Treatment with embryonic stem-like cells into osteochondral defects in sheep femoral condyles

Background Articular cartilage has poor intrinsic capacity for regeneration because of its avascularity and very slow cellular turnover. Defects deriving from trauma or joint disease tend to be repaired with fibrocartilage rather than hyaline cartilage. Consequent degenerative processes are related to the width and depth of the defect. Since mesenchymal stem cells (MSCs) deriving from patients affected by osteoarthritis have a lower proliferative and chondrogenic activity, the systemic or local delivery of heterologous cells may enhance regeneration or inhibit the progressive loss of joint tissue. Embryonic stem cells (ESCs) are very promising, since they can self-renew for prolonged periods without differentiation and can differentiate into tissues from all the 3 germ layers. To date only a few experiments have used ESCs for the study of the cartilage regeneration in animal models and most of them used laboratory animals. Sheep, due to their anatomical, physiological and immunological similarity to humans, represent a valid model for translational studies. This experiment aimed to evaluate if the local delivery of male sheep embryonic stem-like (ES-like) cells into osteochondral defects in the femoral condyles of adult sheep can enhance the regeneration of articular cartilage. Twenty-two ewes were divided into 5 groups (1, 2, 6, 12 and 24 months after surgery). Newly formed tissue was evaluated by macroscopic, histological, immunohistochemical (collagen type II) and fluorescent in situ hybridization (FISH) assays. Results Regenerated tissue was ultimately evaluated on 17 sheep. Samples engrafted with ES-like cells had significantly better histologic evidence of regeneration with respect to empty defects, used as controls, at all time periods. Conclusions Histological assessments demonstrated that the local delivery of ES-like cells into osteochondral defects in sheep femoral condyles enhances the regeneration of the articular hyaline cartilage, without signs of immune rejection or teratoma for 24 months after engraftment.</br

Chronic pancreatitis in dogs : a retrospective study of clinical, clinicopathological, and histopathological findings in 61 cases

The objective of the present study was to characterize the clinical, clinicopathologic, and histopathologic findings of dogs with chronic pancreatitis. The necropsy database at Texas A&M University was searched for reports of dogs with histologic evidence of chronic pancreatitis defined as irreversible histologic changes of the pancreas, i.e. fibrosis and atrophy. Medical records and necropsy reports were retrieved and reviewed. A reference necropsy population of 100 randomly selected dogs was used for signalment and concurrent disease comparisons. Cases were categorized as clinical or incidental chronic pancreatitis based on the presence of vomiting, decreased appetite, or both versus neither of these signs. All archived pancreata samples were evaluated histologically and scored using a published pancreatic scoring system. A total of 61 dogs with chronic pancreatitis were included in the study. The most frequent clinical signs were lethargy, decreased appetite, vomiting, and diarrhea. Compared to the reference necropsy population, chronic pancreatitis cases were more likely to be older, neutered, and of the non-sporting/toy breed group and to have concurrent endocrine, hepatobiliary, or neurologic diseases. Clinical chronic pancreatitis cases had significantly higher histological scores for pancreatic necrosis and peripancreatic fat necrosis. Clinical chronic pancreatitis cases were significantly more likely to have hepatobiliary or endocrine disease as well as increased liver enzyme activities, and cholesterol and bilirubin concentrations. In conclusion, clinical disease resulting from chronic pancreatitis might be related to the presence of pancreatic necrosis and pancreatic fat necrosis. The signalment, presentation, and concurrent diseases of dogs with chronic pancreatitis are similar to those previously reported for dogs with acute pancreatitis.http://www.elsevier.com/locate/tvjlam2013ab201

Chronic pancreatitis in dogs: A retrospective study of clinical, clinicopathological, and histopathological findings in 61 cases

The objective of the present study was to characterize the clinical, clinicopathologic, and histopathologic findings of dogs with chronic pancreatitis. The necropsy database at Texas A&M University was searched for reports of dogs with histologic evidence of chronic pancreatitis defined as irreversible histologic changes of the pancreas, i.e. fibrosis and atrophy. Medical records and necropsy reports were retrieved and reviewed. A reference necropsy population of 100 randomly selected dogs was used for signalment and concurrent disease comparisons. Cases were categorized as clinical or incidental chronic pancreatitis based on the presence of vomiting, decreased appetite, or both versus neither of these signs. All archived pancreata samples were evaluated histologically and scored using a published pancreatic scoring system. A total of 61 dogs with chronic pancreatitis were included in the study. The most frequent clinical signs were lethargy, decreased appetite, vomiting, and diarrhea. Compared to the reference necropsy population, chronic pancreatitis cases were more likely to be older, neutered, and of the non-sporting/toy breed group and to have concurrent endocrine, hepatobiliary, or neurologic diseases. Clinical chronic pancreatitis cases had significantly higher histological scores for pancreatic necrosis and peripancreatic fat necrosis. Clinical chronic pancreatitis cases were significantly more likely to have hepatobiliary or endocrine disease as well as increased liver enzyme activities, and cholesterol and bilirubin concentrations. In conclusion, clinical disease resulting from chronic pancreatitis might be related to the presence of pancreatic necrosis and pancreatic fat necrosis. The signalment, presentation, and concurrent diseases of dogs with chronic pancreatitis are similar to those previously reported for dogs with acute pancreatitis.http://www.elsevier.com/locate/tvjlam2013ab201

Population genomics of sub-Saharan Drosophila melanogaster: African diversity and non-African admixture

(ABRIDGED) We report the genome sequencing of 139 wild-derived strains of D. melanogaster, representing 22 population samples from the sub-Saharan ancestral range of this species, along with one European population. Most genomes were sequenced above 25X depth from haploid embryos. Results indicated a pervasive influence of non-African admixture in many African populations, motivating the development and application of a novel admixture detection method. Admixture proportions varied among populations, with greater admixture in urban locations. Admixture levels also varied across the genome, with localized peaks and valleys suggestive of a non-neutral introgression process. Genomes from the same location differed starkly in ancestry, suggesting that isolation mechanisms may exist within African populations. After removing putatively admixed genomic segments, the greatest genetic diversity was observed in southern Africa (e.g. Zambia), while diversity in other populations was largely consistent with a geographic expansion from this potentially ancestral region. The European population showed different levels of diversity reduction on each chromosome arm, and some African populations displayed chromosome arm-specific diversity reductions. Inversions in the European sample were associated with strong elevations in diversity across chromosome arms. Genomic scans were conducted to identify loci that may represent targets of positive selection. A disproportionate number of candidate selective sweep regions were located near genes with varied roles in gene regulation. Outliers for Europe-Africa FST were found to be enriched in genomic regions of locally elevated cosmopolitan admixture, possibly reflecting a role for some of these loci in driving the introgression of non-African alleles into African populations

Broad geographic sampling reveals the shared basis and environmental correlates of seasonal adaptation in Drosophila.

To advance our understanding of adaptation to temporally varying selection pressures, we identified signatures of seasonal adaptation occurring in parallel among Drosophila melanogaster populations. Specifically, we estimated allele frequencies genome-wide from flies sampled early and late in the growing season from 20 widely dispersed populations. We identified parallel seasonal allele frequency shifts across North America and Europe, demonstrating that seasonal adaptation is a general phenomenon of temperate fly populations. Seasonally fluctuating polymorphisms are enriched in large chromosomal inversions, and we find a broad concordance between seasonal and spatial allele frequency change. The direction of allele frequency change at seasonally variable polymorphisms can be predicted by weather conditions in the weeks prior to sampling, linking the environment and the genomic response to selection. Our results suggest that fluctuating selection is an important evolutionary force affecting patterns of genetic variation in Drosophila

What π−π\pi-\pi Scattering Tells Us About Chiral Perturbation Theory

We describe a rearrangement of the standard expansion of the symmetry breaking part of the QCD effective Lagrangian that includes into each order additional terms which in the standard chiral perturbation theory ($\chi$PT) are relegated to higher orders. The new expansion represents a systematic and unambiguous generalization of the standard $\chi$PT, and is more likely to converge rapidly. It provides a consistent framework for a measurement of the importance of additional ``higher order'' terms whose smallness is usually assumed but has never been checked. A method of measuring, among other quantities, the QCD parameters $\hat{m}\langle\bar{q}q\rangle$ and the quark mass ratio $m_s/\hat{m}$ is elaborated in detail. The method is illustrated using various sets of available data. Both of these parameters might be considerably smaller than their respective leading order standard $\chi$PT values. The importance of new, more accurate, experimental information on low-energy $\pi-\pi$ scattering is stressed.Comment: RevTeX 62 pages (6 figures not added, request from any author), IPNO/TH 92-106, PURD-TH-93-0

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN