Decreased interleukin-17RA expression is associated with good prognosis in patients with colorectal cancer and inhibits tumor growth and vascularity in mice.

BACKGROUND: Interleukin-17 (IL-17) is a pro-inflammatory cytokine that plays a vital role in the promotion of tumorigenesis in various cancers, including colorectal cancer (CRC). Based on current evidence, IL-17 binds to interleukin-17 receptor A (IL-17RA); however, the role of IL-17RA has not been elucidated in previous studies on CRC. In this study, we explored the role of IL-17RA in human CRC tissues and the progression of CRC in humans and mice. METHODS: The expressions of IL-17RA and epithelial-mesenchymal transition (EMT)-related genes were examined in CRC cells and tissue samples by quantitative real-time polymerase chain reaction. The role of IL-17RA in pathogenesis and prognosis was evaluated using a Chi-squared test, Kaplan-Meier analysis, univariate, and multivariate Cox regression analysis in 133 CRC patients. A tumor-bearing mice model was executed to evaluate the role of IL-17RA in tumor growth, vascularity and population of infiltrating immune cells. RESULTS: IL-17RA expression was found to be significantly higher in CRC tissues than in adjacent normal tissues. The expression of IL-17RA in Stage IV patients was significantly higher than that in Stages I and II patients. Patients with high IL-17RA expression exhibited significantly worse overall and CRC-specific survival than those with low IL-17RA expression. Functional assessment suggested that the knockdown of IL-17RA expression distinctly suppressed cellular proliferation, migration, invasion, and EMT-related gene expression. In a tumor-bearing mouse model, decreased IL-17RA expression significantly repressed tumor growth and vascularity and reduced the population of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). CONCLUSION: Reduced IL-17RA expression also suppressed cellular proliferation, migration, and invasion, and the expression of EMT genes. Knockdown of IL-17RA inhibited tumor growth and vascularity and decreased the population of Tregs and MDSCs in mouse tumors. Overall, IL-17RA expression was identified to be independently associated with the prognosis of patients with CRC.

The rare circulating tumor microemboli as a biomarker contributes to predicting early colorectal cancer recurrences after medical treatment.

Early prognosis of cancer recurrence remains difficult partially due to insufficient and ineffective screening biomarkers or regimes. This study evaluated the rare circulating tumor microemboli (CTM) from liquid biopsy individually and together with circulating tumor cells (CTCs) and serum CEA/CA19-9 in a panel, on early prediction of colorectal cancer (CRC) recurrence. Stained CTCs/CTM were detected by a microfluidic chip-based automatic rare-cell imaging platform. ROC, AUC, Kaplan-Meier survival, and Cox proportional hazard models regarding 4 selected biomarkers were analyzed. The relative risk, odds ratio, predictive accuracy, and positive/negative predictive value of biomarkers individually and in combination, to predict CRC recurrence were assessed and preliminarily validated. The EpCAM+Hochest+CD45- CTCs/CTM could be found in all cancer stages, where more recurrences were observed in late-stage cases. Significant correlations between CTCs/CTM with metastatic stages and clinical treatment were illustrated. CA19-9 and CTM could be seen as independent risk factors in patient survivals, while stratified patients by grouped biomarkers on the Kaplan-Meier analyses presented more significant differences in predicting CRC recurrences. By monitoring the panel of selected biomarkers, disease progressions of 4 CRC patients during follow-up visits after first treatments within 3 years were predicted successfully. This study unveiled the value of rare CTM on clinical studies and a panel of selected biomarkers on predicting CRC recurrences in patients at the early time after medical treatment, in which the CTM and serum CA19-9 could be applied in clinical surveillance and CRC management to improve the accuracy.

MiSelect R System: the validation of a new detection system of CTCs and their correlation with prognosis in non-metastatic CRC patients.

Circulating tumor cells (CTCs) in blood are accepted as a prognostic marker for patients with metastatic colorectal cancer (CRC). However, there is limited data on the use of CTCs as a prognostic marker for non-metastatic patients. In the current study, we used a rare cell automated analysis platform, the MiSelect R System, to enumerate CTCs from blood in non-metastatic CRC patients, and corelated the number of CTCs with the clinical staging and survival. The presence of CTCs in mesenteric vein blood (MVB) samples from 101 CRC patients was significantly associated with T stage. Patients with 1 or more CTCs per 8 mL of MVB exhibited significantly worse disease-free survival (DFS) and cancer-specific survival (CSS) compared to patient without CTCs. The presence of CTCs before surgery is an independent marker for both DFS and CSS. CTC presence after surgical resection is also a prognostic marker. CTCs are a potentially useful prognostic and predictive biomarker in non-metastatic CRC patients that may further stratify patient's risk status within different stages of disease.

The neural correlates of emotional conflict monitoring as an early manifestation of affective and cognitive declines in persons with Type 2 diabetes.

Patients with Type 2 diabetes are known to be more susceptible to experience dementia and depression/anxiety. The neural circuits of emotional conflict monitoring, as indicated by a Stroop task, might become altered in terms of cognitive and affective impairments in diabetes. This study investigated alterations in the emotional conflict monitoring and associations of corresponding brain activities with metabolic parameters in persons with Type 2 diabetes. Participants with normal cognitive and affective functioning, including 40 persons with Type 2 diabetes and 30 non-diabetes control subjects, underwent a functional MRI paradigm with the face-word emotional Stroop task and detailed cognitive and affective assessments, including the Montreal Cognitive Assessment and Beck Anxiety Inventory. Compared with the controls, people with diabetes exhibited stronger emotional interference, as indicated by differential reaction times between congruent and incongruent trials (Δcon). Δcon was correlated with Montreal Cognitive Assessment test scores and fasting glucose levels. People with diabetes demonstrated altered brain activation and functional connectivity in the neural network for emotional conflict monitoring. The neural network for emotional conflict monitoring mediated the association of pancreatic function with anxiety scores as well as the relationship between Δcon and Montreal Cognitive Assessment scores. Results suggested that alterations in the neural network underlying emotional conflict monitoring might present before clinically measurable cognitive and affective decrements were apparent, thereby bridging the gap between dementia and anxiety/depression in persons with diabetes.

Enhanced prognostic value of combined circulating tumor cells and serum carcinoembryonic antigen in patients with colorectal cancer.

BACKGROUND: Circulating tumor cells (CTCs) have been investigated as a potential biomarker for predicting prognosis and monitoring therapeutic responses in colorectal cancer (CRC). However, the sensitivity of CTCs detection is low, thus limiting the clinical utility of CTCs. We aim to examine the clinicopathological parameters that improve prognosis prediction for CRC using CTCs as a biomarker. METHODS: We enumerated CTCs in 186 CRC patients and associated the number of CTCs with the clinicopathological features and overall survival (OS) using a univariate and multivariate Cox regression model and Kaplan-Meier survival analysis. RESULTS: The presence of CTCs from 186 CRC patients was significantly associated with stage, preoperational carcinoembryonic antigen (CEA), and CA19-9 levels. Using Kaplan-Meier survival and Cox regression analysis, patients with five or more CTCs exhibited significantly worse OS compared to patients with fewer than five CTCs. The combination of CTCs with tumor marker CEA has a better OS prediction than individual CTCs or CEA and serves as a more effective prediction model in patients with CRC. CONCLUSION: We identified that patients with more than five CTCs exhibited significantly worse OS. Additionally, patients with the normal level of CEA, but who also had more than five CTCs trended towards a worse OS.

Stomatin modulates adipogenesis through the ERK pathway and regulates fatty acid uptake and lipid droplet growth.

Regulation of fatty acid uptake, lipid production and storage, and metabolism of lipid droplets (LDs), is closely related to lipid homeostasis, adipocyte hypertrophy and obesity. We report here that stomatin, a major constituent of lipid raft, participates in adipogenesis and adipocyte maturation by modulating related signaling pathways. In adipocyte-like cells, increased stomatin promotes LD growth or enlargements by facilitating LD-LD fusion. It also promotes fatty acid uptake from extracellular environment by recruiting effector molecules, such as FAT/CD36 translocase, to lipid rafts to promote internalization of fatty acids. Stomatin transgenic mice fed with high-fat diet exhibit obesity, insulin resistance and hepatic impairments; however, such phenotypes are not seen in transgenic animals fed with regular diet. Inhibitions of stomatin by gene knockdown or OB-1 inhibit adipogenic differentiation and LD growth through downregulation of PPARγ pathway. Effects of stomatin on PPARγ involves ERK signaling; however, an alternate pathway may also exist.

Potential Values of Circulating microRNA-21 to Predict Early Recurrence in Patients with Colorectal Cancer after Treatments.

Insufficient prognosis of local recurrence contributes to the poor progression-free survival rate and death in colorectal cancer (CRC) patients. Various biomarkers have been explored in predicting CRC recurrence. This study investigated the expressions of plasma/exosomal microRNA-21 (miR-21) in 113 CRC patients by qPCR, their values of predicting CRC recurrence, and the possibility to improve the prognostic efficacy in early CRC recurrence in stratified patients by combined biomarkers including circulating miR-21s, circulating tumour cells/microemboli (CTCs/CTM), and serum carcinoembryonic antigen (CEA)/carbohydrate antigen 19-9 (CA19-9). Expressions of plasma and exosomal miR-21s were significantly correlated (p < 0.0001) in all and late-stage patients, presenting similar correlations with other biomarkers. However, stage IV patients stratified by a high level of exosomal miR-21 and stage I to III patients stratified by a high level of plasma miR-21 displayed significantly worse survival outcomes in predicting CRC recurrence, suggesting their different values to predict CRC recurrence in stratified patients. Comparable and even better performances in predicting CRC recurrence in late-stage patients were found by CTCs/CTM from our blood samples as sensitive biomarkers. Improved prognosing efficacy in CRC recurrence and better outcomes to significantly differentiate recurrence in stratified patients could be obtained by analysing combined biomarkers.

Distant Metastasis of Tongue Squamous Cell Carcinoma Presenting as Multiple Subdermal and Intramuscular Cysts: A Case Report.

The most common sites of distant metastasis (DM) in squamous cell carcinoma (SCC) of the tongue are the lung, bone, and liver; the early identification of metastasis to other sites is difficult. This case report discusses a 48-year-old male initially diagnosed with advanced-stage left tongue SCC, which was treated with wide excision, left radical neck dissection, and adjuvant concurrent chemoradiotherapy. Two months after completing adjuvant therapy, multiple painful nodules without local erythematous changes or warmth were found in the bilateral posterior neck and right medial thigh. Ultrasonography of these nodules revealed a cystic structure. Fine needle aspiration cytology revealed metastatic SCC. The disease progressed despite salvage chemotherapy, and the patient passed away 4 months after the formation of the nodules. Subdermal and intramuscular cysts as the initial presentation of DM have rarely been reported. The identification of unusual cysts, even those outside the head and neck, should raise concern.

Using bioinformatics approaches to investigate driver genes and identify BCL7A as a prognostic gene in colorectal cancer.

Colorectal cancer (CRC) results from the uncontrolled growth of cells in the colon, rectum, or appendix. The 5-year relative survival rate for patients with CRC is 65% and is correlated with the stage at diagnosis (being 91% for stage I at diagnosis versus 12% for stage IV). This study aimed to identify CRC driver genes to assist in the design of a cancer panel to detect gene mutations during clinical early-stage screening and identify genes for use in prognostic assessments and the evaluation of appropriate treatment options. First, we utilized bioinformatics approaches to analyze 354 paired sequencing profiles from The Cancer Genome Atlas (TCGA) to identify CRC driver genes and analyzed the sequencing profiles of 38 patients with >5 years of follow-up data to search for prognostic genes. The results revealed eight driver genes and ten prognostic genes. Next, the presence of the identified gene mutations was verified using tissue and blood samples from Taiwanese CRC patients. The results showed that the set identified gene mutations provide high coverage for driver gene screening, and APC, TP53, PIK3CA, and FAT4 could be detected in blood as ctDNA test targets. We further found that BCL7A gene mutation was correlated with prognosis in CRC (log-rank p-value = 0.02), and that mutations of BCL7A could be identified in ctDNA samples. These findings may be of value in clinical early cancer detection, disease monitoring, drug development, and treatment efforts in the future.

Highly Correlated Recurrence Prognosis in Patients with Metastatic Colorectal Cancer by Synergistic Consideration of Circulating Tumor Cells/Microemboli and Tumor Markers CEA/CA19-9.

Circulation tumor cells (CTCs) play an important role in metastasis and highly correlate with cancer progression; thus, CTCs could be considered as a powerful diagnosis tool. Our previous studies showed that the number of CTCs could be utilized for recurrence prediction in colorectal cancer (CRC); however, the odds ratio was still lower than five. To improve prognosis in CRC patients, we analyzed CTC clusters/microemboli, CTC numbers, and carcinoembryonic antigen (CEA)/carbohydrate antigen 19-9 (CA19-9) levels using a self-assembled cell array (SACA) chip system for recurrence prediction. In CRC patients, the presence of CTC clusters/microemboli may have higher correlation in metastasis when compared to the high number of CTCs. Additionally, when both the number of CTCs and serum CEA levels are high, very high odds ratios of 24.4 and 17.1 are observed in patients at all stages and stage III of CRC, respectively. The high number of CTCs and CTC clusters/microemboli simultaneously suggests the high chance of relapse (odds ratio 8.4). Overall, the characteristic of CTC clusters/microemboli, CEA level, and CTC number have a clinical potential to enhance CRC prognosis.

The microRNA-210-Stathmin1 Axis Decreases Cell Stiffness to Facilitate the Invasiveness of Colorectal Cancer Stem Cells.

Cell migration is critical for regional dissemination and distal metastasis of cancer cells, which remain the major causes of poor prognosis and death in patients with colorectal cancer (CRC). Although cytoskeletal dynamics and cellular deformability contribute to the migration of cancer cells and metastasis, the mechanisms governing the migratory ability of cancer stem cells (CSCs), a nongenetic source of tumor heterogeneity, are unclear. Here, we expanded colorectal CSCs (CRCSCs) as colonospheres and showed that CRCSCs exhibited higher cell motility in transwell migration assays and 3D invasion assays and greater deformability in particle tracking microrheology than did their parental CRC cells. Mechanistically, in CRCSCs, microRNA-210-3p (miR-210) targeted stathmin1 (STMN1), which is known for inducing microtubule destabilization, to decrease cell elasticity in order to facilitate cell motility without affecting the epithelial-mesenchymal transition (EMT) status. Clinically, the miR-210-STMN1 axis was activated in CRC patients with liver metastasis and correlated with a worse clinical outcome. This study elucidates a miRNA-oriented mechanism regulating the deformability of CRCSCs beyond the EMT process.

Fabrication and Physical Properties of Single-Crystalline Βeta-FeSi2 Nanowires.

In this study, self-catalyzed ß-FeSi2 nanowires, having been wanted but seldom achieved in a furnace, were synthesized via chemical vapor deposition method where the fabrication of ß-FeSi2 nanowires occurred on Si (100) substrates through the decomposition of the single-source precursor of anhydrous FeCl3 powders at 750-950 °C. We carefully varied temperatures, duration time, and the flow rates of carrier gases to control and investigate the growth of the nanowires. The morphology of the ß-FeSi2 nanowires was observed with scanning electron microscopy (SEM), while the structure of them was analyzed with X-ray diffraction (XRD) and transmission electron microscopy (TEM). The growth mechanism has been proposed and the physical properties of the iron disilicide nanowires were measured as well. In terms of the magnetization of ß-FeSi2, nanowires were found to be different from bulk and thin film; additionally, longer ß-FeSi2 nanowires possessed better magnetic properties, showing the room-temperature ferromagnetic behavior. Field emission measurements demonstrate that ß-FeSi2 nanowires can be applied in field emitters.

An integrative analysis of 5HTT-mediated mechanism of hyperactivity to non-threatening voices.

The tonic model delineating the serotonin transporter polymorphism's (5-HTTLPR) modulatory effect on anxiety points towards a universal underlying mechanism involving a hyper-or-elevated baseline level of arousal even to non-threatening stimuli. However, to our knowledge, this mechanism has never been observed in non-clinical cohorts exhibiting high anxiety. Moreover, empirical support regarding said association is mixed, potentially because of publication bias with a relatively small sample size. Hence, how the 5-HTTLPR modulates neural correlates remains controversial. Here we show that 5-HTTLPR short-allele carriers had significantly increased baseline ERPs and reduced fearful MMN, phenomena which can nevertheless be reversed by acute anxiolytic treatment. This provides evidence that the 5-HTT affects the automatic processing of threatening and non-threatening voices, impacts broadly on social cognition, and conclusively asserts the heightened baseline arousal level as the universal underlying neural mechanism for anxiety-related susceptibilities, functioning as a spectrum-like distribution from high trait anxiety non-patients to anxiety patients.

RAB27B-activated secretion of stem-like tumor exosomes delivers the biomarker microRNA-146a-5p, which promotes tumorigenesis and associates with an immunosuppressive tumor microenvironment in colorectal cancer.

The dynamic cell-cell communication is essential for tissue homeostasis in normal physiological circumstances and contributes to a diversified tumor microenvironment. Although exosomes are extracellular vesicles that actively participate in cell-cell interaction by shutting cellular components, impacts of tumor exosomes in the context of cancer stemness remain elusive. Here, we expand colorectal cancer stem cells (CRCSCs) as cancer spheroids and demonstrate that the ß-catenin/Tcf-4-activated RAB27B expression is required for the secretion of CRCSC exosomes. In an exosomal RNA sequencing analysis, a switch of exosomal RNA species from retrotransposons to microRNAs (miRNAs) is identified upon expanding CRCSCs. miRNA-146a-5p (miR-146a) is the major miRNA in CRCSC exosomes and exosomal miR-146a promotes stem-like properties and tumorigenicity by targeting Numb in recipient CRC cells. Among 53 CRC patients, those with abundant exosomal miR-146a expression in serum exhibits higher miR-146aHigh /NumbLow CRCSC traits, an increased number of tumor-filtrating CD66(+) neutrophils and a decreased number of tumor-infiltrating CD8(+) T cells. Our study elucidates a unique mechanism of tumor exosome-mediated stemness expansion.

Author Correction: MicroRNA-146a directs the symmetric division of Snail-dominant colorectal cancer stem cells.

In the version of Supplementary Fig. 6c originally published with this Article, the immunoprecipitation (IP) and immunoblotting (IB) tags in the top panel were mislabelled. In addition, in Supplementary Fig. 6e, the blot of the IP: Numb; IB: ß-Trcp panel for HCT15 was mistakenly duplicated for HCT116. The correct versions of these figures are shown below. An independent repeat of the experiments presented in Supplementary Fig. 6c and e, showing results that are consistent with those reported in the unprocessed blots, have been deposited in figshare ( 10.6084/m9.figshare.7570685 ).

Enumerating Circulating Tumor Cells with a Self-Assembled Cell Array (SACA) Chip: A Feasibility Study in Patients with Colorectal Cancer.

Colorectal cancer (CRC) is the second most common cause of cancer-related death worldwide. Detecting and enumerating circulating tumor cells (CTCs) in patients with colorectal cancer emerged as an important prognostic tool which provides a direct estimate of metastatic potential. Improving the turnaround time and decreasing sample volume is critical for incorporating this liquid biopsy tool into routine practice. The objective of the current study was to validate the clinical feasibility of a self-assembled cell array (SACA) chip, a CTC counting platform with less than 4 h turnaround time, in patients with newly diagnosed colorectal cancers. In total, 179 patients with newly diagnosed colorectal cancers from a single institute were enrolled. Epithelial cell adhesion molecule positive (EpCAM(+)), cluster of differentiation 45 negative (CD45(-)) cells were isolated and enumerated from 2 mL of peripheral vein blood (PB) and inferior mesenteric vein blood (IMV) samples obtained during surgery. We found that the CTC count in PB but not IMV correlates with disease stages. Neoadjuvant chemotherapy did not lead to decreased CTC count in both types of blood samples. With cutoffs of four CTCs per 2 mL of blood, and serum carcinoembryonic antigen (CEA) level of 5 ng/mL, patients with non-metastatic disease were more likely to experience recurrence if they had high PB CTC count and high serum CEA concentration (odds ratio, 8.9). Our study demonstrates the feasibility of enumerating CTCs with a SACA chip in patients with colorectal cancer.

Dysregulation of endothelial colony-forming cell function by a negative feedback loop of circulating miR-146a and -146b in cardiovascular disease patients.

Functional impairment of endothelial colony-forming cells (ECFCs), a specific cell lineage of endothelial progenitor cells (EPCs) is highly associated with the severity of coronary artery disease (CAD), the most common type of cardiovascular disease (CVD). Emerging evidence show that circulating microRNAs (miRNAs) in CAD patients' body fluid hold a great potential as biomarkers. However, our knowledge of the role of circulating miRNA in regulating the function of ECFCs and the progression of CAD is still in its infancy. We showed that when ECFCs from healthy volunteers were incubated with conditioned medium or purified exosomes of cultured CAD ECFCs, the secretory factors from CAD ECFCs dysregulated migration and tube formation ability of healthy ECFCs. It is known that exosomes influence the physiology of recipient cells by introducing RNAs including miRNAs. By using small RNA sequencing (smRNA-seq), we deciphered the circulating miRNome in the plasma of healthy individual and CAD patients, and found that the plasma miRNA spectrum from CAD patients was significantly different from that of healthy control. Interestingly, smRNA-seq of both healthy and CAD ECFCs showed that twelve miRNAs that had a higher expression in the plasma of CAD patients also showed higher expression in CAD ECFCs when compared with healthy control. This result suggests that these miRNAs may be involved in the regulation of ECFC functions. For identification of potential mRNA targets of the differentially expressed miRNA in CAD patients, cDNA microarray analysis was performed to identify the angiogenesis-related genes that were down-regulated in CAD ECFCs and Pearson's correlation were used to identify miRNAs that were negatively correlated with the identified angiogenesis-related genes. RT-qPCR analysis of the five miRNAs that negatively correlated with the down-regulated angiogenesis-related genes in plasma and ECFC of CAD patients showed miR-146a-5p and miR-146b-5p up-regulation compared to healthy control. Knockdown of miR-146a-5p or miR-146b-5p in CAD ECFCs enhanced migration and tube formation activity in diseased ECFCs. Contrarily, overexpression of miR-146a-5p or miR-146b-5p in healthy ECFC repressed migration and tube formation in ECFCs. TargetScan analysis showed that miR-146a-5p and miR-146b-5p target many of the angiogenesis-related genes that were down-regulated in CAD ECFCs. Knockdown of miR-146a-5p or miR-146b-5p restores CAV1 and RHOJ levels in CAD ECFCs. Reporter assays confirmed the direct binding and repression of miR-146a-5p and miR-146b-5p to the 3'-UTR of mRNA of RHOJ, a positive regulator of angiogenic potential in endothelial cells. Consistently, RHOJ knockdown inhibited the migration and tube formation ability in ECFCs. Collectively, we discovered the dysregulation of miR-146a-5p/RHOJ and miR-146b-5p/RHOJ axis in the plasma and ECFCs of CAD patients that could be used as biomarkers or therapeutic targets for CAD and other angiogenesis-related diseases.

Lipid raft-associated stomatin enhances cell fusion.

Membrane fusions that occur during vesicle transport, virus infection, and tissue development, involve receptors that mediate membrane contact and initiate fusion and effectors that execute membrane reorganization and fusion pore formation. Some of these fusogenic receptors/effectors are preferentially recruited to lipid raft membrane microdomains. Therefore, major constituents of lipid rafts, such as stomatin, may be involved in the regulation of cell-cell fusion. Stomatin produced in cells can be released to the extracellular environment, either through protein refolding to pass across lipid bilayer or through exosome trafficking. We report that cells expressing more stomatin or exposed to exogenous stomatin are more prone to undergoing cell fusion. During osteoclastogenesis, depletion of stomatin inhibited cell fusion but had little effect on tartrate-resistant acid phosphatase production. Moreover, in stomatin transgenic mice, increased cell fusion leading to enhanced bone resorption and subsequent osteoporosis were observed. With its unique molecular topology, stomatin forms molecular assembly within lipid rafts or on the appositional plasma membranes, and promotes membrane fusion by modulating fusogenic protein engagement.-Lee, J.-H., Hsieh, C.-F., Liu, H.-W., Chen, C.-Y., Wu, S.-C., Chen, T.-W., Hsu, C.-S., Liao, Y.-H., Yang, C.-Y., Shyu, J.-F., Fischer, W. B., Lin, C.-H. Lipid raft-associated stomatin enhances cell fusion.

Decreased expression of stomatin predicts poor prognosis in HER2-positive breast cancer.

BACKGROUND: Human epidermal growth factor receptor-2 (HER2) is a transmembrane tyrosine kinase receptor that is overexpressed in 25 to 30 % of human breast cancers and is preferentially localized in lipid rafts. Stomatin is a membrane protein that is absent from the erythrocyte plasma membrane in patients with congenital stomatocytosis and is the major component of the lipid raft. RESULTS: In a total of 68 clinical cases of HER2-positive breast cancer, the absence of stomatin expression was associated with a decreased 5-year survival (65 % vs. 93 %, p = 0.005) by survival analysis. For stage I-III HER2-positive breast cancer, the absence of stomatin expression was associated with a decreased 5-year disease-free survival (57 % vs. 81 %, p = 0.016) and was an independent prognostic factor by multivariate analysis. Negative stomatin expression predicts distant metastases in a hazard ratio of 4.0 (95 % confidence interval from 1.3 to 12.5). CONCLUSIONS: These results may suggest that stomatin is a new prognostic indicator for HER2-positive breast cancer.

Identification of human cytomegalovirus in tumour tissues of colorectal cancer and its association with the outcome of non-elderly patients.

Increasing evidence suggests that human cytomegalovirus (HCMV) plays an oncomodulatory role in human cancers. In colorectal cancer (CRC), presence of HCMV in tumours has been associated with a poor outcome in elderly patients. This study aimed to investigate the association between HCMV and the outcome of non-elderly patients with CRC. In tumour samples, HCMV DNA was detected by PCR. Viral transcript and protein were detected by in situ hybridization (ISH) and immunohistochemical staining (IHC), respectively. Clinical, pathological and survival data were compared between patients with HCMV-positive and -negative tumours. Quantitative reverse transcription PCR (qRT-PCR) was used to analyse the expression levels of cellular signals related to CRC progression and metastasis. Among 89 CRC non-elderly patients aged <65 years, HCMV was detected in 31 (34.8 %) tumour samples by PCR. By ISH and IHC, viral transcript and protein specifically localized to the cytoplasm of neoplastic mucosal epithelium. Outcome analysis revealed a more favourable disease-free survival (DFS) rate in patients with HCMV-positive tumours (P<0.01), specifically in patients with stage III disease. In a multivariate Cox proportional-hazard model, tumoural presence of HCMV independently predicted a higher DFS rate (hazard ratio 0.22; 95 % confidence interval 0.075-0.66, P<0.01). By qRT-PCR, the tumoural levels of interleukin-1 were relatively lower in samples positive for HCMV. The results suggest that HCMV may influence the outcome of CRC in an age-dependent manner and possibly has a dual oncomodulatory effect. How the virus interacts with the tumour microenvironment should be further studied.