TGF-beta receptor 2 downregulation in tumour-associated stroma worsens prognosis and high-grade tumours show more tumour-associated macrophages and lower TGF-beta1 expression in colon carcinoma: a retrospective study

<p>Abstract</p> <p>Background</p> <p>Histological phenotype and clinical behaviour of malignant tumours are not only dependent on alterations in the epithelial cell compartment, but are affected by their interaction with inflammatory cells and tumour-associated stroma. Studies in animal models have shown influence of tumour-associated macrophages (TAM) on histological grade of differentiation in colon carcinoma. Disruption of transforming growth factor beta (TGF-beta) signalling in tumour cells is related to more aggressive clinical behaviour. Expression data of components of this pathway in tumour-associated stroma is limited.</p> <p>Methods</p> <p>Tissue micro arrays of 310 colon carcinomas from curatively resected patients in UICC stage II and III were established. In a first step we quantified amount of CD68 positive TAMs and expression of components of TGF-beta signalling (TGF-beta1, TGF-beta receptors type 1 and 2, Smad 3 and 4) in tumour and associated stroma. Further we analyzed correlation to histological and clinical parameters (histological grade of differentiation (low-grade (i.e. grade 1 and 2) vs. high-grade (i.e. grade 3 and 4)), lymph node metastasis, distant metastasis, 5 year cancer related survival) using Chi-square or Fisher's exact test, when appropriate, to compare frequencies, Kaplan-Meier method to calculate 5-year rates of distant metastases and cancer-related survival and log rank test to compare the rates of distant metastases and survival. To identify independent prognostic factors Cox regression analysis including lymph node status and grading was performed.</p> <p>Results</p> <p>High-grade tumours and those with lymph node metastases showed higher rates of TAMs and lower expression of TGF-beta1. Loss of nuclear Smad4 expression in tumor was associated with presence of lymph node metastasis, but no influence on prognosis could be demonstrated. Decrease of both TGF-beta receptors in tumour-associated stroma was associated with increased lymph node metastasis and shorter survival. Stromal TGF-beta receptor 2 expression was an independent prognostic factor for cancer related survival.</p> <p>Conclusion</p> <p>Histological phenotype and clinical behaviour of colon cancer is not only influenced by mutational incidents in tumour cells but also affected by interaction of tumour tissue with inflammatory cells like macrophages and associated stroma and TGF-beta signalling is one important part of this crosstalk. Further studies are needed to elucidate the exact mechanisms.</p

A study of genomic instability in early preneoplastic colonic lesions

It is difficult to explain the differential rates of progression of premalignant colonic lesions and differences in behaviour of morphologically similar lesions. Heterogeneity for microsatellite instability (MSI) and promoter methylation in driving these phenomena forward may explain this; however, no previous analysis has examined this in detail at the gland level, the smallest unit of colorectal premalignant lesions. We aimed to carry out an analysis of gland level genomic instability for MSI and promoter methylation. MSI occurred significantly more frequently (20%) in colonic glands than has previously been observed in whole colorectal polyps. Significant promoter methylation was seen in MLH1,PMS2,MLH3 and MSH3 as well as significant heterogeneity for both MSI and promoter methylation. Methylation and MSI may have a significant role in driving forward colorectal carcinogenesis, although in the case of MSI, this association is less clear as it occurs significantly more frequently than previously thought, and may simply be a passenger in the adenoma-carcinoma sequence. Promoter methylation in MLH1,MLH3,MSH3 and PMS2 was also found to be significantly associated with MSI and should be investigated further. A total of 273 colorectal glands (126 hyperplastic, 147 adenomatous) were isolated via laser capture microdissection (targeted at regions of MLH1 loss) from 93 colonic polyps and tested for MSI, and promoter methylation of the DNA mismatch repair genes MLH1,MSH2,MLH3,MSH6,PMS2,MGMT and MLH3 via methylation specific multiplex ligation-dependent probe amplification. Logistic regression modelling was then used to identify significant associations between promoter methylation and gland histological type and MSI status

A common biological basis of obesity and nicotine addiction

J. Kaprio ja J. Tuomilehto työryhmien jäseniä (yht. 281).Peer reviewe

Predicting treatment outcome in depression: an introduction into current concepts and challenges

Improving response and remission rates in major depressive disorder (MDD) remains an important challenge. Matching patients to the treatment they will most likely respond to should be the ultimate goal. Even though numerous studies have investigated patient-specific indicators of treatment efficacy, no (bio)markers or empirical tests for use in clinical practice have resulted as of now. Therefore, clinical decisions regarding the treatment of MDD still have to be made on the basis of questionnaire- or interview-based assessments and general guidelines without the support of a (laboratory) test. We conducted a narrative review of current approaches to characterize and predict outcome to pharmacological treatments in MDD. We particularly focused on findings from newer computational studies using machine learning and on the resulting implementation into clinical decision support systems. The main issues seem to rest upon the unavailability of robust predictive variables and the lacking application of empirical findings and predictive models in clinical practice. We outline several challenges that need to be tackled on different stages of the translational process, from current concepts and definitions to generalizable prediction models and their successful implementation into digital support systems. By bridging the addressed gaps in translational psychiatric research, advances in data quantity and new technologies may enable the next steps toward precision psychiatry

Early adversity as the prototype gene x environment interaction in mental disorders?

Childhood adversity (CA) as a significant stressor has consistently been associated with the development of mental disorders. The interaction between CA and genetic variants has been proposed to play a substantial role in disease etiology.& nbsp;In this review, we focus on the gene by environment (GxE) paradigm, its background and interpretation and stress the necessity of its implementation in psychiatric research. Further, we discuss the findings supporting GxCA interactions, ranging from candidate gene studies to polygenic and genome-wide approaches, their strengths and limitations. To illustrate potential underlying epigenetic mechanisms by which GxE effects are translated, we focus on results from FKBP5 x CA studies and discuss how molecular evidence can supplement previous GxE findings.& nbsp;In conclusion, while GxE studies constitute a valuable line of investigation, more harmonized GxE studies in large, deep-phenotyped, longitudinal cohorts, and across different developmental stages are necessary to further substantiate and understand reported GxE findings