Copy number alterations and allelic ratio in relation to recurrence of rectal cancer

Background

In rectal cancer, total mesorectal excision surgery combined with preoperative (chemo)radiotherapy reduces local recurrence rates but does not improve overall patient survival, a result that may be due to the harmful side effects and/or co-morbidity of preoperative treatment. New biomarkers are needed to facilitate identification of rectal cancer patients at high risk for local recurrent disease. This would allow for preoperative (chemo)radiotherapy to be restricted to high-risk patients, thereby reducing overtreatment and allowing personalized treatment protocols. We analyzed genome-wide DNA copy number (CN) and allelic alterations in 112 tumors from preoperatively untreated rectal cancer patients. Sixty-six patients with local and/or distant recurrent disease were compared to matched controls without recurrence. Results were validated in a second cohort of tumors from 95 matched rectal cancer patients. Additionally, we performed a meta-analysis that included 42 studies reporting on CN alterations in colorectal cancer and compared results to our own data.

Results

The genomic profiles in our study were comparable to other rectal cancer studies. Results of the meta-analysis supported the hypothesis that colon cancer and rectal cancer may be distinct disease entities. In our discovery patient study cohort, allelic retention of chromosome 7 was significantly associated with local recurrent disease. Data from the validation cohort were supportive, albeit not statistically significant, of this finding.

Conclusions

We showed that retention of heterozygosity on chromosome 7 may be associated with local recurrence in rectal cancer. Further research is warranted to elucidate the mechanisms and effect of retention of chromosome 7 on the development of local recurrent disease in rectal cancer.

Electronic supplementary material

The online version of this article (doi:10.1186/s12864-015-1550-0) contains supplementary material, which is available to authorized users.     

FGF signalling through RAS/MAPK and PI3K pathways regulates cell movement and gene expression in the chicken primitive streak without affecting E-cadherin expression

Background  

FGF signalling regulates numerous aspects of early embryo development. During gastrulation in amniotes, epiblast cells undergo an epithelial to mesenchymal transition (EMT) in the primitive streak to form the mesoderm and endoderm. In mice lacking FGFR1, epiblast cells in the primitive streak fail to downregulate E-cadherin and undergo EMT, and cell migration is inhibited. This study investigated how FGF signalling regulates cell movement and gene expression in the primitive streak of chicken embryos.     

Testing hypotheses that link wood anatomy to cavitation resistance and hydraulic conductivity in the genus Acer

? Vulnerability to cavitation and conductive efficiency depend on xylem anatomy. We tested a large range of structure-function hypotheses, some for the first time, within a single genus to minimize phylogenetic 'noise' and maximize detection of functionally relevant variation. ? This integrative study combined in-depth anatomical observations using light, scanning and transmission electron microscopy of seven Acer taxa, and compared these observations with empirical measures of xylem hydraulics. ? Our results reveal a 2 MPa range in species' mean cavitation pressure (MCP). MCP was strongly correlated with intervessel pit structure (membrane thickness and porosity, chamber depth), weakly correlated with pit number per vessel, and not related to pit area per vessel. At the tissue level, there was a strong correlation between MCP and mechanical strength parameters, and some of the first evidence is provided for the functional significance of vessel grouping and thickenings on inner vessel walls. In addition, a strong trade-off was observed between xylem-specific conductivity and MCP. Vessel length and intervessel wall characteristics were implicated in this safety-efficiency trade-off. ? Cavitation resistance and hydraulic conductivity in Acer appear to be controlled by a very complex interaction between tissue, vessel network and pit characteristics.     

Gastric cancers of Western European and African patients show different patterns of genomic instability

Background

Infection with H. pylori is important in the etiology of gastric cancer. Gastric cancer is infrequent in Africa, despite high frequencies of H. pylori infection, referred to as the African enigma. Variation in environmental and host factors influencing gastric cancer risk between different populations have been reported but little is known about the biological differences between gastric cancers from different geographic locations. We aim to study genomic instability patterns of gastric cancers obtained from patients from United Kingdom (UK) and South Africa (SA), in an attempt to support the African enigma hypothesis at the biological level.

Methods

DNA was isolated from 67 gastric adenocarcinomas, 33 UK patients, 9 Caucasian SA patients and 25 native SA patients. Microsatellite instability and chromosomal instability were analyzed by PCR and microarray comparative genomic hybridization, respectively. Data was analyzed by supervised univariate and multivariate analyses as well as unsupervised hierarchical cluster analysis.

Results

Tumors from Caucasian and native SA patients showed significantly more microsatellite instable tumors (p < 0.05). For the microsatellite stable tumors, geographical origin of the patients correlated with cluster membership, derived from unsupervised hierarchical cluster analysis (p = 0.001). Several chromosomal alterations showed significantly different frequencies in tumors from UK patients and native SA patients, but not between UK and Caucasian SA patients and between native and Caucasian SA patients.

Conclusions

Gastric cancers from SA and UK patients show differences in genetic instability patterns, indicating possible different biological mechanisms in patients from different geographical origin. This is of future clinical relevance for stratification of gastric cancer therapy.

     

Intimal lining layer macrophages but not synovial sublining macrophages display an IL-10 polarized-like phenotype in chronic synovitis

Introduction

Synovial tissue macrophages play a key role in chronic inflammatory arthritis, but the contribution of different macrophage subsets in this process remains largely unknown. The main in vitro polarized macrophage subsets are classically (M1) and alternatively (M2) activated macrophages, the latter comprising interleukin (IL)-4 and IL-10 polarized cells. Here, we aimed to evaluate the polarization status of synovial macrophages in spondyloarthritis (SpA) and rheumatoid arthritis (RA).

Methods

Expression of polarization markers on synovial macrophages, peripheral blood monocytes, and in vitro polarized monocyte-derived macrophages from SpA versus RA patients was assessed by immunohistochemistry and flow cytometry, respectively. The polarization status of the intimal lining layer and the synovial sublining macrophages was assessed by double immunofluorescence staining.

Results

The expression of the IL-10 polarization marker cluster of differentiation 163 (CD163) was increased in SpA compared with RA intimal lining layer, but no differences were found in other M1 and M2 markers between the diseases. Furthermore, no significant phenotypic differences in monocytes and in vitro polarized monocyte-derived macrophages were seen between SpA, RA, and healthy controls, indicating that the differential CD163 expression does not reflect a preferential M2 polarization in SpA. More detailed analysis of intimal lining layer macrophages revealed a strong co-expression of the IL-10 polarization markers CD163 and cluster of differentiation 32 (CD32) but not any of the other markers in both SpA and RA. In contrast, synovial sublining macrophages had a more heterogeneous phenotype, with a majority of cells co-expressing M1 and M2 markers.

Conclusions

The intimal lining layer but not synovial sublining macrophages display an IL-10 polarized-like phenotype, with increased CD163 expression in SpA versus RA synovitis. These differences in the distribution of the polarized macrophage subset may contribute to the outcome of chronic synovitis.     

Are needles of Pinus pinaster more vulnerable to xylem embolism than branches? New insights from X‐ray computed tomography

Plants can be highly segmented organisms with an independently redundant design of organs. In the context of plant hydraulics, leaves may be less embolism resistant than stems, allowing hydraulic failure to be restricted to distal organs that can be readily replaced. We quantified drought‐induced embolism in needles and stems of Pinus pinaster using high‐resolution computed tomography (HRCT). HRCT observations of needles were compared with the rehydration kinetics method to estimate the contribution of extra‐xylary pathways to declining hydraulic conductance. High‐resolution computed tomography images indicated that the pressure inducing 50% of embolized tracheids was similar between needle and stem xylem (P_{50 needle xylem} = ?3.62 MPa, P_{50 stem xylem} = ?3.88 MPa). Tracheids in both organs showed no difference in torus overlap of bordered pits. However, estimations of the pressure inducing 50% loss of hydraulic conductance at the whole needle level by the rehydration kinetics method were significantly higher (P_{50 needle} = ?1.71 MPa) than P_{50 needle xylem} derived from HRCT. The vulnerability segmentation hypothesis appears to be valid only when considering hydraulic failure at the entire needle level, including extra‐xylary pathways. Our findings suggest that native embolism in needles is limited and highlight the importance of imaging techniques for vulnerability curves.     

Effects of age,replicative lifespan and growth rate of human nucleus pulposus cells on selecting age range for cell-based biological therapies for degenerative disc diseases

Autologous disc cell implantation, growth factors and gene therapy appear to be promising therapies for disc regeneration. Unfortunately, the replicative lifespan and growth kinetics of human nucleus pulposus (NP) cells related to host age are unclear. We investigated the potential relations among age, replicative lifespan and growth rate of NP cells, and determined the age range that is suitable for cell-based biological therapies for degenerative disc diseases. We used NP tissues classified by decade into five age groups: 30s, 40s, 50s, 60s and 70s. The mean cumulative population doubling level (PDL) and population doubling rate (PDR) of NP cells were assessed by decade. We also investigated correlations between cumulative PDL and age, and between PDR and age. The mean cumulative PDL and PDR decreased significantly in patients in their 60s. The mean cumulative PDL and PDR in the younger groups (30s, 40s and 50s) were significantly higher than those in the older groups (60s and 70s). There also were significant negative correlations between cumulative PDL and age, and between PDR and age. We found that the replicative lifespan and growth rate of human NP cells decreased with age. The replicative potential of NP cells decreased significantly in patients 60 years old and older. Young individuals less than 60 years old may be suitable candidates for NP cell-based biological therapies for treating degenerative disc diseases.     

The effects of Pierce's disease on leaf and petiole hydraulic conductance in Vitis vinifera cv. Chardonnay

In this study, we test the hypothesis that the symptoms of Pierce's Disease (PD) result from the occlusion of xylem conduits by the bacteria Xylella fastidiosa ( Xf ). Four treatments were imposed on greenhouse-grown Vitis vinifera cv. Chardonnay: well-watered and deficit-irrigated plants with and without petiole inoculation with Xf . The hydraulic conductance of the stem-petiole junction ( k _jun) and leaves ( k _leaf) were measured, and Xf concentrations were established by quantitative polymerase chain reaction (qPCR). Leaf hydraulic conductance decreased with increasing leaf scorch symptoms in both irrigation treatments. The positive relationship between Xf concentration and symptom formation in deficit-irrigated plants suggests that water-stress increases susceptibility to PD. In field-grown vines, water relations of symptomatic leaves were similar to naturally senescing leaves but differed from green control leaves. Overall, these results suggest that the development of PD symptoms represents a form of accelerated senescence as part of a systemic response of the plant to Xf infection.     

Molecular docking analysis of SARS-CoV-2 linked RNA dependent RNA polymerase (RdRp) with compounds from Plectranthus amboinicus

It is of interest to document the moelcular docking analysis of SARS-CoV-2 linked RNA dependent RNA polymerase (RdRp) with compounds from Plectranthus amboinicus. Hence, we report the binding features of rutin, Luteolin, Salvianolic acid A, Rosmarinic acid and p-Coumaric acid with the target protein SARS-CoV-2 linked RNA dependent RNA polymerase (RdRp) for further consideration.