Metastasis of breast cancer occurs primarily through the lymphatic system, and the extent of lymph node involvement is a key prognostic factor for the disease. Whereas the significance of ...angiogenesis for tumor progression has been well documented, the ability of tumor cells to induce the growth of lymphatic vessels (lymphangiogenesis) and the presence of intratumoral lymphatic vessels have been controversial. Using a novel marker for lymphatic endothelium, LYVE-1, we demonstrate here the occurrence of intratumoral lymphangiogenesis within human breast cancers after orthotopic transplantation onto nude mice. Vascular endothelial growth factor (VEGF)-C overexpression in breast cancer cells potently increased intratumoral lymphangiogenesis, resulting in significantly enhanced metastasis to regional lymph nodes and to lungs. The degree of tumor lymphangiogenesis was highly correlated with the extent of lymph node and lung metastases. These results establish the occurrence and biological significance of intratumoral lymphangiogenesis in breast cancer and identify VEGF-C as a molecular link between tumor lymphangiogenesis and metastasis.
Adhesive interactions involving CD44, the cell surface receptor for hyaluronan, underlie fundamental processes such as inflammatory leukocyte homing and tumor metastasis. Regulation of such events is ...critical and appears to be effected by changes in CD44 N-glycosylation that switch the receptor “on” or “off” under appropriate circumstances. How altered glycosylation influences binding of hyaluronan to the lectin-like Link module in CD44 is unclear, although evidence suggests additional flanking sequences peculiar to CD44 may be involved. Here we show using X-ray crystallography and NMR spectroscopy that these sequences form a lobular extension to the Link module, creating an enlarged HA binding domain and a formerly unidentified protein fold. Moreover, the disposition of key N-glycosylation sites reveals how specific sugar chains could alter both the affinity and avidity of CD44 HA binding. Our results provide the necessary structural framework for understanding the diverse functions of CD44 and developing novel therapeutic strategies.
Although angiogenesis is a prerequisite for the growth of most human solid tumours, alternative mechanisms of vascularisation can be adopted. We have previously described a non-angiogenic growth ...pattern in liver metastases of colorectal adenocarcinomas (CRC) in which tumour cells replace hepatocytes at the tumour-liver interface, preserving the liver architecture and co-opting the sinusoidal blood vessels. The aim of this study was to determine whether this replacement pattern occurs during liver metastasis of breast adenocarcinomas (BC) and whether the lack of an angiogenic switch in such metastases is due to the absence of hypoxia and subsequent vascular fibrinogen leakage. The growth pattern of 45 BC liver metastases and 28 CRC liver metastases (73 consecutive patients) was assessed on haematoxylin- and eosin-stained tissue sections. The majority of the BC liver metastases had a replacement growth pattern (96%), in contrast to only 32% of the CRC metastases (P<0.0001). The median carbonic anhydrase 9 (CA9) expression (M75 antibody), as a marker of hypoxia, (intensity x % of stained tumour cells) was 0 in the BC metastases and 53 in the CRC metastases (P<0.0001). There was CA9 expression at the tumour-liver interface in only 16% of the BC liver metastases vs 54% of the CRC metastases (P=0.002). There was fibrin (T2G1 antibody) at the tumour-liver interface in only 21% of the BC metastases vs 56% of the CRC metastases (P=0.04). The median macrophage count (Chalkley morphometry; KP-1 anti-CD68 antibody) at the interface was 4.3 and 7.5, respectively (P<0.0001). Carbonic anhydrase 9 score and macrophage count were positively correlated (r=0.42; P=0.002) in all metastases. Glandular differentiation was less in the BC liver metastases: 80% had less than 10% gland formation vs only 7% of the CRC metastases (P<0.0001). The liver is a densely vascularised organ and can host metastases that exploit this environment by replacing the hepatocytes and co-opting the vasculature. Our findings confirm that a non-angiogenic pattern of liver metastasis indeed occurs in BC, that this pattern of replacement growth is even more prevalent than in CRC, and that the process induces neither hypoxia nor vascular leakage.
It is now more than 100 years since the coconut rhinoceros beetle (CRB:
L.) was first detected in the Pacific Island state of Samoa. The exotic pest from Asia became the principal pest of coconut ...palms in Samoa and, from this first point of invasion, spread to several surrounding countries in the South-West Pacific Ocean. An intensive control operation was initiated, but the beetle could not be eliminated. Various pest management strategies were attempted but had limited success until the introduction of a biological control agent (BCA), Oryctes rhinoceros nudivirus (OrNV), during the late 1960s and early 1970s. The biocontrol release was very successful and became the prime example of "classical biological control" of an insect pest by a virus. Changing economic and social conditions in Samoa and other islands of the Pacific require a re-evaluation of the threat of CRB to coconut production to suggest how the IPM system may be modified to meet future needs. Therefore, it is timely to review the history of CRB in Samoa and summarize experiences in development of an integrated pest management (IPM) system limiting the impact of the pest. We also present results from a recent study conducted in 2020 on the island of Upolu to define the current status of the CRB population and its BCA, OrNV. The lessons from Samoa, with its long history of containment and management of CRB, are applicable to more recent invasion sites. Recommendations are provided to modify the IPM programme to enhance the sustainable control of CRB and support the ongoing coconut replantation program promoted by the Samoan government.
B3GNT2 is responsible for elongation of cell surface long-chain polylactosamine, which influences the regulation of the immune response, making it an attractive target for immunomodulation. In the ...development of amide containing B3GNT2 inhibitors guided by structure-based drug design, imidazolones were found to successfully serve as amide bioisosteres. This novel imidazolone isosteric strategy alleviated torsional strain of the amide bond on binding to B3GNT2 and improved potency, isoform selectivity, as well as certain physicochemical and pharmacokinetic properties. Herein, we present the synthesis, SAR, X-ray cocrystal structures, and in vivo PK properties of imidazol-4-ones in the context of B3GNT2 inhibition.
Prostate cancer (PCa) is the most common male cancer in the United Kingdom and we aimed to identify clinically relevant biomarkers corresponding to stage progression of the disease.
We used enhanced ...proteomic profiling of PCa progression using iTRAQ 3D LC mass spectrometry on high-quality serum samples to identify biomarkers of PCa.
We identified >1000 proteins. Following specific inclusion/exclusion criteria we targeted seven proteins of which two were validated by ELISA and six potentially interacted forming an 'interactome' with only a single protein linking each marker. This network also includes accepted cancer markers, such as TNF, STAT3, NF-κB and IL6.
Our linked and interrelated biomarker network highlights the potential utility of six of our seven markers as a panel for diagnosing PCa and, critically, in determining the stage of the disease. Our validation analysis of the MS-identified proteins found that SAA alongside KLK3 may improve categorisation of PCa than by KLK3 alone, and that TSR1, although not significant in this model, might also be a clinically relevant biomarker.
A number of next-generation sequencing (NGS) technologies such as Roche/454, Illumina and AB SOLiD have recently become available. These technologies are capable of generating hundreds of thousands ...or tens of millions of short DNA sequence reads at a relatively low cost. These NGS technologies, now referred as second-generation sequencing (SGS) technologies, are being utilized for de novo sequencing, genome re-sequencing, and whole genome and transcriptome analysis. Now, new generation of sequencers, based on the 'next-next' or third-generation sequencing (TGS) technologies like the Single-Molecule Real-Time (SMRT™) Sequencer, Heliscope™ Single Molecule Sequencer, and the Ion Personal Genome Machine™ are becoming available that are capable of generating longer sequence reads in a shorter time and at even lower costs per instrument run. Ever declining sequencing costs and increased data output and sample throughput for NGS and TGS sequencing technologies enable the plant genomics and breeding community to undertake genotyping-by-sequencing (GBS). Data analysis, storage and management of large-scale second or TGS projects, however, are essential. This article provides an overview of different sequencing technologies with an emphasis on forthcoming TGS technologies and bioinformatics tools required for the latest evolution of DNA sequencing platforms.
Purpose The aim of this study was to perform a systematic review and meta-analysis of the short- and long-term outcomes of stapled haemorrhoidopexy. Methods A literature search identified randomised ...controlled trials comparing stapled haemorrhoidopexy with Milligan-Morgan/Ferguson haemorrhoidectomy. Data were extracted independently for each study and differences analysed with fixed and random effects models. Results Thirty-four randomised trials and two systematic reviews were identified, and 29 trials included. Stapled haemorrhoidopexy was statistically superior for hospital stay (p < 0.001) and numerically superior for post-operative pain (peri-operative and mid-term), operation time and bleeding (post-operative and long-term). Recurrent prolapse and re-intervention for recurrence were more frequent following stapled haemorrhoidopexy. No difference was observed in the rates of complications. Conclusions Stapled haemorrhoidopexy reduces the length of hospital stay and may have an advantage in terms of decreased operating time, reduced post-operative pain and less bleeding but is associated with an increased rate of recurrent prolapse.
To describe a protocol for use in young children and adolescents for determining language representation.
We performed 130 fMRI studies in 48 children and 17 adults. Verb generation (VG) and ...orthographic lexical retrieval (OLR) were used. The localization and lateralization of activation was rated visually. Regional voxel counts measured asymmetry and extent of activation.
Activation was predominantly left-lateralized (children 85%, adults 94%), and there was no difference in the localization of activation for either paradigm. Children's typical sites of activation included mesial (96%), inferior (94%) and middle frontal (92%) gyri, the inferior (85%) and superior (65%) temporal cortex, and the cerebellum (67%). Less frequently activated sites were insular (50%) and posterior parietal (48%) cortices. Quantitative asymmetry index scores and visual inspection of laterality were concordant. Greater quantitative asymmetry for VG than OLR occurred in children. Laterality was not related to age, sex, task proficiency, or handedness. Frontal region voxel counts lower in children than adults and left sided counts correlated with task proficiency.
Language fMRI can be performed in young children using resources available to clinical centers. The similarity in frequency of left language lateralization between children and adults suggests that language representation establishes early in development. The reduced amount of frontal region of interest activation in task-specific regions in children may reflect different levels of ability. However, the left-right distribution of activation does not appear to depend on task performance or age. These normative data provide a basis for decisions about language laterality in pediatric patients.
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