New early Eocene tapiromorph perissodactyls from the Ghazij Formation of Pakistan, with implications for mammalian biochronology in Asia

Early Eocene mammals from Indo-Pakistan have only recently come under study. Here we describe the first tapiromorph perissodactyls from the subcontinent. Gandheralophus minor n. gen. and n. sp. and G. robustus n. sp. are two species of Isectolophidae differing in size and in reduction of the anterior dentition. Gandheralophus is probably derived from a primitive isectolophid such as Orientolophus hengdongensis from the earliest Eocene of China, and may be part of a South Asian lineage that also contains Karagalax from the middle Eocene of Pakistan. Two specimens are referred to a new, unnamed species of Lophialetidae. Finally, a highly diagnostic M3 and a molar fragment are described as the new eomoropid chalicothere Litolophus ghazijensis sp. nov. The perissodactyls described here, in contrast to most other mammalian groups published from the early Eocene of Indo-Pakistan, are most closely related to forms known from East and Central Asia. Tapiromorpha are diverse and biochronologically important in the Eocene there and our results allow the first biochronological correlation between early Eocene mammal faunas in Indo-Pakistan and the rest of Asia. We suggest that the upper Ghazij Formation of Pakistan is best correlated with the middle or late part of the Bumbanian Asian Land-Mammal Age, while the Kuldana and Subathu Formations of Pakistan and India are best correlated with the Arshantan Asian Land-Mammal Age

Digital Cranial Endocast of Hyopsodus (Mammalia, “Condylarthra”): A Case of Paleogene Terrestrial Echolocation?

We here describe the endocranial cast of the Eocene archaic ungulate Hyopsodus lepidus AMNH 143783 (Bridgerian, North America) reconstructed from X-ray computed microtomography data. This represents the first complete cranial endocast known for Hyopsodontinae. The Hyopsodus endocast is compared to other known “condylarthran” endocasts, i. e. those of Pleuraspidotherium (Pleuraspidotheriidae), Arctocyon (Arctocyonidae), Meniscotherium (Meniscotheriidae), Phenacodus (Phenacodontidae), as well as to basal perissodactyls (Hyracotherium) and artiodactyls (Cebochoerus, Homacodon). Hyopsodus presents one of the highest encephalization quotients of archaic ungulates and shows an “advanced version” of the basal ungulate brain pattern, with a mosaic of archaic characters such as large olfactory bulbs, weak ventral expansion of the neopallium, and absence of neopallium fissuration, as well as more specialized ones such as the relative reduction of the cerebellum compared to cerebrum or the enlargement of the inferior colliculus. As in other archaic ungulates, Hyopsodus midbrain exposure is important, but it exhibits a dorsally protruding largely developed inferior colliculus, a feature unique among “Condylarthra”. A potential correlation between the development of the inferior colliculus in Hyopsodus and the use of terrestrial echolocation as observed in extant tenrecs and shrews is discussed. The detailed analysis of the overall morphology of the postcranial skeleton of Hyopsodus indicates a nimble, fast moving animal that likely lived in burrows. This would be compatible with terrestrial echolocation used by the animal to investigate subterranean habitat and/or to minimize predation during nocturnal exploration of the environment

Home-based subcutaneous immunoglobulin G replacement therapy under real-life conditions in children and adults with antibody deficiency

Background: Subcutaneous immunoglobulin (SCIG) therapy is an alternative to intravenous immunoglobulin (WIG) therapy.Methods: We evaluated the efficacy and safety of the SCIG Vivaglobin (R) (formerly known as Beriglobin (R) SC) under real-life conditions in a post-marketing observational study in 82 patients with primary or secondary antibody deficiencies. Health-related quality of life (HRQoL) was evaluated in a subset of 30 patients previously treated with WIG (including 11 children <14 years) using the Short Form 36 (SF-36) for patients >= 14 years of age (adults) and the Child Health Questionnaire - Parental Form 50 (CHQ-PF50) for children <14 years of age. Treatment preferences were assessed in adults.Results: The mean serum immunoglobulin G (IgG) trough level during SCIG treatment (7.5 g/L) was higher than during previous IVIG treatment (6.6 g/L; p<0.01). The investigators assessed the efficacy of SCIG therapy as "excellent" in 89% of patients. No systemic adverse drug reactions were observed. Improvements by >= 5 points were observed in 5 of 8 SF-36 subscales and in 6 of 12 CHQ-PF50 subscales. Statistically significant improvements (p <= 0.05) were observed for the SF-36 subscales of bodily pain, general health perceptions, and vitality (adults), and for the CHQ-PF50 subscales of general health perceptions, parental impact - time, parental impact - emotional, and family activities (children). Patients preferred SCIG over WIG therapy (92%) and home therapy over therapy at the clinic/physician (83%).Conclusion: This study confirms that therapy with Vivaglobin (R) at home is effective, safe, well tolerated, and improves quality of life in patients with antibody deficiency

Epidermal growth factor mediates detachment from and invasion through collagen I and Matrigel in Capan-1 pancreatic cancer cells

BACKGROUND: Pancreatic adenocarcinoma is a highly invasive neoplasm. Epidermal growth factor (EGF) and its receptor are over expressed in pancreatic cancer, and expression correlates with invasion and metastasis. We hypothesized that EGF receptor and integrin signalling pathways interact in mediating cellular adhesion and invasion in pancreatic cancer, and that invasiveness correlates temporally with detachment from extracellular matrix. METHODS: We tested this hypothesis by investigating the role of EGF in mediating adhesion to and invasion through collagen I and Matrigel in the metastatic pancreatic adenocarcinoma cell line Capan-1. Adhesion and invasion were measured using in vitro assays of fluorescently-labeled cells. Adhesion and invasion assays were also performed in the primary pancreatic adenocarcinoma cell line MIA PaCa-2. RESULTS: EGF inhibited adhesion to collagen I and Matrigel in Capan-1 cells. The loss of adhesion was reversed by AG825, an inhibitor of erbB2 receptor signalling and by wortmannin, a PI3K inhibitor, but not by the protein synthesis inhibitor cycloheximide. EGF stimulated invasion through collagen I and Matrigel at concentrations and time courses similar to those mediating detachment from these extracellular matrix components. Adhesion to collagen I was different in MIA PaCa-2 cells, with no significant change elicited following EGF treatment, whereas treatment with the EGF family member heregulin-alpha elicited a marked increase in adhesion. Invasion through Matrigel in response to EGF, however, was similar to that observed in Capan-1 cells. CONCLUSION: An inverse relationship exists between adhesion and invasion capabilities in Capan-1 cells but not in MIA PaCa-2 cells. EGF receptor signalling involving the erbB2 and PI3K pathways plays a role in mediating these events in Capan-1 cells

A simple and reproducible scoring system for EGFR in colorectal cancer: application to prognosis and prediction of response to preoperative brachytherapy

The aim of this study was to determine the predictive and prognostic value of epidermal growth factor receptor (EGFR) expression in rectal cancers treated with preoperative high-dose rate brachytherapy and in mismatch-repair (MMR)-proficient colorectal cancers (CRCs), respectively. We validate the use of receiver operating characteristic (ROC) curve analysis to select cutoff scores for EGFR overexpression for the end points studied. Immunohistochemistry (IHC) for EGFR was performed on 82 rectal tumour biopsies and 1197 MMR-proficient CRCs using a tissue microarray. Immunoreactivity was scored as the percentage of positive tumour cells by three pathologists and the inter-observer reliability was assessed. ROC curve-derived cutoffs were used to analyse the association of EGFR overexpression, tumour response and several clinicopathological features including survival. The scoring method was found to be reproducible in rectal cancer biopsies and CRCs. The selected cutoff scores from ROC curve analysis for each clinicopathological feature were highly consistent among pathologists. EGFR overexpression was associated with response to radiotherapy (P-value <0.001) and with worse survival time (P-value <0.001). In multivariate analysis, EGFR overexpression was independently associated with adverse prognosis (P-value <0.001). Epidermal growth factor receptor is a predictive marker of response to preoperative radiotherapy and an independent adverse prognostic factor CRC

An annotated bibliography of C.J. van der Klaauw with notes on the impact of his work

Van der Klaauw was a professor of Descriptive Zoology in the period 1934–1958. This paper presents a concise annotated overview of his publications. In his work three main topics can be recognized: comparative anatomy of the mammalian auditory region, theoretical studies about ecology and ecological morphology, and vertebrate functional morphology. In particular van der Klaauw developed new concepts on functional morphology, based upon a holistic approach. A series of studies in functional morphology of Vertebrates by his students is added. An overview of recent morphological and theoretical studies show that this new approach had a long lasting impact in studies of functional morphology

Assessment of epidermal growth factor receptor (EGFR) expression in primary colorectal carcinomas and their related metastases on tissue sections and tissue microarray

Metastatic colorectal carcinomas (CRC) resistant to chemotherapy may benefit from targeting monoclonal therapy cetuximab when they express the epidermal growth factor receptor (EGFR). Because of its clinical implications, we studied EGFR expression by immunohistochemistry on tissue sections of primary CRC (n=32) and their related metastases (n=53). A tissue microarray (TMA) was generated from the same paraffin blocks to determine whether this technique could be used for EGFR screening in CRC. On tissue sections, 84% of the primary CRC and 94% of the metastases were EGFR-positive. When matched, they showed a concordant EGFR-positive status in 78% of the cases. Moreover, staining intensity and extent of EGFR-positive cells in the primary CRC correlated with those observed in the synchronous metastases. On TMA, 65% of the primary CRC, 66% of the metastases, and 43% of the matched primary CRC metastases were EGFR-positive. There was no concordant EGFR status between the primary and the metastatic sites. A strong discrepancy of EGFR status was noted between TMA and tissue sections. In conclusion, EGFR expression measured in tissue sections from primary CRC and their related metastases was found to be similar and frequent, but it was significantly underestimated by the TMA technique

Comparative study of T84 and T84SF human colon carcinoma cells: in vitro and in vivo ultrastructural and functional characterization of cell culture and metastasis

To better understand the relationship between tumor heterogeneity, differentiation, and metastasis, suitable experimental models permitting in vitro and in vivo studies are necessary. A new variant cell line (T84SF) exhibiting an altered phenotype was recently selected from a colon cancer cell line (T84) by repetitive plating on TNF-alpha treated human endothelial cells and subsequent selection for adherent cells. The matched pair of cell lines provides a useful system to investigate the extravasation step of the metastatic cascade. Since analysis of morphological differences can be instructive to the understanding of metastatic potential of tumor cells, we compared the ultrastructural and functional phenotype of T84 and T84SF cells in vitro and in vivo. The reported ultrastructural features evidence differences between the two cell lines; selected cells showed a marked pleomorphism of cell size and nuclei, shape, and greater surface complexity. These morphological differences were also coupled with biochemical data showing a distinct tyrosine phosphorylation-based signaling, an altered localization of beta-catenin, MAPK, and AKT activation, as well as an increased expression in T84SF cells of Bcl-X-L, a major regulator of apoptosis. Therefore, these cell lines represent a step forward in the development of appropriate models in vitro and in vivo to investigate colon cancer progression

DNA Methylation Profiles of Primary Colorectal Carcinoma and Matched Liver Metastasis

BACKGROUND: The contribution of DNA methylation to the metastatic process in colorectal cancers (CRCs) is unclear. METHODS: We evaluated the methylation status of 13 genes (MINT1, MINT2, MINT31, MLH1, p16, p14, TIMP3, CDH1, CDH13, THBS1, MGMT, HPP1 and ERα) by bisulfite-pyrosequencing in 79 CRCs comprising 36 CRCs without liver metastasis and 43 CRCs with liver metastasis, including 16 paired primary CRCs and liver metastasis. We also performed methylated CpG island amplification microarrays (MCAM) in three paired primary and metastatic cancers. RESULTS: Methylation of p14, TIMP3 and HPP1 in primary CRCs progressively decreased from absence to presence of liver metastasis (13.1% vs. 4.3%; 14.8% vs. 3.7%; 43.9% vs. 35.8%, respectively) (P<.05). When paired primary and metastatic tumors were compared, only MGMT methylation was significantly higher in metastatic cancers (27.4% vs. 13.4%, P = .013), and this difference was due to an increase in methylation density rather than frequency in the majority of cases. MCAM showed an average 7.4% increase in DNA methylated genes in the metastatic samples. The numbers of differentially hypermethylated genes in the liver metastases increased with increasing time between resection of the primary and resection of the liver metastasis. Bisulfite-pyrosequencing validation in 12 paired samples showed that most of these increases were not conserved, and could be explained by differences in methylation density rather than frequency. CONCLUSIONS: Most DNA methylation differences between primary CRCs and matched liver metastasis are due to random variation and an increase in DNA methylation density rather than de-novo inactivation and silencing. Thus, DNA methylation changes occur for the most part before progression to liver metastasis