12 and 13.9/16, respectively).Median scores to barriers to FOBT and colonoscopy were intermediate (22.5/36 and 35.8/60, respectively). Notably, a vast majority (86.1%) were willing to participate in CRC screening programs initiated by the government, and 46.9% agreed to undergo screening tests even as out-of-pocket expense. @*Conclusion@#The UP-PGH CRC KAP Questionnaire as well as the Filipino translation of the Rawl Questionnaire are reliable and valid tools in extensively assessing the knowledge of Filipinos on CRC and willingness to undergo screening, as well as the benefits of and barriers to FOBT and colonoscopy. Knowledge scores were modest suggesting that directed educational campaigns and awareness programs can aid in increasing awareness about CRC and its screening. Household income and highest educational attainment were significantly positively correlated with knowledge scores, and perceived benefits of and barriers to CRC screening. Scores were generally comparable between urban and rural communities.