Explore the vast range of titles available.

Background Circular RNAs (circRNAs) play a critical role in colorectal cancer (CRC) progression, including metastasis. However, the detailed molecular mechanism is not fully understood. Methods Differentially expressed circRNAs between primary KM12C and liver metastatic KM12L4 colon cancer cells were identified by microarray. The expression of circRNAs was measured by semi-quantitative (semi-qPCR) and real time-quantitative PCR (RT-qPCR). Metastatic potential including invasive and migratory abilities, and liver metastasis were examined by transwell assays and intrasplenic injection, respectively. CircPPFIA1-associated microRNA (miRNA) and RNA-binding protein (RBP) were screened by an antisense oligonucleotide (ASO) pulldown experiment. The effects of circPPFIA1 on target gene expression were evaluated by RT-qPCR and western blot analyses. Results By analyzing circRNA microarray data, we identified two anti-metastatic circRNAs generated from PPFIA1 with different length, which named circPPFIA1-L (long) and -S (short). They were significantly downregulated in liver metastatic KM12L4 cells compared to primary KM12C cells. The knockdown of circPPFIA1s in KM12C enhanced metastatic potential and increased liver metastasis. Conversely, overexpression of circPPFIA1s weakened metastatic potential and inhibited liver metastasis. circPPFIA1s were found to function as sponges of oncogenic miR-155-5p and Hu antigen R (HuR) by an ASO pulldown experiment. circPPFIA1s upregulated tumor-suppressing CDX1 expression and conversely downregulated oncogenic RAB36 by decoying miR-155-5p and by sequestering HuR, respectively. Conclusion Our findings demonstrate that circPPFIA1s inhibit the liver metastasis of CRC via the miR-155-5p/CDX1 and HuR/RAB36 pathways.

Although stromal fibroblasts play a critical role in cancer progression, their identities remain unclear as they exhibit high heterogeneity and plasticity. Here, a master transcription factor (mTF) constructing core-regulatory circuitry, PRRX1 , which determines the fibroblast lineage with a myofibroblastic phenotype, is identified for the fibroblast subgroup. PRRX1 orchestrates the functional drift of fibroblasts into myofibroblastic phenotype via TGF-β signaling by remodeling a super-enhancer landscape. Such reprogrammed fibroblasts have myofibroblastic functions resulting in markedly enhanced tumorigenicity and aggressiveness of cancer. PRRX1 expression in cancer-associated fibroblast (CAF) has an unfavorable prognosis in multiple cancer types. Fibroblast-specific PRRX1 depletion induces long-term and sustained complete remission of chemotherapy-resistant cancer in genetically engineered mice models. This study reveals CAF subpopulations based on super-enhancer profiles including PRRX1 . Therefore, mTFs, including PRRX1 , provide another opportunity for establishing a hierarchical classification system of fibroblasts and cancer treatment by targeting fibroblasts. Cancer associated fibroblasts are an important and highly heterogeneous component of the tumor microenvironment. Here the authors identify PRRX1 as a master transcription factor determining a fibroblast lineage with myofibroblastic phenotype, associated with unfavourable prognosis in several cancer types.

Patients with pathologic complete response (pCR) achievement can consider local excision or “watch and wait” strategy instead of a radical surgery. This study analyzed the predictive factors of pCR in rectal cancer patients who underwent radical operation after neoadjuvant chemoradiotherapy (nCRT). This study also analyzed the recurrence patterns in patients who achieved pCR and the oncologic outcomes and prognostic factors by ypStage. Between 2000 and 2013, 1,089 consecutive rectal cancer patients who underwent radical resection after nCRT were analyzed. These patients were classified into two groups according to pCR. The clinicopathologic and oncologic outcomes were analyzed and compared between the two groups. Multivariate analysis was conducted on factors related to pCR. The proportion of patients achieving pCR was 18.2% (n = 198). The pCR group demonstrated earlier clinical T and N stages, smaller tumor size, better differentiation, and a lower percentage of circumferential resection margin (CRM) involvement than did the non-pCR group. The prognostic factors associated with poorer disease-free survival were high preoperative carcinoembryonic antigen levels, non-pCR, poor histology, lymphatic/perineural invasion, and involvement of CRM. Multivariate analysis revealed that clinical node negativity, tumor size < 4 cm, and well differentiation were significant independent clinical predictors for achieving pCR. Patients with pCR displayed better long-term outcomes than those with non-pCR. The pCR-prediction model, based on predictive factors, is potentially useful for prognosis and for prescribing a treatment strategy in patients with advanced rectal cancer who need nCRT.

Acculturative stress and social support play important roles in suicide-related phenomena among adolescent immigrants. To examine their contributions, measures of acculturative and general life stress and a measure of multiple sources of social support were used to predict psychological distress and suicidal ideation among Korean-born high school students residing in the US. Korean students who were sojourning without both parents were compared to Korean students who immigrated with both parents, Korean students who remained in Korea, and American high school students in the US (total N = 227; 56.8% female). The sojourning group reported higher levels of life stress, distress, psychological symptoms, and suicidal ideation than the other groups. Within the two acculturating groups, levels of distress, symptoms, and suicidal ideation were associated with life stress, lack of parental support, and not living with both parents. The findings have important implications for suicide prevention among immigrant adolescents, and imply that parental support is particularly protective.

Texture analysis generates image parameters from F-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT). Although some parameters correlate with tumor biology and clinical attributes, their types and implications can be complex. To overcome this limitation, pseudotime analysis was applied to texture parameters to estimate changes in individual sample characteristics, and the prognostic significance of the estimated pseudotime of primary tumors was evaluated. Our subjects were 224 rectal cancer patients who underwent pretherapeutic FDG PET/CT and neoadjuvant concurrent chemoradiation therapy (CCRT). Texture parameters of the primary tumor were extracted from FDG PET/CT images acquired before neoadjuvant CCRT. The pseudotime of the primary tumor was successfully derived from texture parameters using the Phenopath tool. Clinico-pathologic features were obtained and survival analysis was performed. Pseudotime, metabolic tumor volume (MTV), and total lesion glycolysis (TLG) demonstrated significant associations with overall survival. Unlike MTV and TLG, pseudotime was an independent prognostic factor for overall survival (hazard ratio = 4.807, p-value = 0.037). Pseudotime analysis integrates various metabolic texture parameters into a single metric. Pseudotime estimated from FDG PET/CT images of primary tumors shows superior prognostic significance to conventional PET parameters in patients with locally advanced rectal cancer treated with tri-modality therapy.

The aim of this study was to evaluate the clinicopathologic features and prognosis of signet ring cell (SRC) carcinoma and compare them with those of mucinous and poorly differentiated adenocarcinomas of the colorectum. The clinicopathologic data of 35 patients with primary SRC carcinoma were reviewed and compared with the data from 294 patients with mucinous and 252 patients with poorly differentiated adenocarcinoma. Eighty percent of the SRC patients presented with more advanced disease (stages III and IV), whereas 55.1% and 64.7% of the patients in the mucinous and poorly differentiated groups had advanced disease at diagnosis, respectively (80% vs 55.1%, P = .04 and 80.0% vs 64.7%, P = .437). Median survival time for patients with SRC was 18.4 months (95% confidence interval 10.4 to 19.6). Three- and 5-year survival rates in the SRC group were 33.7% and 25.3%, respectively. The overall survival rate of patients with SRC was significantly poorer than that of patients with mucinous or poorly differentiated adenocarcinoma ( P < .001). SRC of the colorectum is characterized by advanced stage at diagnosis with lower rates of curative resection. It tends to affect younger patients with more propensity for lymphovascular invasion.

Colorectal cancer is a devastating disease with a low 5-year survival rate. Recently, many researchers have studied the mechanisms of tumor progression related to the tumor microenvironment. Here, we addressed the prognostic value of tumor-associated macrophages (TAMs) using a total of 232 CRC patient tissue samples and investigated the mechanisms underlying TAM-related colon cancer progression with respect to PI3Kγ regulation using in vitro, in vivo, and ex vivo approaches. Patients with M2/M1 < 3 had significantly improved progression-free survival and overall survival compared with patients with M2/M1 > 3. M1 and M2 macrophages elicited opposite effects on colon cancer progression via the FBW7-MCL-1 axis. Blocking macrophage PI3Kγ had cytotoxic effects on colon cancer cells and inhibited epithelial–mesenchymal transition features by regulating the FBW7-MCL-1 axis. The results of this study suggest that macrophage PI3Kγ may be a promising target for immunotherapy in colon cancer.Cancer treatment: turning the tide against colon cancerDrugs that target a specific subset of immune cells could render colorectal tumors more susceptible to immunological destruction by the host. The cellular composition of a tumor profoundly affects the odds of progression or survival, and some immune cell types can stall the antitumor response rather than strengthening it. Researchers led by Yong Beom Cho of Sungkyunkwan University, Seoul, South Korea, explored the impact of various subpopulations of macrophages, cells that help coordinate the immune counterattack against cancer. The researchers learned that the relative balance between M2 and M1 subtypes of macrophages correlates with colorectal cancer outcomes, patients with less M2 and more M1 activity generally faring better. They also uncovered a strategy for inhibiting M2 activity, which unleashes a more-aggressive response against the tumor and could thus offer a useful therapeutic approach.

BackgroundStatins preferentially promote tumor-specific apoptosis by depleting isoprenoid such as farnesyl pyrophosphate and geranylgeranyl pyrophosphate. However, statins have not yet been approved for clinical cancer treatment due, in part, to poor understanding of molecular determinants on statin sensitivity. Here, we investigated the potential of statins to elicit enhanced immunogenicity of KRAS-mutant (KRASmut) tumors.MethodsThe immunogenicity of treated cancer cells was determined by western blot, flow cytometry and confocal microscopy. The immunotherapeutic efficacy of mono or combination therapy using statin was assessed in KRASmut tumor models, including syngeneic colorectal cancer and genetically engineered lung and pancreatic tumors. Using NanoString analysis, we analyzed how statin influenced the gene signatures associated with the antigen presentation of dendritic cells in vivo and evaluated whether statin could induce CD8+ T-cell immunity. Multiplex immunohistochemistry was performed to better understand the complicated tumor-immune microenvironment.ResultsStatin-mediated inhibition of KRAS prenylation provoked severe endoplasmic reticulum (ER) stress by attenuating the anti-ER stress effect of KRAS mutation, thereby resulting in the immunogenic cell death (ICD) of KRASmut cancer cells. Moreover, statin-mediated ICD enhanced the cross-priming ability of dendritic cells, thereby provoking CD8+ T-cell immune responses against KRASmut tumors. Combination therapy using statin and oxaliplatin, an ICD inducer, significantly enhanced the immunogenicity of KRASmut tumors and promoted tumor-specific immunity in syngeneic and genetically engineered KRASmut tumor models. Along with immune-checkpoint inhibitors, the abovementioned combination therapy overcame resistance to PD-1 blockade therapies, improving the survival rate of KRASmut tumor models.ConclusionsOur findings suggest that KRAS mutation could be a molecular target for statins to elicit potent tumor-specific immunity.

Background Previous investigations of transcriptomic signatures of cancer patient survival and post-therapy relapse have focused on tumor tissue. In contrast, here we show that in colorectal cancer (CRC) transcriptomes derived from n ormal tissues a djacent to t umors (NATs) are better predictors of relapse. Results Using the transcriptomes of paired tumor and NAT specimens from 80 Korean CRC patients retrospectively determined to be in recurrence or nonrecurrence states, we found that, when comparing recurrent with nonrecurrent samples, NATs exhibit a greater number of differentially expressed genes (DEGs) than tumors. Training two prognostic elastic net-based machine learning models—NAT-based and tumor-based in our Samsung Medical Center (SMC) cohort, we found that NAT-based model performed better in predicting the survival when the model was applied to the tumor-derived transcriptomes of an independent cohort of 450 COAD patients in TCGA. Furthermore, compositions of tumor-infiltrating immune cells in NATs were found to have better prognostic capability than in tumors. We also confirmed through Cox regression analysis that in both SMC-CRC as well as in TCGA-COAD cohorts, a greater proportion of genes exhibited significant hazard ratio when NAT-derived transcriptome was used compared to when tumor-derived transcriptome was used. Conclusions Taken together, our results strongly suggest that NAT-derived transcriptomes and immune cell composition of CRC are better predictors of patient survival and tumor recurrence than the primary tumor.

A previous phase II clinical trial of adipose‐derived stem cell (ASC) therapy for fistulae associated with Crohn's disease, a devastating condition with a high recurrence rate, demonstrated safety and therapeutic potential with a 1‐year sustained response. In the present study, 41 of the 43 phase II trial patients were followed for an additional year, regardless of response in the initial year. At 24 months, complete healing was observed in 21 of 26 patients (80.8%) in modified per protocol analysis and 27 of 36 patients (75.0%) in modified intention‐to‐treat analysis. No adverse events related to ASC administration were observed. Furthermore, complete closure after initial treatment was well‐sustained. These results strongly suggest that autologous ASCs may be a novel treatment option for Crohn's fistulae. A previous phase II clinical trial of adipose‐derived stem cell (ASC) therapy for fistulae associated with Crohn's disease demonstrated safety and therapeutic potential with a 1‐year sustained response. In the present study, 41 of the 43 patients were followed for an additional year. No adverse events related to ASC administration were observed, and complete closure after initial treatment was well‐sustained, suggesting that this may be a novel treatment option.