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in category pathology

686 results found. For more information, click each entry to expand.

581: Heme Attenuates Endogenous Opioid Levels in Leukocytes of HIV positive individuals with Chronic Widespread Pain
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Posted 25 Apr 2020

Heme Attenuates Endogenous Opioid Levels in Leukocytes of HIV positive individuals with Chronic Widespread Pain
145 downloads bioRxiv pathology

Saurabh Aggarwal, Jennifer J DeBerry, Israr Ahmad, Prichard Lynn, Cary Dewitte, Simran Malik, Jessica S Merlin, Burel R Goodin, Sonya L. Heath, Sadis Matalon

The prevalence of chronic widespread pain (CWP) in people with HIV (PWH) is high, yet the underlying mechanisms are elusive. Leukocytes synthesize the endogenous opioid, β-endorphin (β-END), within their endoplasmic reticulum (ER). When released into plasma, β-END dampens nociceptive transmission by binding to opioid receptors on sensory neurons. In the present study, we hypothesized that heme-induced ER stress attenuates leukocyte levels/release of β-END, thereby increasing pain sensitivity in PWH. Results demonstrate that PWH with CWP have fragile erythrocytes, high plasma levels of cell-free heme, and impaired heme metabolism. Leukocytes from PWH with CWP also had high ER stress and low β-END compared to PWH without CWP and HIV-negative individuals with or without pain. In vitro heme exposure decreased β-END levels/secretion in murine monocytes/macrophages, which was prevented by treatment with sodium 4-phenylbutyrate, an ER stress inhibitor. To mimic hemolytic effects in a preclinical model in vivo, C57BL/6 mice were injected with phenylhydrazine hydrochloride (PHZ). PHZ increased cell-free heme and ER stress, decreased leukocyte β-END levels and hindpaw mechanical sensitivity thresholds. Treatment of PHZ-injected mice with the heme scavenger, hemopexin, blocked these effects, suggesting that heme-induced ER stress and a subsequent decrease in leukocyte β-END may contribute to CWP in PWH. ### Competing Interest Statement The authors have declared no competing interest.

582: Cannabidiol Attenuates Pulmonary Arterial Hypertension by Normalizing the Mitochondrial Function in Vascular Smooth Muscle Cells
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Posted 05 Nov 2020

Cannabidiol Attenuates Pulmonary Arterial Hypertension by Normalizing the Mitochondrial Function in Vascular Smooth Muscle Cells
143 downloads bioRxiv pathology

Xiaohui Lu, Jingyuan Zhang, Huijiao Liu, Wenqiang Ma, Xin Tan, Shubin Wang, Yu Leo, Fazheng Ren, Xiru Li, Xiangdong Li

Pulmonary artery hypertension (PAH) is a chronic disease associated with enhanced proliferation of pulmonary artery smooth muscle cells (PASMCs) and dysfunctional mitochondria, which was with limited therapeutic options. It has been proved that cannabidiol (CBD) had antioxidant effects in many cardiovascular diseases, whereas the efficacy of CBD in PAH is unknown. To defined the effect of CBD in PAH, we explored the functions of CBD in both PASMCs proliferation test in vitro, and preventive and therapeutic PAH rodent models in vivo. The roles of CBD in mitochondria function and the oxidant stress were assessed in human PASMCs and PAH mice. We found that CBD significantly inhibited hyperproliferation of hypoxia-induced PASMCs, and intragastrically administered CBD could reverse the pathological changes in both Sugen-hypoxia and MCT-induced PAH mice models. Mechanical analysis demonstrated that CBD alleviated PAH by recovering mitochondrial energy metabolism, normalizing the hypoxia-induced oxidant stress, inhibiting abnormal glycolysis and lactate accumulation in cannabinoids receptors-independent manner. Thus, CBD could be a potential drug for PAH.

583: Calcified chondroid mesenchymal neoplasms with FN1-receptor tyrosine kinase gene fusions including MERTK, TEK, FGFR2, and FGFR1: a molecular and clinicopathologic analysis
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Posted 03 Sep 2020

Calcified chondroid mesenchymal neoplasms with FN1-receptor tyrosine kinase gene fusions including MERTK, TEK, FGFR2, and FGFR1: a molecular and clinicopathologic analysis
143 downloads medRxiv pathology

Yajuan Liu, Wenjing Wang, Jeffrey Yeh, Yu Wu, Jose G Mantilla, Christopher DM Fletcher, Robert Ricciotti, Eleanor Chen

Translocations involving FN1 have been described in a variety of neoplasms, which share the presence of cartilage matrix and a variable extent of calcification. Fusions of FN1 to FGFR1 or FGFR2 have been reported in nine soft tissue chondromas, mostly demonstrated indirectly by FISH analysis. Delineation of FN1 fusions with various partner genes will facilitate our understanding of the pathogenesis and diagnostic classification of these neoplasms. In this study, we present molecular, clinical and pathologic features of 9 cartilaginous soft tissue neoplasms showing a predilection for the TMJ region and the extremities. We analyzed for gene fusions with precise breakpoints using targeted RNA-seq with a 115-gene panel, including FN1, FGFR1 and FGFR2. All 9 cases were positive for a gene fusion, including two novel fusions, FN1-MERTK and FN1-TEK, each in one case, recurrent FN1-FGFR2 in 5 cases, FN1-FGFR1 without the Ig3 domain in one case, and FGFR1-PLAG1 in one case. The breakpoints in the 5' partner gene FN1 ranged from exons 11-48, retaining the domains of signal peptide, FN1, FN2, and/or FN3, while the 3 ' partner genes retained the trans-membrane domain, tyrosine kinase domains and /or Ig domain. The tumors with FN1-FGFR1, FN1-FGFR2 and FN1-MERTK fusions are generally characterized by nodular/lobular growth of polygonal to stellate cells within a chondroid matrix, often accompanied by various patterns of calcification. These features resemble those as described for the chondroblastoma-like variant of soft tissue chondroma. Additional histologic findings include calcium pyrophosphate dehydrate deposition and features resembling tenosynovial giant cell tumor. Overall, while the tumors from our series show significant morphologic overlap with chondroblastoma-like soft tissue chondroma, we describe novel findings that expand the morphologic spectrum of these neoplasms and have therefore labeled them as calcified chondroid mesenchymal neoplasms. These neoplasms represent a distinct pathologic entity given the presence of recurrent FN1-receptor tyrosine kinase fusions.

584: Radiographic and clinical risk factors of total knee arthroplasty in asymptomatic knees; a 15-year follow-up study
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Posted 23 Oct 2019

Radiographic and clinical risk factors of total knee arthroplasty in asymptomatic knees; a 15-year follow-up study
143 downloads bioRxiv pathology

Flemming Kromann Nielsen, Anne Grethe Jurik, Anette Jørgensen, Niels Egund

Background Radiographic signs of osteoarthritis (OA) are frequent in knees without symptoms. The long-term impact of these findings is not completely elucidated.  We wanted to evaluate whether radiographic or clinical baseline findings are associated with the risk of total knee arthroplasty (TKA) in knees without symptomatic OA but with clinical OA of the other knee during a mean follow-up period of 15 years. Methods A follow-up analysis was performed in 100 persons with unilateral, clinical knee OA according to the ACR (American College of Rheumatology) criteria, who participated in a clinical trial between 2000 and 2002. Baseline radiographs of the contralateral, non-symptomatic knee were available in 88 participants at follow-up. Data on TKA procedures were extracted from the Danish National Patient Register at follow-up. Radiographic and clinical findings were analyzed for associations with subsequent TKA. Results At follow-up, 40 % had received a TKA in their non-symptomatic knee. The risk of TKA was significantly associated with baseline joint space narrowing (risk ratio (RR) 1.6 (95% confidence interval (95% CI) 1.4 to 1.9)), osteophytes (RR 1.5 (95% CI 1.3 to 1.8)) and subchondral sclerosis (RR 2.4 (95% CI 1.6 to 3.7)). Among the clinical findings, only baseline body mass index (BMI) was significantly associated with the risk of TKA (RR 1.4 (95% CI 1.1 to 1.8)). Conclusions Radiographic OA changes and BMI at baseline were significantly associated with the long-term risk of TKA in persons without symptomatic knee OA but with symptomatic OA in the contralateral knee, implying that radiographic OA findings are important prognostic factors regardless of symptoms.

585: Energy dynamics for systemic configurations of virus-host coevolution
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Posted 15 May 2020

Energy dynamics for systemic configurations of virus-host coevolution
143 downloads bioRxiv pathology

Alessandra Romano, Marco Casazza, Francesco Gonella

Virus cause multiple outbreaks, for which comprehensive tailored therapeutic strategies are still missing. Virus and host cell dynamics are strictly connected, and convey in virion assembly to ensure virus spread in the body. Study of the systemic behavior of virus-host interaction at the single-cell level is a scientific challenge, considering the difficulties of using experimental approaches and the limited knowledge of the behavior of emerging novel virus as a collectivity. This work focuses on positive-sense, single-stranded RNA viruses, like human coronaviruses, in their virus individual host interaction, studying the changes induced in the host cell bioenergetics. A systems-thinking representation, based on stock-flow diagramming of virus-host interaction at the cellular level, is used here for the first time to simulate the system energy dynamics. We found that reducing the energy flow which fuels virion assembly is the most affordable strategy to limit the virus spread, but its efficacy is mitigated by the contemporary inhibition of other flows relevant for the system. ### Competing Interest Statement The authors have declared no competing interest.

586: Accurate recognition of colorectal cancer with semi-supervised deep learning on pathological images
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Posted 14 Jul 2020

Accurate recognition of colorectal cancer with semi-supervised deep learning on pathological images
142 downloads bioRxiv pathology

Gang Yu, Ting Xie, Chao Xu, Xing-Hua Shi, Chong Wu, Run-Qi Meng, Xiang-He Meng, Kuan-Song Wang, Hong-Mei Xiao, Hong-Wen Deng

Purposes: The machine-assisted recognition of colorectal cancer using pathological images has been mainly focused on supervised learning approaches that suffer from a significant bottleneck of requiring a large number of labeled training images. The process of generating high quality image labels is time-consuming, labor-intensive, and thus lags behind the quick accumulation of pathological images. We hypothesize that semi-supervised deep learning, a method that leverages a small number of labeled images together with a large quantity of unlabeled images, can provide a powerful alternative strategy for colorectal cancer recognition. Method: We proposed semi-supervised classifiers based on deep learning that provide pathological predictions at both patch-level and the level of whole slide image (WSI). First, we developed a semi-supervised deep learning framework based on the mean teacher method, to predict the cancer probability of an individual patch by utilizing patch-level data generated by dividing a WSI into many patches. Second, we developed a patient-level method utilizing a cluster-based and positive sensitivity strategy on WSIs to predict whether the WSI or the associated patient has cancer or not. We demonstrated the general utility of the semi-supervised learning method for colorectal cancer prediction utilizing a large data set (13,111 WSIs from 8,803 subjects) gathered from 13 centers across China, the United States and Germany. On this data set, we compared the performances of our proposed semi-supervised learning method with those from the prevailing supervised learning methods and six professional pathologists. Results: Our results confirmed that semi-supervised learning model overperformed supervised learning models when a small portion of massive data was labeled, and performed as well as a supervised learning model when using massive labeled data. Specifically, when a small amount of training patches (~3,150) was labeled, the proposed semi-supervised learning model plus ~40,950 unlabeled patches performed better than the supervised learning model (AUC: 0.90±0.06 vs. 0.84±0.07,P value=0.02). When more labeled training patches (~6,300) were available, the semi-supervised learning model plus ~37,800 unlabeled patches still performed significantly better than a supervised learning model (AUC: 0.98±0.01vs. 0.92±0.04, P value=0.0004), and its performance had no significant difference compared with a supervised learning model trained on massive labeled patches (~44,100) (AUC:0.98±0.01 vs. 0.987±0.01, P value=0.134). Through extensive patient-level testing of 12,183 WSIs in 12 centers, we found no significant difference on patient-level diagnoses between the semi-supervised learning model (~6,300 labeled, ~37,800 unlabeled training patches) and a supervised learning model (~44,100 labeled training patches) (average AUC: 97.40% vs. 97.96%, P value=0.117). Moreover, the diagnosis accuracy of the semi-supervised learning model was close to that of human pathologists (average AUC: 97.17% vs. 96.91%). Conclusions: We reported that semi-supervised learning can achieve excellent performance at patch-level and patient-level diagnoses for colorectal cancer through a multi-center study. This finding is particularly useful since massive labeled data are usually not readily available. We demonstrated that our newly proposed semi-supervised learning method can accurately predict colorectal cancer that matched the average accuracy of pathologists. We thus suggested that semi-supervised learning has great potentials to build artificial intelligence (AI) platforms for medical sciences and clinical practices including pathological diagnosis. These new platforms will dramatically reduce the cost and the number of labeled data required for training, which in turn will allow for broader adoptions of AI-empowered systems for cancer image analyses. Keywords: colorectal cancer; artificial intelligence; semi-supervised learning; pathological diagnosis. ### Competing Interest Statement The authors have declared no competing interest.

587: Climatic drivers of Verticillium dahliae occurrence in Mediterranean olive-growing areas of southern Spain
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Posted 21 Apr 2020

Climatic drivers of Verticillium dahliae occurrence in Mediterranean olive-growing areas of southern Spain
142 downloads bioRxiv pathology

Juan Miguel Requena-Mullor, Jose Manuel García-Garrido, Pedro Antonio García, Estefanía Rodríguez

Verticillium wilt, caused by the soil-borne fungus Verticillium dahliae, is one of the most harmful diseases in Mediterranean olive-growing areas. Although, the effects of both soil temperature and moisture on V. dahliae are well known, there is scant knowledge about what climatic drivers affect the occurrence of the pathogen on a landscape scale. Here, we investigate what climatic drivers determine V. dahliae occurrence in olive-growing areas in southern Spain. In order to bridge this gap in knowledge, a landscape-scale field survey was carried out to collect data on the occurrence of V. dahliae in 779 olive groves in Granada province. Forty models based on competing combinations of climatic variables were fitted and evaluated using information-theoretic methods. A model that included a multiplicative combination of seasonal and extreme climatic variables was found to be the most viable one. Isothermality and the seasonal distribution of precipitation were the most important variables influencing the occurrence of the pathogen. The isothermal effect was in turn modulated by the seasonality of rainfall, and this became less negative as seasonality increases. Thus, V. dahliae occurs more frequently in olive-growing areas where the day-night temperature oscillation is lower than the summer-winter one. We also found that irrigation reduced the influence of isothermality on occurrence. Our results demonstrate that long-term "sophisticated" climatic factors rather than “primary” variables, such as annual trends, can better explain the spatial patterns of V. dahliae occurrence in Mediterranean, southern Spain. One important implication of our study is that appropriate irrigation management, when temperature oscillation approaches optimal conditions for V. dahliae to thrive, may reduce the appearance of symptoms in olive trees.

588: Presence of polyadenylated 3′ tail in RNA of Pepper mild mottle virus allows the Oligo(dT)18 in Priming cDNA Synthesis of its genomic RNA template
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Posted 13 Apr 2020

Presence of polyadenylated 3′ tail in RNA of Pepper mild mottle virus allows the Oligo(dT)18 in Priming cDNA Synthesis of its genomic RNA template
142 downloads bioRxiv pathology

Nidhi Kumari, Vivek Sharma, Sneha Choudhary, P.N. Sharma

The PCR amplification of majority of the ssRNA of both genomic and non-genomic mRNA is accomplished by RT-PCR. The mRNA is subjected to cDNA synthesis using reverse transcriptase and either Oligo(dT)18, or random or gene specific reverse primers based priming strategies. The choice of primer largely depends on the nature of 3 prime terminus of mRNA and length of cDNA synthesized. In general, oligo(dT)18 is the preferred choice for mRNAs having poly(A) tail at 3 prime terminus. In general, tobamoviruses lack any poly(A) tail at their 3 prime untranslated region (UTR) which forms a tRNA like structure and upstream pseudoknot domain except tow viruses viz., Hibiscus latent Fort Pierce virus (HLFPV) and Hibiscus latent Singapore virus (HLSV) which accommodate internal poly(A) sequences of 46 and 87 nucleotides long, respectively in their 3 prime UTR. However, determination of full nucleotide sequence of Pepper mild mottle virus (PMMoV) using an oligo(dT)18 primed cDNA as template indicated the libertinism of oligo(dT)18 in priming cDNA synthesis of RNA template which are known to lack poly(A) tail. at the end or internally at its 3 prime end. Moreover, coat protein (CP) gene of PMMoV and bean common mosaic virus (BCMV) (Potyvirus with a poly(A) tract at its 3 prime end) was amplified using cDNA primed with random primer as well as oligo(dT)18 was successfully amplified but with significant variation in the intensity of the amplification band in case of PMMoV but not in BCMV. This clearly indicated the presence of PMMoV mRNA with polyadenylated 3 prime tail in total RNA isolated from PMMoV infected capsicum leaves with abundance of non-polyadenylated PMMoV genomic RNA (gRNA). Hence, we hypothesize that the generation of polyadenylated RNA population during the infection cycle of PMMoV in pepper may be possible reason for libertinism of oligo(dT)18 in priming cDNA synthesis of RNA template isolated from PMMoV infected leaves followed by amplification of entire PMMoV genome through RT-PCR. This is first study indicating the presence of polyadenylated or polyadenylated rich regions in PMMoV gRNA acquired during the infection cycle in pepper. ### Competing Interest Statement The authors have declared no competing interest.

589: Prognostic significance of Substance P/ Neurokinin 1 receptor and its association with hormonal receptors in breast carcinoma
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Posted 28 Jun 2020

Prognostic significance of Substance P/ Neurokinin 1 receptor and its association with hormonal receptors in breast carcinoma
141 downloads bioRxiv pathology

Riffat Mehboob, Syed Amir Gilani, Amber Hassan, Imrana Tanvir, Rizwan Ullah Khan, Shaista Javaid, Javed Akram, Sadaf, Fridoon Ahmad, Miguel Munoz

To evaluate the expression and Immunolocalization of Substance P (SP)/ Neurokinin-1 Receptor (NK-1R) in Breast Carcinoma (BC) patients and it’s association with routine proliferative markers (ER, PR, HER2/ neu and Ki-67). Methods A cross-sectional study was performed on 34 cases of BC. There were 23 cases of group A (Grade III), 8 of group B (Grade II) and only 3 cases of group C (Grade I). Age range comprised of patients from 20-80 years and the mean age of patients was 45.74 years. HE, ER, PR, HER2 and Ki-67 staining was performed as routine biomarkers. Samples were then processed for immunomarkers study of Substance P and NK-1R immunohistochemistry was performed for few cases. Results 14/23 cases (61%) of group A, 7/8 cases (88%) of group B and 2/3 (67%) cases of group C were SP positive. Overall, strong staining (≥ 10% tumors cells), labeled as “3+”, was observed in 9/14 (64.2%) cases of group A and 1/8 (12.5%) case of group B. Moderate staining labelled as “2+” (in ≥ 10% tumor cells) was observed in 3/14 (21.4%) cases of group A, 4/8 (50%) cases of group B. weak positive staining “1+” was observed in only 2/14 (14.28%) cases of group A, 2/8 (25%) cases of group B and all 2/2 (100%) cases of group C. Conclusions SP and NK-1R is overexpressed in breast carcinomas and there is significant association between grade of tumor and their overexpression. It may serve as a novel biomarker for grading of BC. We also suggest that NK-1R antagonists as a potential therapeutic strategy to inhibit and manage BC. Key Points ### Competing Interest Statement The authors have declared no competing interest.

590: Abdominal single-step quantitative susceptibility mapping with spherical mean value filter and structure prior-based regularization
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Posted 16 Jul 2020

Abdominal single-step quantitative susceptibility mapping with spherical mean value filter and structure prior-based regularization
141 downloads bioRxiv pathology

Anton Abyzov, Bernard E. Van Beers, Philippe Garteiser

Abdominal quantitative susceptibility mapping (QSM), especially in small animals, is challenging because of respiratory motion and blood flow that, in addition to noise, deteriorate the quality of the input data. Efficient artefact suppression in QSM reconstruction is crucial in these conditions. Single-step QSM algorithms combine background field removal and magnetic field-to-susceptibility inverse problem regularization in a single optimization equation. Here, we propose a single-step QSM algorithm that uses spherical mean value kernels of different radii for background field removal and structure prior (consistency with magnitude image) with L1 norm for regularization. The optimization problem is solved using the split-Bregman method on the graphic processor unit. The method was compared with previously reported single-step methods: a method using discrete Laplacian instead of spherical mean value kernels, a method using total variational penalty instead of structure prior, and a method using L2 norm for structure prior. With the proposed method relative to the previous ones, a numerical susceptibility phantom was reconstructed more precisely. In living mice, susceptibility maps with more homogeneous liver, higher contrast between liver and blood vessels, and well-preserved structural details were obtained. In patients, susceptibility maps with more homogeneous subcutaneous fat and higher contrast between subcutaneous fat and liver were obtained. These results show the potential of the proposed single-step method for abdominal QSM in small animals and humans. ### Competing Interest Statement The authors have declared no competing interest.

591: Towards resilient beef cattle production systems: Impact of truck contamination and information sharing on foot-and-mouth disease spreading
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Posted 18 Apr 2020

Towards resilient beef cattle production systems: Impact of truck contamination and information sharing on foot-and-mouth disease spreading
139 downloads bioRxiv pathology

Qihui Yang, Don M Gruenbacher, Jessica L Heier Stamm, David E Amrine, Gary L Brase, Scott A DeLoach, Caterina M. Scoglio

As cattle movement data in the United States are scarce due to the absence of mandatory traceability programs, previous epidemic models for U.S. cattle production systems heavily rely on contact rates estimated based on expert opinions and survey data. These models are often based on static networks and ignore the sequence of movement, possibly overestimating the epidemic sizes. In this research, we adapt and employ an agent-based model that simulates beef cattle production and transportation in southwest Kansas to analyze the between-premises transmission of a highly contagious disease, the foot-and-mouth disease. First, we assess the impact of truck contamination on the disease transmission with the truck agent following an independent clean-infected-clean cycle. Second, we add an information-sharing functionality such that producers/packers can trace back and forward their trade records to inform their trade partners during outbreaks. Scenario analysis results show that including indirect contact routes between premises via truck movements can significantly increase the amplitude of disease spread, compared with equivalent scenarios that only consider animal movement. Mitigation strategies informed by information sharing can dramatically improve the system resilience against epidemics, highlighting the benefit of promoting information sharing in the cattle industry. In addition, we identify salient characteristics that must be considered when designing an information-sharing strategy, including the number of days to trace back and forward in the trade records and the role of different cattle supply chain stakeholders. Sensitivity analysis results show that epidemic sizes are sensitive to variations in parameters of fomite survival time and indirect contact transmission probability and future studies can focus on a more accurate estimation of these parameters. ### Competing Interest Statement The authors have declared no competing interest.

592: Distinct Long-term Effects of Precision X-Radiation on Reflex Saliva Flow Rate and Tissue Integrity in a Preclinical Model of Chronic Hyposalivation
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Posted 30 May 2020

Distinct Long-term Effects of Precision X-Radiation on Reflex Saliva Flow Rate and Tissue Integrity in a Preclinical Model of Chronic Hyposalivation
138 downloads bioRxiv pathology

Syed Mohammed Musheer Aalam, Ishaq A. Viringipurampeer, Matthew C. Walb, Erik J. Tryggestad, Chitra P. Emperumal, Jianning Song, Xuewen Xu, Rajan Saini, Isabelle M.A. Lombaert, Jann N. Sarkaria, Joaquin Garcia, Jeffrey R. Janus, Nagarajan Kannan

Chronic salivary hypofunction and xerostomia are common side effects of radiation therapy which is an essential component in the curative management in patients with head & neck cancers. Over the years, improvements in delivery techniques such as image-guided intensity modulated radiation therapy have led to improvement in cancer management but chronic hyposalivation continues to be a challenge that causes long-term health implications resulting in compromised quality of life. Recent advances in salivary stem cell research promise new frontier in the treatment of radiation-induced hyposalivation by initiating regeneration of radiation-damaged salivary parenchymal cells. Lack of a standard preclinical immunodeficient model to assess radiation-induced changes objectively and quantitatively in salivary flow rates will impede rapid progress towards the development of cellular therapies for chronic salivary dysfunction and attendant xerostomia. Herein, we report the first fully characterized novel cone-beam computed tomography (CBCT)-guided precision ionizing radiation (IR) induced chronic hyposalivation model in radiosensitive, immunodeficient transgenic NSG-SGM3 mice expressing three human cytokines including c-KIT ligand/stem cell factor. Additionally, we also report a novel and instantaneous method to objectively assess the kinetics of pilocarpine-stimulated salivary flowrate. Comprehensive structural and functional characterization of salivary glands revealed previously unknown and highly complex gender, age, IR dose and salivary gland subtype-specific effects of salivary-ablative precision IR. ### Competing Interest Statement The authors have declared no competing interest.

593: Spontaneous liver disease in wild-type C57BL/6JOlaHsd mice fed semisynthetic diet
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Posted 08 Apr 2020

Spontaneous liver disease in wild-type C57BL/6JOlaHsd mice fed semisynthetic diet
138 downloads bioRxiv pathology

Onne A.H.O. Ronda, Bert J. M. van de Heijning, Alain de Bruin, Rachel E. Thomas, Ingrid Martini, Martijn Koehorst, Albert Gerding, Mirjam H. Koster, Vincent W. Bloks, Angelika Jurdzinski, Niels L. Mulder, Rick Havinga, Eline M. van der Beek, Dirk-Jan Reijngoud, Folkert Kuipers, Henkjan J. Verkade

Mouse models are frequently used to study mechanisms of human diseases. Recently, we observed a spontaneous bimodal variation in liver weight in C57BL/6JOlaHsd mice fed a semisynthetic diet. We now characterized the spontaneous variation in liver weight and its relationship with parameters of hepatic lipid and bile acid (BA) metabolism. In male C57BL/6JOlaHsd mice fed AIN-93G from birth to postnatal day (PN)70, we measured plasma BA, lipids, Very low-density lipoprotein (VLDL)-triglyceride (TG) secretion, and hepatic mRNA expression patterns. Mice were sacrificed at PN21, PN42, PN63 and PN70. Liver weight distribution was bimodal at PN70. Mice could be subdivided into two nonoverlapping groups based on liver weight: 0.6 SD 0.1 g (approximately one-third of mice, small liver; SL), and 1.0 SD 0.1 g (normal liver; NL; p<0.05). Liver histology showed a higher steatosis grade, inflammation score, more mitotic figures and more fibrosis in the SL versus the NL group. Plasma BA concentration was 14-fold higher in SL (p<0.001). VLDL-TG secretion rate was lower in SL mice, both absolutely (-66%, p<0.001) and upon correction for liver weight (-44%, p<0.001). Mice that would later have the SL-phenotype showed lower food efficiency ratios during PN21-28, suggesting the cause of the SL phenotype is present at weaning (PN21). Our data show that approximately one-third of C57BL/6JOlaHsd mice fed semisynthetic diet develop spontaneous liver disease with aberrant histology and parameters of hepatic lipid, bile acid and lipoprotein metabolism. Study designs involving this mouse strain on semisynthetic diets need to take the SL phenotype into account. Plasma lipids may serve as markers for the identification of the SL phenotype. ### Competing Interest Statement

594: Large-Scale Testing using Tapestry Pooling
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Posted 13 Oct 2020

Large-Scale Testing using Tapestry Pooling
138 downloads medRxiv pathology

Anirudh Chakravarthy, Srikar Krishna, Sumana Ghosh, Ajay Tomar, Sriram Varahan, Ajit Rajwade, Sabyasachi Ghosh, Nimay Gupta, Rishi Agarwal, Himanshu Payal, Prantik Chakraborty, Krishna Vishal Vemula, Akanksha Vyas, Ritesh Goru, Sandeep Krishna, Dasaradhi Palakodeti, Manoj Gopalkrishnan

We have previously described Tapestry Pooling, a scheme to enhance the capacity of RT-qPCR testing, and provided experimental evidence with spiked synthetic RNA to show that it can help to scale testing and restart the economy. Here we report on validation studies with Covid19 patient samples for the Tapestry Pooling scheme with prevalence in the range of 1% to 2%. We pooled RNA extracted from patient samples that were previously tested for Covid19, sending each sample to three pools. Following three different pooling schemes, we pipetted 320 samples into 48 pools with pool size of 20 at prevalence rate of 1.6%, 500 samples into 60 pools with pool size of 25 at prevalence rate of 2%, and 961 samples into 93 pools with pool size of 31 at prevalence rate of 1%. Of the 191 RT-qPCR experiments that we performed, only one pool was incorrect (false negative). Our recovery algorithm correctly called results for the individual samples, with a 100% sensitivity and a 99.9% specificity, with only one false positive across all the 1,781 blinded results required to be called. We show up to 10X savings in number of tests required at a range of prevalence rates and pool sizes. These experiments establish that Tapestry Pooling is robust enough to handle the diversity of sample constitutions and viral loads seen in real-world samples.

595: Prevalence of Major Limb Loss (MLL) in Post conflict Acholi sub-region of Northern Uganda: Cross sectional study
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Posted 14 May 2020

Prevalence of Major Limb Loss (MLL) in Post conflict Acholi sub-region of Northern Uganda: Cross sectional study
137 downloads bioRxiv pathology

Pamela Atim, Constantine S Loum, Tom R Okello, Samuel M Magada, Walter Onen Yagos, Peter Abelle, Emmanuel B Moro, Jonathan Huck, Anthony Redmond, Mahesh Nirmalan

Background Awareness of residual disabilities amongst people living in countries recovering from prolonged armed conflicts and their socio-economic consequences is increasing. Robust data on the prevalence of such disabilities are important for planning cost effective health services. This study outlines the first community-based prevalence study of Major Limb Loss (MLL) in the Acholi sub region of Northern Uganda. The generic lessons learnt are relevant to many other post-conflict societies in Asia and Africa. Methods A cross sectional survey using random cluster sampling was conducted across 8,000 households in eight districts, of which 7,864 were suitable for analysis. The households were sampled randomly using a high-resolution population model generated using a combination of census data and artificial intelligence. Data were collected using semi-structured questionnaires administered by trained staff, and results were statistically analysed to identify patterns. Results Data obtained from 7,864 households demonstrated that 47.9% (3,763) of households contained people with disabilities, and 3.0%, (237) of households contained people living with MLL. Of those exhibiting disabilities, the most common types were physical disabilities affecting mobility and other conditions limiting vision or hearing. Our analysis suggests that MLL sufferers are disproportionately male, older and less well educated than the general population. Using the identified prevalence rate of MLL (0.6%) and an estimated population value for the Acholi Sub-Region of 1.9 million, we estimate that there are approximately 11,400 MLL sufferers in the region who require long-term rehabilitation services. Conclusions This is the first large scale study on the prevalence of MLL following the Ugandan civil war - known for extreme forms of violence, cruelty and mutilation. Our study demonstrates the magnitude of the problem still faced by the affected people, almost 15 years after the end of large scale combat, and the relative paucity of rehabilitation services to meet their needs. Suitable alternative health policy frameworks are required to address these relatively invisible needs.

596: Less physical activity and more varied and disrupted sleep is associated with a less favorable metabolic profile in adolescents
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Posted 31 Jan 2020

Less physical activity and more varied and disrupted sleep is associated with a less favorable metabolic profile in adolescents
137 downloads bioRxiv pathology

Vaka Rognvaldsdottir, Robert J. Brychta, Soffia M. Hrafnkelsdottir, Kong Y Chen, Sigurbjorn A. Arngrimsson, Erlingur Johannsson, Sigridur L. Guðmundsdottir

Background: Sleep and physical activity are modifiable behaviors that play an important role in preventing overweight, obesity, and metabolic health problems. Studies of the association between concurrent objective measures of sleep, physical activity, and metabolic risk factors among adolescents are limited. Objective: The aim of the study was to examine the association between metabolic risk factors and objectively measured school day physical activity and sleep duration, quality, onset, and variability in adolescents. Materials and Methods: We measured one school week of free-living sleep and physical activity with wrist actigraphy in 252 adolescents (146 girls), aged 15.8±0.3 years. Metabolic risk factors included body mass index, waist circumference, total body and trunk fat percentage, resting blood pressure, and fasting glucose and insulin levels. Multiple linear regression adjusted for sex, parental education, and day length was used to assess associations between metabolic risk factors and sleep and activity parameters. Results: On average, participants went to bed at 00:22±0.88 hours and slept 6.2±0.7 hours/night, with 0.83±0.36 hours of awakenings/night. However, night-to-night variability in sleep duration (0.87±0.57 hours) and bedtime (0.79±0.58 hours) was considerable. Neither average sleep duration nor mean bedtime was associated with any metabolic risk factors. However, greater night-to-night variability in sleep duration was associated with higher total body (β=1.9±0.9 %/h, p=0.03) and trunk fat percentage (β=1.6±0.7 %/h, p=0.02), poorer sleep quality (more hours of awakening) was associated with higher systolic blood pressure (β=4.9±2.2 mmHg/h, p=0.03), and less physical activity was associated with higher trunk fat percentage (p=0.04) and insulin levels (p=0.01). Conclusion: Greater nightly variation in sleep, lower sleep quality, and less physical activity was associated with a less favorable metabolic profile in adolescents. These findings support the idea that, along with an adequate amount of sleep and physical activity, a regular sleep schedule is important to the metabolic health of adolescents.

597: Estimation of cellularity in tumours treated with Neoadjuvant therapy: A comparison of Machine Learning algorithms
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Posted 11 Apr 2020

Estimation of cellularity in tumours treated with Neoadjuvant therapy: A comparison of Machine Learning algorithms
135 downloads bioRxiv pathology

Mauricio Alberto Ortega-Ruíz, Cefa Karabağ, Victor García Garduño, Constantino Carlos Reyes-Aldasoro

This paper describes a method for residual tumour cellularity (TC) estimation in Neoadjuvant treatment (NAT) of advanced breast cancer. This is determined manually by visual inspection by a radiologist, then an automated computation will contribute to reduce time workload and increase precision and accuracy. TC is estimated as the ratio of tumour area by total image area estimated after the NAT. The method proposed computes TC by using machine learning techniques trained with information on morphological parameters of segmented nuclei in order to classify regions of the image as tumour or normal. The data is provided by the 2019 SPIE Breast challenge, which was proposed to develop automated TC computation algorithms. Three algorithms were implemented: Support Vector Machines, Nearest K-means and Adaptive Boosting (AdaBoost) decision trees. Performance based on accuracy is compared and evaluated and the best result was obtained with Support Vector Machines. Results obtained by the methods implemented were submitted during ongoing challenge with a maximum of 0.76 of prediction probability of success. ### Competing Interest Statement The authors have declared no competing interest.

598: Ultrasound Monitoring of Descending Aortic Aneurysms and Dissections in Mice
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Posted 20 Apr 2020

Ultrasound Monitoring of Descending Aortic Aneurysms and Dissections in Mice
135 downloads bioRxiv pathology

Hisashi Sawada, Michael K. Franklin, Jessica J Moorleghen, Deborah A Howatt, Masayoshi Kukida, Hong S. Lu, Alan Daugherty

Several modalities, such as computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound, are available to visualize mouse aortas.[1][1]-[3][2] CT and MRI enable us to obtain reliable images of the aorta and its branches. However, CT requires vascular contrast and MRI is procedurally complex. Thus, these modalities are used only occasionally for in vivo monitoring of mouse studies. High frequency ultrasonography is a common approach for aortic monitoring in mice.[4][3] The standard ultrasound approach using a para-sternal view can visualize the aortic root, ascending aorta, and aortic arch, while this approach cannot visualize the descending region due to the presence of lungs and ribs. Therefore, the ability to perform in vivo monitoring of descending aortic diseases in mice has been an impediment. This study reports a para-spinal dorsal approach for ultrasound imaging of mouse descending aortas. ### Competing Interest Statement The authors have declared no competing interest. [1]: #ref-1 [2]: #ref-3 [3]: #ref-4

599: First report of the sexual stage of the flax pathogen Mycosphaerella linicola in France and its impact on pasmo epidemiology
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Posted 18 Jun 2020

First report of the sexual stage of the flax pathogen Mycosphaerella linicola in France and its impact on pasmo epidemiology
135 downloads bioRxiv pathology

Delphine Paumier, Blandine Bammé, Annette Penaud, Romain Valade, Frédéric Suffert

We performed a three-year field survey in France to characterize the dynamics of sexual reproduction in Mycosphaerella linicola , the causal agent of pasmo, during the interepidemic period. Cohorts of fruiting bodies were sampled from linseed straw during the autumn and winter and carefully observed, focusing on pseudothecia, asci and ascospores. A sequence of experimental steps corresponding to Koch’s postulates confirmed in July 2014, for the first time in France and continental Europe, the widespread presence of the sexual stage of M. linicola in plant host tissues. The developmental dynamics of pseudothecia on straw, expressed as the change over time in the percentage of mature pseudothecia, was similar in all three years. Pseudothecia appeared in late summer, with peak maturity reached in October. A temporal shift, thought to be due to early autumn rainfall, was highlighted in one of the three years. These observations suggest that sexual reproduction plays a significant role in the epidemiology of pasmo in France. A resurgence of M. linicola infections in spring flax is thought to have occurred in recent years, due to the increase in the area under flax. The presence of the sexual stage of this pathogen probably increased the quantitative impact of residues of winter linseed (used for oil) and flax straw (left on the soil for retting and used for fibers) as an interepidemic ‘brown bridge’. This case study highlights how certain parts of a disease cycle, in this case the sexual phase, can become crucial due to changes in production conditions. ### Competing Interest Statement The authors have declared no competing interest.

600: Combined abdominal heterotopic heart and aorta transplant model in mice
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Posted 06 Mar 2020

Combined abdominal heterotopic heart and aorta transplant model in mice
135 downloads bioRxiv pathology

Hao Dun, Li Ye, Yuehui Zhu, Brian W. Wong

Background: Allograft vasculopathy (AV) remains a major obstacle to long-term allograft survival. While the mouse aortic transplantation model has been proven as a useful tool for study of the pathogenesis of AV, simultaneous transplantation of the aorta alongside the transplantation of another organ may reveal more clinically relevant mechanisms that contribute to the pathogenesis of chronic allograft rejection. Therefore, we developed a combined abdominal heart and aorta transplantation model in mice which benefits from reducing animal and drug utilization, while providing an improved model to study the progressive nature of AV. Methods: The middle of the infrarenal aorta of the recipient mouse was ligatured between the renal artery and its bifurcation. Proximal and distal aortotomies were performed at this site above and below the ligature, respectively, for the subsequent anastomoses of the donor aorta and heart grafts to the recipient infrarenal aorta in an end-to-side fashion. The distal anastomotic site of the recipient infrarenal aorta was connected with the outlet of the donor aorta. Uniquely, the proximal anastomotic site on the recipient infrarenal aorta was shared to connect with both the inlet of the donor aorta and the inflow tract to the donor heart. The outflow tract from the donor heart was connected to the recipient inferior vena cava (IVC). Results: The median times for harvesting the heart graft, aorta graft, recipient preparation and anastomosis were 11.5, 8.0, 9.0 and 40.5 min, respectively, resulting in a total median ischemic time of 70 min. The surgery survival rate was more than 96% (29/30). Both the syngeneic C57Bl/6 aorta and heart grafts survived more than 90 days in 29 C57Bl/6 recipients. Further, Balb/c to C57Bl/6 allografts treated with anti-CD40L and CTLA4.Ig survived more than 90 days with a 100% (3/3) survival rate. (3/3). Conclusions: This model is presented as a new tool for researchers to investigate transplant immunology and assess immunosuppressive strategies. It is possible to share a common anastomotic stoma on the recipient abdominal aorta to reconstruct both the aorta graft entrance and heart graft inflow tract. This allows for the study of allogeneic effects on both the aorta and heart from the same animal in a single survival surgery. ### Competing Interest Statement The authors have declared no competing interest.

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