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bioRxiv2017

Stability of Commonly Used Haematological Parameters in Samples Stored at 33°C, 22°C and 4°C

AimThis study aimed to investigate the analytical bias and imprecision in haematological parameters induced by storage at 4{degrees}C, 22{degrees}C and 33 {degrees}C.\n\nMethodsThree K2EDTA anticoagulated vials of blood were collected from each of twenty blood donors and stored at 4{degrees}C, 22{degrees}C and 33{degrees}C respectively. Readings from each vial were taken at 0, 4, 6, 12, 24, 48 and 72 hours after collection on the Sysmex XP-100 analyser. The mean and median shift of the parameters relative to the baseline and the coefficient of variation for each time-temperature combination were calculated. The shift was compared to the maximum acceptable bias.\n\nResultsHaemoglobin, Red Blood Cell Count, White Blood Cell Count, Mean Corpuscular Haemoglobin were stable for at least twenty four hours at 33{degrees}C. Haematocrit, Mean Corpuscular Volume and Platelet Counts were stable for less than four hours at 33{degrees}C. All the above parameters were stable for longer at 22{degrees}C and 4{degrees}C. The three-part differential count showed instability within four hours at 33 {degrees}C.\n\nConclusionsStrict pre-analytical control is needed at 33{degrees}C or above due to the marked instability of most parameters. However, Haemoglobin, Red Blood Cell Count, White Blood Cell Count and Mean Corpuscular Haemoglobin remain relatively stable even at 33{degrees}C.\n\nKey MessageHaematology samples exposed to temperatures of 33{degrees}C or above show rapid change in MCV, HCT,MCHC, RDW, Platelet Counts and three-part differential counts. Settings where prolonged exposure to these temperatures cannot be avoided should rely on the more stable parameters of Haemoglobin, RBC Counts, MCH and WBC Counts.

pathology↗

bioRxiv2017

Multiplex staining by sequential immunostaining and antibody removal on routine tissue sections

Multiplexing (mplx), labeling for multiple immunostains the very same cell or tissue section in situ, has raised considerable interest. The methods proposed include the use of labelled primary antibodies, spectral separation of fluorochromes, bleaching of the fluorophores or chromogens, blocking of previous antibody layers, all in various combinations. The major obstacles to the diffusion of this technique are high costs in custom antibodies and instruments, low throughput, scarcity of specialized skills or facilities.\n\nWe have validated a method based on common primary and secondary antibodies and diffusely available fluorescent image scanners. It entails rounds of four-color indirect immunofluorescence, image acquisition and removal (stripping) of the antibodies, before another stain is applied. The images are digitally registered and the autofluorescence is subtracted. Removal of antibodies is accomplished by disulphide cleavage and a detergent or by a chaotropic salt treatment, this latter followed by antigen refolding. More than thirty different antibody stains can be applied to one single section from routinely fixed and embedded tissue. This method requires a modest investment in hardware and materials and uses freeware image analysis software. Mplx on routine tissue sections is a high throughput tool for in situ characterization of neoplastic, reactive, inflammatory and normal cells.

pathology↗

bioRxiv2017

Robust diagnosis of Ewing sarcoma by immunohistochemical detection of super-enhancer-driven EWSR1-ETS targets

Ewing sarcoma is an undifferentiated bone-associated cancer. Although molecular detection of pathognomonic EWSR1-ETS fusions such as EWSR1-FLI1 enables definitive diagnosis, substantial confusion can arise if molecular diagnostics are unavailable. Diagnosis based solely on the conventional immunohistochemical marker CD99 is unreliable due to its abundant expression in morphological mimics. This study aimed to identify novel diagnostic immunohistochemical markers for Ewing sarcoma.\n\nWe analyzed 768 expression microarrays representing 21 tumor entities including Ewing-like sarcomas to nominate candidate biomarkers. These candidates were validated by immunohistochemistry (IHC) in a tissue microarray (TMA) comprising 174 samples. Microarray, chromatin immunoprecipitation and sequencing (ChIP-Seq) data, and reporter assays were employed to analyze their EWSR1-FLI1-dependency.\n\nOur comparative expression analyses revealed that ATP1A1, BCL11B, and GLG1 constitute specific markers for Ewing sarcoma. Analysis of ChIP-Seq and microarray datasets showed that their expression is EWSR1-FLI1-dependent. This outcome corresponded to EWSR1-FLI1-binding to proximal super-enhancers, which showed high activity in reporter assays. Consistently, high ATP1A1, BCL11B, and GLG1 expressions were detected by IHC. Automated cut-off-finding and combination-testing in the TMA demonstrated that detection of high BCL11B and/or GLG1 expression is sufficient to reach 96% specificity for Ewing sarcoma. While 88% of tested Ewing-like sarcomas displayed strong CD99-immunoreactivity, none displayed combined high expression of BCL11B and GLG1.\n\nCollectively, we provide evidence that ATP1A1, BCL11B, and GLG1 are EWSR1-FLI1 targets, of which BCL11B and GLG1 offer a fast, simple and cost-efficient way to diagnose Ewing sarcoma by IHC. We anticipate that these markers will significantly reduce the number of misdiagnosed patients, and thus improve patient care.

pathology↗

bioRxiv2017

A mouse model of necrotic biliary pancreatitis induced by combining gallstone formation and ligation of the biliary-pancreatic duct

ObjectiveThe aim of the present investigation is to develop a mouse model of biliary pancreatitis with characteristics of both gallstone formation and pancreatitis, mimicking the human etiology and pathphysiological character.\n\nDesignMale C57BL/6 mice were fed with chow, high fat/cholesterol and lithogenic diet for 12 weeks respectively. Laparotomy was done followed by ligation of pancreatic duct (PD), bile duct and pancreatic duct (BPD), or sham operation.\n\nResultsLittle or no evidence of pancreatitis was observed in PD group of mice fed with chow or high fat/cholesterol diet, or in the tail of pancreata removed from animals fed with lithogenic diet. In the head of pancreas, pancreas damage was dramatically more severe in the lithogenic group. When bile reflux was blocked by BPD, pancreas damage markedly reduced to level of chow diet group. The lithogenic diet group also developed significantly more severe multi organ dysfunction syndrome (MODS) in the lung, kidney and liver. The severity of pancreatitis is associated with persistent high bile level of cholesterol and bile acid after obstruction of the biliary-pancreatic duct. Cholesterol crystal aggravated injury of pancreatic acinar cells caused by taurocholate. After obstruction of the biliary-pancreatic duct, in the lithogenic diet group, liver Abcg8 and Cyp7a1 was up-regulated, compared to the control group.\n\nConclusionWe developed a mouse model of severe biliary pancreatitis in both local pancreas damage and MODS. This model provides a sound explanation for the Opie theory dilemma and a potential therapeutical direction in clinical practice as well.\n\nSummary statementA biliary pancreatitis has characters of both gallstone and pancreatitis, mimicking human etiology and pathophysiology, which gave a clear answer to the long time Opie theory dilemma.

pathology↗

bioRxiv2017

Histopathological Effects of Therapeutic Doses of Combined XO-Inhibitors and ACE-Inhibitors on the Expression of VEGF-A in the Myocardium and Renal Cortex in Chronic Hypertensive Albino Rats

BackgroundHypertension is risk factor for development of congestive heart failure. The pathogenesis of myocardial and renal cortex changes in hypertension includes structural remodeling and fibrosis.\n\nAim of studyis to evaluate the effects of therapeutic doses of combined XO-Inhibitors and ACE-Inhibitors on expression of VEGF-A in the myocardium and renal cortex in chronic hypertensive albino rats.\n\nMaterial & MethodsThirty male albino rats were divided into: Group I: (control group), Group II (Non-treated Hypertensive rats), Group III (Allopurinol-treated Hypertensive rats), Group IV (Captopril-treated Hypertensive rats) and Group V (Allopurinol-Captopril-treated Hypertensive rats). At 4 and 8 weeks, the rats were anesthetized followed by obtaining of heart and left kidney to be stained with Masson trichrome and Anti-Vascular endothelial growth factor-A antibody.\n\nResultsGroup II, one month hypertensive rats showed, myocardium showed disarray with significant increase in interstitial fibrosis. The renal cortex showed evidences indicating glomerulosclerosis. Immunohistochemistry, there was high significant decrease in the number of cells of renal cortex with +ve expression of VEGF-A. Later, they showed marked significant increase in interstitial fibrosis. In Group III, myocardium and renal cortex showed high significant increase in interstitial fibrosis. After two month, there were high significant decrease in the surface area of interstitial fibrosis in myocardium and renal cortex with high significant decrease number of the myocardium with +ve expression of VEGaF-A. In Group IV, myocardium showed disarray with marked significant reduction in interstitial fibrosis. The renal cortex showed marked significant reduction in the interstitial fibrosis with significant decrease in the number of cells with +ve expression of VEGF-A. Later, myocardium showed the most high marked significant reduction in interstitial fibrosis with highly significant increase in number of cells with positive expression of VEGF-A. In Group V after two month, both myocardium and renal cortex showed nearly normal architecture with marked significant reduction in interstitial fibrosis.\n\nConclusionsLong term therapy with the combination between allopurinol and captopril decreases the fibrotic changes associated with hypertension and enhances the process of angiogenesis.

pathology↗

bioRxiv2017

Prognostic biomarkers in oral squamous cell carcinoma: a systematic review

Over the years, several tumor biomarkers have been suggested to foresee the prognosis of oral squamous cell carcinoma (OSCC) patients. Here, we present a systematic review to identify, evaluate and summarize the evidence for OSCC reported markers. Eligible studies were identified through a literature search of MEDLINE/PubMed until January 2016. We included primary articles reporting overall survival, disease-free survival and cause-specific survival as outcomes. Our findings were analysed using REporting recommendations for tumor MARKer prognostic studies (REMARK), QuickGo tool and SciCurve trends. We found 41 biomarkers, mostly proteins evaluated by immunohistochemistry. The selected studies are of good quality, although, any study referred to a sample size determination. Considering the lack of follow-up studies, the molecules are still potential biomarkers. Further research is required to validate these biomarkers in well-designed clinical cohort-based studies.

pathology↗

bioRxiv2017

Impaired brain glymphatic flow in a rodent model of chronic liver disease and minimal hepatic encephalopathy

Neuronal function is exquisitely sensitive to alterations in extracellular environment. In patients with hepatic encephalopathy (HE), accumulation of metabolic waste products and noxious substances in the interstitial fluid of the brain may contribute to neuronal dysfunction and cognitive impairment. In a rat model of chronic liver disease, we used an emerging dynamic contrast-enhanced MRI technique to assess the efficacy of the glymphatic system, which facilitates clearance of solutes from the brain. We identified discrete brain regions (olfactory bulb, prefrontal cortex and hippocampus) of altered glymphatic flow, which aligned with cognitive/behavioural deficits. Although the underlying pathophysiological mechanisms remain unclear, this study provides the first experimental evidence of impaired glymphatic clearance in HE.

pathology↗

bioRxiv2017

Pangenomic analysis reveals pathogen-specific regions and novel effector candidates in Fusarium oxysporum f.sp. cepae

A reference-quality assembly of Fusarium oxysporum f. sp. cepae (Foc), the causative agent of onion basal rot has been generated along with genomes of additional pathogenic and non-pathogenic isolates. Phylogenetic analysis confirmed a single origin of the Foc pathogenic lineage.\n\nGenome alignments with other F. oxysporum ff. spp. and non pathogens revealed high levels of syntenic conservation of core chromosomes but little synteny between lineage specific (LS) chromosomes. Four LS contigs in Foc totaling 3.9 Mb were designated as pathogen-specific (PS). A two-fold increase in segmental duplication events was observed between LS regions of the genome compared to within core regions or from LS regions to the core.\n\nRNA-seq expression studies identified candidate effectors expressed in planta, consisting of both known effector homologs and novel candidates. FTF1 and a subset of other transcription factors implicated in regulation of effector expression were found to be expressed in planta.

pathology↗

bioRxiv2017

Investigation of the role of a macromolecular complex of CFTR-NHERF2-LPA2 in the fluid hemostasis and inflammatory responses in intestinal epithelial cells

CFTR is a cAMP-regulated chloride channel located in the apical surface of intestinal epithelial cells; where it forms a macromolecular complex with NHERF2 and LPA2. CFTR has been shown to play a role in the pathogenies of several types of secretory diarrheas. Inflammatory bowel disease (IBD) is a chronic condition of intestine characterized by severe inflammation and mucosal destruction, genetic analysis has shown that LPA contribute to IBD and patients of cystic fibrosis also display the phenotype of diarrhea. The purpose of this study is to investigate if this complex plays a role in the inflammatory responses of intestinal epithelium.\n\nWe then explored the role of this complex in maintaining the integrity of tight junction and inflammatory responses in these cells. In vitro assays show that inhibiting CFTR or LPA2 in the intestinal epithelial cell could disrupt the epithelial cell junction, and reduce the TER of intestinal epithelial cells in both mouse and human cell line. EUSA assay show that intriguing LPA2 through LPS or LPA can increase the secretion of IL-8, while inhibiting or SiRNA knockdown of LPA2 can decrease the secretion of IL-8 in mouse or human intestinal epithelial cells. The CFTR inhibitor can reduce the IL-8 secretion in both mouse and human cell line, the deletion of CFTR in mouse intestine does not affect the IL-8 level, but the knockdown of CFTR in human cell line reduced the IL-8 protein level. The deletion of CFTR in human also reduced the IL-8 mRNA level. This indicates the CFTR-LPA complex is necessary for the expression of IL-8.

pathology↗

bioRxiv2018

Identification of powdery mildew resistance QTL in Fragaria x ananassa

The obligate biotrophic fungus Podosphaera aphanis is the causative agent of powdery mildew on cultivated strawberry (Fragaria x ananassa). Genotypes from two bi-parental mapping populations Emily x Fenella and Redgauntlet x Hapil were phenotyped for powdery mildew disease severity in a series of field trials. Here we report multiple QTL associated with resistance to powdery mildew, identified in ten phenotyping events conducted across different years and locations. Seven QTL show a level of stable resistance across multiple phenotyping events however many other QTL were represented in a single phenotyping event and therefore must be considered transient. One of the identified QTL was closely linked to an associated resistance gene across the wider germplasm. Furthermore, a preliminary association analysis identified a novel conserved locus for further investigation. Our data suggests that resistance is highly complex and that multiple additive sources of quantitative resistance to powdery mildew exist across strawberry germplasm. Implementation of the reported markers in marker-assisted breeding or genomic selection would lead to improved powdery mildew resistant strawberry cultivars, particularly where the studied parents, progeny and close pedigree material are included in breeding germplasm.\n\nKey MessagePowdery mildew resistance in two strawberry mapping populations is controlled by both stable and transient novel QTL of moderate effect. Some transferability of QTL across wider germplasm was observed.

pathology↗

bioRxiv2017

A Novel Uropathogenic Escherichia Coli Genome (strain D3) and Comparative Analysis with Other Uropathogenic and Nonpathogenic Strains

BackgroundBacterial urinary tract infections are extremely prevalent, with half of women having at least one infection at some point in their lives. Most often the causative pathogen is the common gut microbe Escherichia coli. One such E. coli, strain D3, caused a bladder infection in a male adult, and was resistant to multiple antibiotics. We sequenced and assembled the genome of D3, and present it along with a comparative analysis against other pathogenic and nonpathogenic E. Coli strains.\n\nResultsBy comparing the predicted proteins of D3 with those from 5 uropathogenic and 7 nonpathogenic E. Coli strains, we generated a list of 38 genes present in most (4-5) pathogenic strains, but absent in all nonpathogenic strains. Among these were 9 proteins of the Pap fimbrial operon, which has previously been associated with cell adherence and the formation of biofilms. Lastly, we analyzed the list of predicted genes uniquely present in D3 compared to all other strains, and identified multiple transposable elements.\n\nConclusionsThe presence of fimbria in most pathogenic E. coli strains, and their absence in nonpathogenic ones, suggests that they play a role in pathogenicity, a notion supported by previous work. We also found that D3-specific genes are strongly enriched with transposases, recombinases, and integrase, suggesting that these mobile elements have been inserted or expanded in D3, relative to other strains in the study.

pathology↗

bioRxiv2017

Galectin-3 and N-acetylglucosamine promote myogenesis and improve skeletal muscle function in the mdx model of Duchenne muscular dystrophy

The muscle membrane, sarcolemma, must be firmly attached to the basal lamina. The failure of proper attachment results in muscle injury, which is the underlying cause of Duchenne muscular dystrophy (DMD), where mutations in the dystrophin gene disrupts the firm adhesion. In DMD patients, even moderate contraction causes damage, leading to progressive muscle degeneration. The damaged muscles are repaired through myogenesis. Consequently, myogenesis is highly active in DMD patients, and the repeated activation of myogenesis leads to the exhaustion of the myogenic stem cells. Therefore, approaches to reducing the risk of the exhaustion are to develop a treatment that strengthens the interaction between the sarcolemma and the basal lamina, and increases the efficiency of myogenesis. Galectin-3 is an oligosaccharide-binding protein and known to be involved in cell-cell interactions and cell-matrix interactions. Galectin-3 is expressed in myoblasts and skeletal muscle while its function in muscle remains elusive. In this study, we found evidence that galectin-3 and the monosaccharide N-acetylglucosamine, which increases the ligands (oligosaccharides) of galectin-3, promotes myogenesis in vitro. Moreover, in the mdx mouse model of DMD, treatment with N-acetylglucosamine increased the muscle force production. Our results demonstrate that treatment with N-acetylglucosamine can mitigate the burden of DMD.

pathology↗

bioRxiv2017

Endothelial Cell-Specific MCPIP Deletion Causes Endothelial Dysfunction and Impairs Post-ischemic Angiogenesis in Vivo

Vascular endothelial cells (ECs) play an important role in angiogenesis and inflammatory responses. MCPIP (also known as Zc3h12a or Regnase-1), a newly identified suppressor of cytokine signaling, is expressed in endothelial cells. To directly test the role of endothelium-derived MCPIP in cardiovascular pathophysiology, we specifically targeted deletion of the murine MCPIP gene in the endothelium by using the loxP/Cre system. A floxed MCPIP knock in mouse line was crossbred with VEcadherin5-Cre mice to generate offspring with deletion of the MCPIP gene in ECs (ECKO). Ablation of MCPIP in ECs resulted in systemic inflammation, anemia, splenomegaly, increased vessel permeability, muscle wasting, endothelial dysfunction, thrombus formation, impaired blood perfusion, and reduced lifespan in these mice. Serum levels of cytokines, chemokines, and biomarkers of EC dysfunction were significantly elevated in the ECKO mice, suggesting a hypercytokinemia. These mice also were more susceptible to lipopolysaccharide-induced death. When subjected to ischemia, these mice showed defective post-ischemic angiogenesis and impaired blood flow recovery in hind limb ischemia and stroke models, as well as in wound healing. This effect was associated with an increased cellular infiltration, cytokine expression, and decreased angiogenic factors. Moreover, MCPIP-deficient ECs displayed decreased vascular sprouting and tube elongation in ex vivo aortic ring assay. MCPIP-knockdown in cultured ECs enhanced NF-{kappa}B activity and dysregulated synthesis of microRNAs linked with elevated cytokines and biomarkers of EC dysfunction. These data show, for the first time, that constitutive expression of MCPIP in ECs is essential to maintain ECs in a quiescent state by serving as an important negative feedback regulator that keeps the inflammatory signaling suppressed.

pathology↗

bioRxiv2017

Accurate Discrimination of 23 Major Cancer Types via Whole Genome Somatic Mutation Patterns

The two strongest factors predicting a human cancers clinical behaviour are the primary tumours anatomic organ of origin and its histopathology. However, roughly 3% of the time a cancer presents with metastatic disease and no primary can be determined even after a thorough radiological survey. A related dilemma arises when a radiologically defined mass is sampled by cytology yielding cancerous cells, but the cytologist cannot distinguish between a primary tumour and a metastasis from elsewhere.\n\nHere we use whole genome sequencing (WGS) data from the ICGC/TCGA PanCancer Analysis of Whole Genomes (PCAWG) project to develop a machine learning classifier able to accurately distinguish among 23 major cancer types using information derived from somatic mutations alone. This demonstrates the feasibility of automated cancer type discrimination based on next-generation sequencing of clinical samples. In addition, this work opens the possibility of determining the origin of tumours detected by the emerging technology of deep sequencing of circulating cell-free DNA in blood plasma.

cancer biology↗

bioRxiv2017

Label-free quantitative screening of breast tissue using Spatial Light Interference Microscopy (SLIM)

Breast cancer is the most common type of cancer among women worldwide. The standard histopathology of breast tissue, the primary means of disease diagnosis, involves manual microscopic examination of stained tissue by a pathologist. Because this method relies on qualitative information, it can result in inter-observer variation. Furthermore, for difficult cases the pathologist often needs additional markers of malignancy to help in making a diagnosis. We present a quantitative method for label-free tissue screening using Spatial Light Interference Microscopy (SLIM). By extracting tissue markers of malignancy based on the nanostructure revealed by the optical path-length, our method provides an objective and potentially automatable method for rapidly flagging suspicious tissue. We demonstrated our method by imaging a tissue microarray comprising 68 different subjects - 34 with malignant and 34 with benign tissues. Three-fold cross validation results showed a sensitivity of 94% and specificity of 85% for detecting cancer. The quantitative biomarkers we extract provide a repeatable and objective basis for determining malignancy. Thus, these disease signatures can be automatically classified through machine learning packages, since our images do not vary from scan to scan or instrument to instrument, i.e., they represent intrinsic physical attributes of the sample, independent of staining quality.

pathology↗

bioRxiv2017

Diabetic Retinopathy detection through integration of Deep Learning classification framework

This document represents a brief account of ongoing project for Diabetic Retinopathy Detection (DRD) through integration of state-of the art Deep Learning methods. We make use of deep Convolutional Neural Networks (CNNs), which have proven revolutionary in multiple fields of computer vision including medical imaging, and we bring their power to the diagnosis of eye fundus images. For training our models we used publicly available Kaggle data set. For testing we used portion of Kaggle data withheld from training and Messidor-2 reference standard. Neither withheld Kaggle images, nor Messidor-2 were used for training. For Messidor-2 we achieved sensitivity 99%, specificity 71%, and AUC 0.97. These results close to recent state-of-the-art models trained on much larger data sets and surpass average results of diabetic retinopathy screening when performed by trained optometrists. With continuous development of our Deep Learning models we expect to further increase the accuracy of the method and expand it to cataract and glaucoma diagnostics.

pathology↗

bioRxiv2017

Pediatric Bone Age Assessment Using Deep Convolutional Neural Networks

Skeletal bone age assessment is a common clinical practice to diagnose endocrine and metabolic disorders in child development. In this paper, we describe a fully automated deep learning approach to the problem of bone age assessment using data from the 2017 Pediatric Bone Age Challenge organized by the Radiological Society of North America. The dataset for this competition consists of 12,600 radiological images. Each radiograph in this dataset is an image of a left hand labeled with bone age and sex of a patient. Our approach utilizes several deep neural network architectures trained end-to-end. We use images of whole hands as well as specific parts of a hand for both training and prediction. This approach allows us to measure the importance of specific hand bones for automated bone age analysis. We further evaluate the performance of the suggested method in the context of skeletal development stages. Our approach outperforms other common methods for bone age assessment.

pathology↗

bioRxiv2018

Targeting the DNM3OS / miR-199a~214 cluster for the treatment of fibroproliferative diseases

Given the paucity of effective treatments for fibrotic disorders, new insights into the deleterious mechanisms controlling fibroblast activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies. Here, we identified the long non-coding RNA DNM3OS as a critical downstream effector of TGF-{beta}-induced myofibroblast activation. Mechanistically, DNM3OS regulates this process in trans by giving rise to 3 distinct profibrotic mature miRNAs (i.e. miR-199a-5p/3p and miR-214-3p), which influence both SMAD and non-SMAD components of TGF-{beta} signaling in a multifaceted way, through two modes of action consisting of either signal amplification or mediation. Finally, we provide preclinical evidence that interfering with DNM3OS function using distinct strategies not only prevents lung and kidney fibrosis but also improves established lung fibrosis, providing thus a novel paradigm for the treatment of refractory fibrotic diseases such as idiopathic pulmonary fibrosis.\n\nOne Sentence SummaryThe DNM3OS lncRNA is a reservoir of fibromiRs with major functions in fibroblast response to TGF-{beta} and represents a valuable therapeutic target for refractory fibrotic diseases such as idiopathic pulmonary fibrosis (IPF).

pathology↗