Potential role of the Eph/ephrin system in colorectal cancer: emerging druggable molecular targets.

The Eph/ephrin system regulates many developmental processes and adult tissue homeostasis. In colorectal cancer (CRC), it is involved in different processes including tumorigenesis, tumor angiogenesis, metastasis development, and cancer stem cell regeneration. However, conflicting data regarding Eph receptors in CRC, especially in its putative role as an oncogene or a suppressor gene, make the precise role of Eph-ephrin interaction confusing in CRC development. In this review, we provide an overview of the literature and highlight evidence that collaborates with these ambiguous roles of the Eph/ephrin system in CRC, as well as the molecular findings that represent promising therapeutic targets.

SOX9 knockout decreases stemness properties in colorectal cancer cells.

Background: Colorectal cancer (CRC) is a leading cause of death worldwide. SRY-box transcription factor 9 (SOX9) participates in organogenesis and cell differentiation in normal tissues but has been involved in carcinogenesis development. Cancer stem cells (CSCs) are a small population of cells present in solid tumors that contribute to increased tumor heterogeneity, metastasis, chemoresistance, and relapse. CSCs have properties such as self-renewal and differentiation, which can be modulated by many factors. Currently, the role of SOX9 in the maintenance of the stem phenotype has not been well elucidated, thus, in this work we evaluated the effect of the absence of SOX9 in the stem phenotype of CRC cells. Methods: We knockout (KO) SOX9 in the undifferentiated CRC cell line HCT116 and evaluated their stemness properties using sphere formation assay, differentiation assay, and immunophenotyping. Results: SOX9-KO affected the epithelial morphology of HCT116 cells and stemness characteristics such as its pluripotency signature with the increase of SOX2 as a compensatory mechanism to induce SOX9 expression, the increase of KLF4 as a differentiation feature, as well as the inhibition of the stem cell markers CD44 and CD73. In addition, SOX9-KO cells gain the epithelial-mesenchymal transition (EMT) phenotype with a significant upregulation of CDH2. Furthermore, our results showed a remarkable effect on first- and second-sphere formation, being SOX9-KO cells less capable of forming high-size-resistant spheres. Nevertheless, CSCs surface markers were not affected during the differentiation assay. Conclusions: Collectively, our findings supply evidence that SOX9 promotes the maintenance of stemness properties in CRC-CSCs.

Decision-making on colorectal cancer screening in Curaçao - interviews with the target population.

BACKGROUND: During the first year of the population based colorectal cancer (CRC) screening program on Curaçao, about 20% of invitees participated. This study explored the target population's perceptions and awareness on CRC (screening), beliefs on the program provision, their preferences and information needs for informed decision-making. METHODS: Semi-structured interviews with 23 individuals, who were not yet invited for CRC screening, were recorded, transcribed, coded and analyzed. RESULTS: CRC (screening) was discussed in the context of personal health, where own responsibility and food were important. Cancer was perceived as an unpredictable disease that causes suffering and leads to death and was also associated with fear. Despite being aware of the program, most respondents were not familiar with the screening procedure. Provision of the screening program was regarded positively and as an opportunity to contribute to health improvement. This seemed related to the expressed trust in the Caribbean Prevention Center (program organizer). Respondents preferred to make independent decisions about CRC screening participation. A personal approach, visual aids and media were the preferred sources of information. CONCLUSION: The results of our interviews suggest that it may be beneficial to provide information on CRC screening in Curaçao within the context of personal health. While including sensitivity to fears and respect for the autonomy of the target population. Finally, electronic media maybe useful in supporting informed decision-making.

Study of long non-coding RNA Tug 1 expression in Egyptian colorectal adenocarcinoma patients

Purpose: Colorectal cancer (CRC) is one of the most fatal tumors worldwide. In Egypt, most CRC cases occur in individuals > 40 years old. TUG1 has been proved to be disrupted in different malignancies and may have a critical role in tumor progression, invasion, and metastasis. However, its role in CRC has not been adequately studied. Materials / Methods: Quantitative real-time polymerase chain reaction (PCR) was used to evaluate the expression levels of long non-coding RNA (LncRNA) taurine upregulated gene 1 (TUG1), in nonmetastatic and metastatic CRC tissues and adjacent noncancerous tissues as control. Results: LncRNA TUG1 expression was significantly upregulated in both nonmetastatic and metastatic CRC tissues, in comparison with the adjacent noncancerous tissue. It was found that TUG1 could have a possible prognostic role in CRC, by comparing the sensitivity and specificity of TUG1 with those of CEA and CA19-9. Conclusion: The results of the current study suggest that the LncRNA TUG1 participates in the malignant behaviors of CRC cells. (AU)

Immunotherapy combined with radiotherapy to reverse immunosuppression in microsatellite stable colorectal cancer.

In recent years, the exploration of immune checkpoint inhibitors (ICIs) has resulted in substantial progress and has changed the pattern of cancer treatment. ICIs have revolutionized the treatment landscape of microsatellite instable colorectal cancer while the efficacy is very limited in patients with microsatellite stable colorectal cancer. Therefore, sensitizing MSS CRC to immunotherapy is a major challenge in the field of CRC immunotherapy. Immunotherapy-based combination therapy is an effective strategy. This review of radiotherapy (RT) as a local treatment has dramatically changed in recent years, and it is now widely accepted that RT can deeply reshape the tumor environment by modulating the immune response. Such evidence gives a strong rationale for the synergism of radiotherapy and immunotherapy, introducing the era of 'immunoradiotherapy'. How to give full play to the synergistic effect of radiotherapy and immunotherapy to improve the therapeutic effect of MSS CRC and bring good prognosis is a hot problem to be solved in the field of cancer treatment.This article reviews the development of CRC immunotherapy, the immune resistance mechanism of MSS CRC, and the impact and potential value of immunotherapy combined with radiotherapy on the immune environment of CRC.

Prediction model of colorectal cancer (CRC) lymph node metastasis based on intestinal bacteria.

BACKGROUND: Lymph node metastasis is the main metastatic mode of CRC. Lymph node metastasis affects patient prognosis. OBJECTIVE: To screen differential intestinal bacteria for CRC lymph node metastasis and construct a prediction model. METHODS: First, fecal samples of 119 CRC patients with lymph node metastasis and 110 CRC patients without lymph node metastasis were included for the detection of intestinal bacterial 16S rRNA. Then, bioinformatics analysis of the sequencing data was performed. Community structure and composition analysis, difference analysis, and intragroup and intergroup correlation analysis were conducted between the two groups. Finally, six machine learning models were used to construct a prediction model for CRC lymph node metastasis. RESULTS: The community richness and the community diversity at the genus level of the two groups were basically consistent. A total of 12 differential bacteria (Agathobacter, Catenibacterium, norank_f__Oscillospiraceae, Lachnospiraceae_FCS020_group, Lachnospiraceae_UCG-004, etc.) were screened at the genus level. Differential bacteria, such as Agathobacter, Catenibacterium, norank_f__Oscillospiraceae, and Lachnospiraceae_FCS020_group, were more associated with no lymph node metastasis in CRC. In the discovery set, the RF model had the highest prediction accuracy (AUC = 1.00, 98.89% correct, specificity = 55.21%, sensitivity = 55.95%). In the test set, SVM model had the highest prediction accuracy (AUC = 0.73, 72.92% correct, specificity = 69.23%, sensitivity = 88.89%). Lachnospiraceae_FCS020_group was the most important variable in the RF model. Lachnospiraceae_UCG - 004 was the most important variable in the SVM model. CONCLUSION: CRC lymph node metastasis is closely related to intestinal bacteria. The prediction model based on intestinal bacteria can provide a new evaluation method for CRC lymph node metastasis.

Methylation detection of circulating tumor cell miR-486-5p/miR-34c-5p in the progression of colorectal cancer.

AIMS: This study set out to examine the expression and methylation levels of miR-486-5p/miR-34c-5p and its mechanism of action based on the microRNA methylation level of circulating tumor cells (CTCs) in colorectal cancer (CRC) through clinical data and tissue detection. METHODS: EGFR and EpCAM immunophospholipid magnetic spheres (EpCAM-IML/EGFR-IML) were synthesized by the thin film method to capture CTCs in peripheral blood. The expression of miR-486-5p/miR-34c-5p was detected via real-time fluorescent quantitative PCR (RT-PCR). Methylation-specific PCR was implemented to detect the methylation level of miR-486-5p/miR-34c-5p, and 5-Aza-dC was used for demethylation treatment to detect the effect of changes in methylation levels on the tumor cells development. Cell Counting Kit-8 (CCK-8) analysis, transwell assay, and flow cytometry were used to determine the effects of demethylation and overexpression on the proliferation, invasion, migration, and apoptosis of CRC cells. RESULTS: The results showed that the expression and methylation levels of the miR-486-5p/miR-34c-5p isolated from CTCs were low and the methylation level was high in tumor cells and tissues. In CRC cell lines, demethylation and overexpression of miR-486-5p/miR-34c-5p could effectively inhibit the proliferation, invasion and migration of tumor cells, and facilitate tumor apoptosis (p < 0.05). CONCLUSION: The constructed CTCs sorting system has characteristics of high specificity and high sensitivity, is a supplement to tissue samples, and has guiding significance for the clinical rational use of drugs and personalized therapy.

Knowledge, Attitudes, and Beliefs About Colorectal Cancer Screening in Puerto Rico.

The purpose of this study was to describe the psychosocial factors influencing participation in colorectal cancer screening (CRCS) among Puerto Rican men and women. We conducted seven focus groups in metropolitan and rural areas of Puerto Rico (PR) with men and women (using gender specific groups) aged 50 to 80 years (n = 51) who were non-adherent to CRC guidelines. The focus group guide included questions related to colorectal cancer (CRC) and CRC screening knowledge, attitudes, and beliefs. We analyzed data using a modified grounded theory approach to identify emergent themes. Focus groups revealed seven major themes that represented barriers to CRCS: (1) lack of CRC knowledge, (2) lack of knowledge about colorectal cancer screening tests as well as the required preparation, (3) embarrassment, (4) low perceived benefit of CRCS and sense of fatalism, (5) transportation (mostly among participants in rural areas), (6) lack of time, and (7) financial burden. All participants understood the benefits of CRCS once the procedure was explained. Additionally, participants reported a lack of provider recommendation for CRCS. In this group of Puerto Rican participants who were non-adherent to CRCS, there were misconceptions about CRC, screening tests available, and preparation and testing procedures. Participants' low levels of knowledge and negative attitudes concerning CRCS and low reported provider recommendation were important deterrents to screening. These findings suggest the need for educational efforts to increase knowledge and attitudes about CRCS and improved patient-provider communication to reduce missed opportunities to recommend.

C5aR1 promotes the progression of colorectal cancer by EMT and activating Wnt/ß-catenin pathway.

BACKGROUND: Colorectal cancer (CRC) is one of the most common malignant cancers in human, and its incidence increases gradually every year. Metastasis is an important factor leading to tumor development. The epithelial-mesenchymal transition (EMT) has been proved to be closely related to tumor metastasis, yet its related mechanism in CRC remains to be explored. METHODS: We obtained the differentially expressed gene C5aR1 with SETDB1 stable overexpression and knockdown cells by RNA-seq. Cell proliferation was tested by CCK8 and colony formation assay. Migration and invasion of CRC cells were determined by the wound healing and transwell invasion assay. The potential pathway of C5aR1 in CRC was preliminarily studied by western blotting. RESULTS: Sequencing results showed that C5aR1 was the most differentially expressed gene. By changing the expression of C5aR1 in CRC cells, this study found that C5aR1 promoted the proliferation, colony formation, migration and invasion of CRC cells in vitro. C5aR1 accelerated the EMT process and the expression of C5aR1 altered the molecular expression of key proteins in the Wnt/ß-catenin pathway. CONCLUSION: C5aR1 promotes the development of CRC and accelerates the EMT process. Furthermore, C5aR1 may involve in the regulation of Wnt/ß-catenin pathway in CRC.

NSABP FC-6: Surgical conversion rate in colorectal cancer patients with unresectable, KRAS wild-type liver metastases receiving mFOLFOX7 plus cetuximab.

PURPOSE: This study sought to determine the R0 resection rate in KRAS wild-type (WT), liver-only metastatic colorectal cancer (CRC) patients initially identified as having unresectable disease who were treated with FOLFOX7 plus cetuximab. Exploratory molecular analyses were undertaken before and after treatment. METHODS: Twenty patients were enrolled. None had prior adjuvant chemotherapy. Cetuximab was added to a FOLFOX7 backbone and administered at 500 mg/m2 every 14 days with dose reductions to 400 and 300 mg/m2 in the event of toxicity. In the absence of toxicity, dose-escalations to 600, 700, and 800 mg/m2 were allowed. The mean dose of cetuximab (mg/m2 /week) throughout the study was 289 mg/m2 . Paired samples were collected for correlative studies, where feasible. RESULTS: We assessed the conversion rates from unresectable to resectable in hepatic-only, KRAS exon 2 WT mCRC. Seventeen of 20 patients undergoing chemotherapy were considered resectable by imaging criteria; R0 resection was achieved in 15/20 patients. Molecular profiling revealed heterogeneity between patients at the gene-expression, pathway signaling, and immune-profile levels. CONCLUSIONS: Although 15/20 (75%) converted to R0 resection, by 2 years, 10/15 R0 resections had recurred. Therefore, chemotherapy plus cetuximab is of limited long-term benefit in this setting. ctDNA analysis may guide additional therapy including immunotherapy.

The value of exosome-derived noncoding RNAs in colorectal cancer proliferation, metastasis, and clinical applications.

Colorectal cancer (CRC) is the third most common cancer in the world today, and its incidence and mortality rates are increasing every year. The ease of proliferation and metastasis of CRC has long been an important reason for its high mortality rate. Exosomes serve as key mediators that mediate communication between tumor cells and various other cells. Non-coding RNAs (ncRNAs) have been shown to play a key role in apoptosis, immunosuppression and proliferation metastasis in cancer. ncRNAs are loaded on exosomes and initiate the onset of metastasis by promoting epithelial-mesenchymal transition (EMT) at the primary site of the tumor. Meanwhile, exosome-derived ncRNAs construct a pre-metastatic niche (PMN) for CRC metastasis by forming an inflammatory microenvironment in distant organs, immunosuppression, and promoting angiogenesis and remodeling of the extracellular matrix. Here, we summarize the specific mechanisms associated with exosome-derived ncRNAs promoting local invasion and metastasis in CRC. Finally, we focus on their value for clinical application in future CRC diagnosis and treatment.

Serum long-noncoding RNA H19 and beta-catenin as biomarkers for early diagnosis of colorectal cancer in egyptian patients: a case control study

Colorectal cancer (CRC) is the third most prevalent cancer and the second most common cause of cancer death; however, its early detection can improve the survival. Colonic polyps are considered one of the CRC's major risk factors. Throughout many biological processes and malignancies, the non-coding RNAs have essential functions. Certain long noncoding RNAs (lncRNAs), including H19, were supposed to be CRC possible biomarkers. Also, H19 has been reported to play a role in regulating the activity of beta-catenin, a protein that regulates cell-to-cell adhesion, as well as gene transcription. The current work aimed to investigate the potential significance of LncRNA H19 relative serum expression level by quantitative polymerase chain reaction (q-PCR) and beta-catenin by enzyme-linked immunosorbent assay (ELISA) as noninvasive biomarkers to discriminate between colorectal cancer and colonic polyps. The statistical analysis of the studied factors revealed that the serum expression of H19 and beta-catenin in cancer cases were substantially greater than colonic polyp cases and normal control. Conclusion: The relative expressions of H19 and beta-catenin in the serum can significantly discriminate patients with CRC from those with polyp and normal controls, which could help when screening for CRC. (AU)

ß-1,4-Galactosyltransferase-V colorectal cancer biomarker immunosensor with label-free electrochemical detection.

ß-1,4-Galactosyltransferase-V (ß-1,4-GalT-V) is a membrane-bound glycoprotein with glycosyltransferase enzyme activity that synthesizes lactosylceramide and glycosylates high-branched N-glycans in the Golgi apparatus. Colorectal cancer (CRC) tumor cells have shown to overexpress these biomolecules concerning normal cells, releasing them into the body fluids. Thus, their detection has been suggested as a diagnosis/prognosis CRC biomarker. We report the first electrochemical immunosensor for the detection of such a novel ß-1,4-GalT-V CRC biomarker. The label-free electrochemical immunosensor covalently coupled an anti-ß-1,4-GalT-V antibody at a mixed self-assembled monolayer-coated screen-printed gold electrode (SPAuE) surface. This functionalized platform captured the ß-1,4-GalT-V glycoprotein from human serum samples with high specificity, which response monitored by electrochemical impedance spectroscopy (EIS) was protein concentration-dependent. The resultant electrochemical immunosensor showed a linear dynamic range from 5 to 150 pM, with a sensitivity of 14 Ω pM-1 and a limit of detection of 7 pM, of clinical relevance. This outstanding performance makes it great potential for including it in a biomarker signature for the early diagnosis/prognosis of CRC.

Detección de mutaciones del Gen KRAS en pacientes paraguayos con cáncer colorrectal / Detection of KRAS Gene mutations in paraguayan patients with colorectal cancer

El estado mutacional del KRAS ha sido considerado como biomarcador para tratamientos biológicos tras varios ensayos clínicos realizados en pacientes con cáncer colorrectal metastásico. Reportes recientes indican que las frecuencias de mutación del gen KRAS en pacientes con CCR de Asia, Europa y Latinoamérica están entre el 24%, 36% y 40%, respectivamente. Paraguay no cuenta con este tipo de informes, a pesar de registrar anualmente en promedio 75 nuevos casos de pacientes diagnosticados con CCR sólo en el Servicio de Cirugía General del Hospital Central del Instituto de Previsión Social (IPS). El presente trabajo ha implementado este análisis de rutina, prerrequisito obligatorio para la administración de fármacos basados en anticuerpos terapéuticos, y revelado una frecuencia de mutación del gen KRAS del 34% en pacientes paraguayos con CCR que acuden a los Servicios del Hospital Central del IPS

The mutational status of the KRAS has been consider as a biomarker for biological treatments after several clinical trials carried out in patient with metastatic colorectal cancer. Recent reports indicate that the KRAS gene mutation frequencies in CRC patients from Asia, Europe, and Latin America are between 24%, 36%, and 40%, respectively. Paraguay does not have this kind of reports, despite registering an average of 75 new cases of patients diagnosed with CRC per year only in the General Surgery Service of the "Central Hospital - Instituto de Prevision Social (IPS)". The present work has implemented this routine analysis, a mandatory prerequisite for the administration of drugs based on therapeutic antibodies and revealed a KRAS gene mutation frequency of 34% in Paraguayan patients with CRC who attend the IPS Central Hospital Services

CRISPR/Cas13-Based Platforms for a Potential Next-Generation Diagnosis of Colorectal Cancer through Exosomes Micro-RNA Detection: A Review.

Colorectal cancer (CRC) is the third most prevalent cancer with the second highest mortality rate worldwide. CRC is a heterogenous disease with multiple risk factors associated, including obesity, smoking, and use of alcohol. Of total CRC cases, 60% are diagnosed in late stages, where survival can drop to about 10%. CRC screening programs are based primarily on colonoscopy, yet this approach is invasive and has low patient adherence. Therefore, there is a strong incentive for developing molecular-based methods that are minimally invasive and have higher patient adherence. Recent reports have highlighted the importance of extracellular vesicles (EVs), specifically exosomes, as intercellular communication vehicles with a broad cargo, including micro-RNAs (miRNAs). These have been syndicated as robust candidates for diagnosis, primarily for their known activities in cancer cells, including immunoevasion, tumor progression, and angiogenesis, whereas miRNAs are dysregulated by cancer cells and delivered by cancer-derived exosomes (CEx). Quantitative polymerase chain reaction (qPCR) has shown good results detecting specific cancer-derived exosome micro-RNAs (CEx-miRNAs) associated with CRC, but qPCR also has several challenges, including portability and sensitivity/specificity issues regarding experiment design and sample quality. CRISPR/Cas-based platforms have been presented as cost-effective, ultrasensitive, specific, and robust clinical detection tools in the presence of potential inhibitors and capable of delivering quantitative and qualitative real-time data for enhanced decision-making to healthcare teams. Thereby, CRISPR/Cas13-based technologies have become a potential strategy for early CRC diagnosis detecting CEx-miRNAs. Moreover, CRISPR/Cas13-based platforms' ease of use, scalability, and portability also showcase them as a potential point-of-care (POC) technology for CRC early diagnosis. This study presents two potential CRISPR/Cas13-based methodologies with a proposed panel consisting of four CEx-miRNAs, including miR-126, miR-1290, miR-23a, and miR-940, to streamline novel applications which may deliver a potential early diagnosis and prognosis of CRC.

The Relationship between AGAMOUS and Cytokinin Signaling in the Establishment of Carpeloid Features.

Gynoecium development is dependent on gene regulation and hormonal pathway interactions. The phytohormones auxin and cytokinin are involved in many developmental programs, where cytokinin is normally important for cell division and meristem activity, while auxin induces cell differentiation and organ initiation in the shoot. The MADS-box transcription factor AGAMOUS (AG) is important for the development of the reproductive structures of the flower. Here, we focus on the relationship between AG and cytokinin in Arabidopsis thaliana, and use the weak ag-12 and the strong ag-1 allele. We found that cytokinin induces carpeloid features in an AG-dependent manner and the expression of the transcription factors CRC, SHP2, and SPT that are involved in carpel development. AG is important for gynoecium development, and contributes to regulating, or else directly regulates CRC, SHP2, and SPT. All four genes respond to either reduced or induced cytokinin signaling and have the potential to be regulated by cytokinin via the type-B ARR proteins. We generated a model of a gene regulatory network, where cytokinin signaling is mainly upstream and in parallel with AG activity.

Characterization of Chilean patients with sporadic colorectal cancer according to the three main carcinogenic pathways: Microsatellite instability, CpG island methylator phenotype and Chromosomal instability.

Molecular classification of colorectal cancer is difficult to implement in clinical settings where hundreds of genes are involved, and resources are limited. This study aims to characterize the molecular subtypes of patients with sporadic colorectal cancer based on the three main carcinogenic pathways microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and chromosomal instability (CIN) in a Chilean population. Although several reports have characterized colorectal cancer, most do not represent Latin-American populations. Our study includes 103 colorectal cancer patients who underwent surgery, without neoadjuvant treatment, in a private hospital between 2008 and 2017. MSI, CIN, and CIMP status were assessed. Frequent mutations in KRAS, BRAF, and PIK3CA genes were analyzed by Sanger sequencing, and statistical analysis was performed by Fisher's exact and/or chi-square test. Survival curves were estimated with Kaplan-Meier and log-rank test. Based on our observations, we can classify the tumors in four subgroups, Group 1: MSI-high tumors (15%) are located in the right colon, occur at older age, and 60% show a BRAF mutation; Group 2: CIN-high tumors (38%) are in the left colon, and 26% have KRAS mutations. Group 3: [MSI/CIN/CIMP]-low/negative tumors (30%) are left-sided, and 39% have KRAS mutations; Group 4: CIMP-high tumors (15%) were more frequent in men and left side colon, with 27% KRAS and 7% presented BRAF mutations. Three percent of patients could not be classified. We found that CIMP-high was associated with a worse prognosis, both in MSI-high and MSI stable patients (p = 0.0452). Group 3 (Low/negative tumors) tend to have better overall survival compared with MSI-high, CIMP-high, and CIN-high tumors. This study contributes to understanding the heterogeneity of tumors in the Chilean population being one of the few characterizations performed in Latin-America. Given the limited resources of these countries, these results allow to improve molecular characterization in Latin-American colorectal cancer populations and confirm the possibility of using the three main carcinogenic pathways to define therapeutic strategies.

Spectrum and Frequency of Tumors, Cancer Risk and Survival in Chilean Families with Lynch Syndrome: Experience of the Implementation of a Registry.

Lynch syndrome (LS) is associated with the highest risk of colorectal (CRC) and several extracolonic cancers. In our effort to characterize LS families from Latin America, this study aimed to describe the spectrum of neoplasms and cancer risk by gender, age and gene, and survival in 34 Chilean LS families. Of them, 59% harbored path_MLH1, 23% path_MSH2, 12% path_PMS2 and 6% path_EPCAM variants. A total of 866 individuals at risk were identified, of which 213 (24.6%) developed 308 neoplasms. In males, CRC was the most common cancer (72.6%), while females showed a greater frequency of extracolonic cancers (58.4%), including uterus and breast (p < 0.0001). The cumulative incidence of extracolonic cancers was higher in females than males (p = 0.001). Path_MLH1 variants are significantly more associated with the development of CRC than extracolonic tumors (59.5% vs. 40.5%) when compared to path_MSH2 (47.5% vs. 52.5%) variants (p = 0.05018). The cumulative incidence of CRC was higher in path_MLH1/path_MSH2 carriers compared to path_PMS2 carriers (p = 0.03). In addition, path_MSH2 carriers showed higher risk of extracolonic tumors (p = 0.002). In conclusion, this study provides a snapshot of the LS profile from Chile and the current LS-associated diagnostic practice and output in Chile. Categorizing cancer risks associated with each population is relevant in the genetic counselling of LS patients.

Vemurafenib downmodulates aggressiveness mediators of colorectal cancer (CRC): Low Molecular Weight Protein Tyrosine Phosphatase (LMWPTP), Protein Tyrosine Phosphatase 1B (PTP1B) and Transforming Growth Factor ß (TGFß).

Colorectal Cancer (CRC) therapy confronts challenges as chemoresistance and side effects. Therefore, drugs with antitumor properties that downmodulate aggressiveness mediators are required. Studies have shown the relevance of Low Molecular Weight Protein Tyrosine Phosphatase (LMWPTP), Protein Tyrosine Phosphatase 1B (PTP1B), and Transforming Growth Factor ß (TGFß) in mediating proliferation, chemoresistance, and metastasis. In this study, we aimed to investigate the responsiveness of colorectal cancer lines (HT29 and HCT116) towards Vemurafenib and whether this treatment could modulate these aggressiveness mediators. Cytotoxicity Assays (MTT and Trypan Exclusion Test) were performed to evaluate the viability of HT29 and HCT116 cells treated with Vemurafenib. Western blotting was performed to analyze the amount and/or the activity of mediators (LMWPTP, PTP1B, TGFß, SMAD3), and the immunoprecipitation was performed to evaluate LMWPTP activity. This study brought up novel aspects of Vemurafenib action in colorectal cancer, which can decrease the activity of protein tyrosine phosphatases (LMWPTP and PTP1B) and the TGFß pathway, making them important in the CRC aggressiveness. By downmodulating colorectal cancer hallmarks, Vemurafenib appears as an interesting candidate for CRC therapeutic protocols.

Outcomes of metastatic colorectal cancer patients in relationship to prior and concurrent antibiotics use; individual patient data analysis of three clinical trials.

BACKGROUND: Antibiotic use at the time of chemotherapy has been linked with inferior outcomes among a number of solid tumors. The current study aims at further assessing this observation among metastatic colorectal cancer patients treated with first-line systemic chemotherapy. METHODS: This is a pooled analysis of three clinical trial datasets (NCT00384176; NCT00272051; NCT00305188) that were accessed from the Project Data Sphere platform. Kaplan-Meier survival estimates were used to evaluate the impact of antibiotic use on overall and progression-free survival and multivariable Cox regression models were employed to further assess this impact. RESULTS: A total of 1446 patients were included in the current analysis. These include 108 patients who received antibiotics before the start of chemotherapy, 499 patients who received antibiotics after the start of chemotherapy, and 839 patients who did not receive antibiotics. Using Kaplan-Meier survival estimates, the use of antibiotics prior to the start of chemotherapy was associated with worse progression-free (P = 0.001) and overall survival (P < 0.001). Likewise, when multivariable Cox regression analyses were conducted, prior antibiotic use is associated with worse progression-free (HR for antibiotic use during chemotherapy versus antibiotic use prior to chemotherapy = 0.764; 95% CI 0.604-0.966; P = 0.024) and overall survival (HR for antibiotic use during chemotherapy versus antibiotic use prior to chemotherapy = 0.710; 95% CI 0.537-0.940; P = 0.017). CONCLUSION: Antibiotic use before (but not following) the start of 5FU-based chemotherapy is associated with worse progression-free and overall survival among patients with metastatic colorectal cancer.