pwc-archive/papers-with-abstracts huggingface dataset:
Cons{é}quences du changement climatique pour les maladies {à} transmission vectorielle et impact en assurance de personnes
Authors: Yannick Drif, Benjamin Roche, Pierre Valade
Date: 2020-11-13 00:00:00

Climate change, which is largely linked to human activities, is already having a considerable impact on our societies. Based on current trends, climate change is expected to accelerate in the coming decades. Beyond its impact on the pace of natural disasters (floods, hurricanes, etc.), climate change may have catastrophic consequences for human life and health. One of the concerns is the increase in the transmission of viruses spread by mosquitoes. Indeed, rising temperatures have a direct positive impact on the viability of mosquitoes in ecosystems, leading to their abundance and thus the risk of exposure of human populations to these pathogens. This study quantifies the consequences of global warming on the risk of epidemics of viruses transmitted by the Aedes Albopictus mosquito in metropolitan France. This mosquito, which is a vector for the Dengue, Chikungunya and Zika viruses, among others, arrived in mainland France in 2004 and has since spread throughout the country. Thanks to the association previously established between the probability of the presence of the mosquito and the average temperature combined with a mathematical model, the probability of an epidemic and the number of people who could be infected and die during a season in each department are estimated. If there is a high degree of heterogeneity in metropolitan France, nearly 2,000 deaths per year could be expected by 2040.
Programmed death ligand 1 expression levels, clinicopathologic features, and survival in surgically resected sarcomatoid lung carcinoma
Authors: Yetkin Agackiran, Funda Aksu, Nalan Akyurek, Caner Ercan, Mustafa Demiroz, Kurtulus Aksu
Date: 2020-11-08 00:00:00
Tasks: Survival Analysis

Aim: To determine the programmed death ligand-1 (PD-L1) expression rates in sarcomatoid lung carcinomas and to compare clinicopathologic features and survival rates of PD-L1-positive and negative patients. Methods: PD-L1 expression was evaluated in 65 surgically resected sarcomatoid carcinomas. The clinicopathologic features of cases with PD-L1-positive and negative tumors were compared. Kaplan-Meier survival analysis was performed. Multiple Cox proportional hazard regression analysis was performed to determine independent predictors of overall survival. Results: PD-L1 antibody positivity was found in 72.3% of surgically resected sarcomatoid lung carcinomas. Regarding histopathologic subtypes, PD-L1 expression was positive in 80.4% of pleomorphic carcinomas, 62.5% of spindle- and/or giant-cell carcinomas, and 16.7% of carcinosarcomas. Pleural invasion was observed in 68.1% of PD-L1-positive cases and 27.8% of PD-L1-negative cases (p = 0.008). No difference in survival was found between PD-L1-positive and negative tumors. The only factor significantly associated with poor survival was the pathological stage of the tumor. Conclusions: This study reveals a high rate of PD-L1 positivity in a large number of sarcomatoid lung carcinoma cases with pleomorphic carcinoma, spindle- and/or giantcell carcinoma, and carcinosarcoma subtypes. The only significantly different clinicopathologic feature in PD-L1-positive cases is pleural invasion. PD-L1 positivity is not a significant predictor of survival in sarcomatoid lung carcinomas.
Searching beyond the usual papillomavirus suspects in squamous carcinomas of the vulva, penis and head and neck
Authors: Marta Félez-Sánchez, Marleny Vergara, Silvia de Sanjosé, Xavier Castellsagué, Laia Alemany, Ignacio Bravo
Date: 2020-11-06 00:00:00

Human Papillomaviruses (HPVs) are involved in the etiology of anogenital and head and neck cancers. The HPV DNA prevalence greatly differs by anatomical site. Indeed, the high rates of viral DNA prevalence in anal and cer-vical carcinomas contrast with the lower fraction of cancer cases attributable to HPVs in other anatomical sites, chiefly the vulva, the penis and head and neck. Here we analyzed 2635 Formalin Fixed Paraffin Embedded surgical samples that had previously tested negative for the presence of HPVs DNA using the SPF10/DEIA procedure, in order to identify the presence of other PVs not explicitly targeted by standard molecular epidemiologic approaches. All samples were reanalyzed using five broad-PV PCR primer sets (CP1/2, FAP6064/FAP64, SKF/SKR, MY9/MY11, MFI/MFII) targeting the main PV main clades. In head and neck carcinoma samples (n = 1141), we recovered DNA from two BetaHPVs, namely HPV20 and HPV21, and from three cutaneous AlphaPVs, namely HPV2, HPV57 and HPV61. In vulvar squamous cell carcinoma samples (n = 902), we found one of the samples containing DNA of one cutaneous HPV, namely HPV2, and 29 samples contained DNA from essentially mucosal HPVs. In penile squamous cell carcinoma samples (n = 592), we retrieved the DNA of HPV16 in 16 samples. Our results show first that the SPF10/DEIA is very sensitive, as we recovered only 2.1% (55/2635) false negative results; second, that although the DNA of cutaneous HPVs can be detected in cancer samples, their relative contribution remains anyway minor (0.23%; 6/2635) and may be neglected for screening and vaccination purposes; and third, their contribution to malignancy is not necessarily warranted and needs to be elucidated.
A biomimetic kidney tubule model
Authors: Elod Mehes, Tana S Pottorf, Marton Gulyas, Sandor Paku, Pamela V. Tran, Andras Czirok
Date: 2020-11-04 00:00:00
Tasks: Cultural Vocal Bursts Intensity Prediction, Drug Discovery, model

A critical barrier in the nephrology field is the lack of appropriate in vitro renal tubule models that allow manipulation of various mechanical factors, facilitating studies of disease pathophysiology and drug discovery. Here we report development of a novel in vitro assay system comprised of a renal tubule within an elasto-plastic extracellular matrix microenvironment. This in vitro tubule mimetic device consists of a container with two, pipette-accessible ports, filament-deposition (3D-) printed into 35 mm cell culture dishes. The container is filled with a hydrogel, such as a collagen I or fibrin gel, while a narrow masking tube is threaded through the ports. Following gelation, the masking material is pulled out leaving a tunnel within the gel. Seeding of the tunnels with M1 or MDCK renal epithelial cells through the side ports results in a monolayer with apical-basal polarity, such that laminin and fibronectin are present on the basal surface, while primary cilia project from the apical side of cells into the tubular lumen. The device is optically accessible, and can be live-imaged by phase contrast or epifluorescence microscopy. The lumen of the epithelial-lined tube can be connected through the side ports to a circulatory flow. We demonstrate that kidney epithelial cells are able to adjust the diameter of the model tubule by myosin-II dependent contractility. Furthermore, cells of the tubule are also able to remodel the surrounding hydrogel leading to budding from the main tubule. We propose that this versatile in vitro model system can be developed into a future pre-clinical tool to study pathophysiology of kidney diseases and identify therapeutic compounds.
Mathematical models of Leukaemia and its treatment: A review
Authors: Salvador Chulián, Álvaro-Martínez Rubio, María Rosa, Víctor M. Pérez-García
Date: 2020-11-04 00:00:00

Leukaemia accounts for around 3% of all cancer types diagnosed in adults, and is the most common type of cancer in children of paediatric age. There is increasing interest in the use of mathematical models in oncology to draw inferences and make predictions, providing a complementary picture to experimental biomedical models. In this paper we recapitulate the state of the art of mathematical modelling of leukaemia growth dynamics, in time and response to treatment. We intend to describe the mathematical methodologies, the biological aspects taken into account in the modelling, and the conclusions of each study. This review is intended to provide researchers in the field with solid background material, in order to achieve further breakthroughs in the promising field of mathematical biology.
A Generic Trauma Severity Computer Method Applied to Pedestrian Collisions
Authors: Christophe Bastien, Clive Neal-Sturgess, Huw Davies
Date: 2020-11-02 00:00:00

In the real world, the severity of traumatic injuries are measured using the Abbreviated Injury Scale (AIS). However the AIS scale cannot currently be computed by using finite element human computer models, which calculate a maximum principal strains (MPS). Further, MPS only establishes a threshold above which a serious or fatal injury occurs. In order to overcome these limitations, a unique Organ Trauma Model (OTM) able to calculate the threat to life of any organ injury is proposed. The focus, in this case is on real world pedestrian brain injuries. The OTM uses a power method, named Peak Virtual Power (PVP), and defines brain white and grey matters trauma responses as a function of impact location and impact speed extracted from the pedestrian collision kinematics. This research has included ageing in the injury severity computation by including soft tissue material degradation, as well as brain volume changes. Further, to account for the limitations of the Lagrangian formulation of the brain model in representing haemorrhage, an approach to include the effects of subdural hematoma is proposed and included as part of the OTM predictions in this study. The OTM model was tested against three real-life pedestrian accidents and has proven to reasonably predict the Post Mortem (PM) outcome. Its AIS predictions are closer to the real world injury severity than standard MPS methods currently recommended. This study suggests that the OTM has the potential to improve forensic predictions as well as contribute to the improvement in vehicle safety design through the ability to measure injury severity. This study concludes that future advances in trauma computing would require the development of a brain model which could predict haemorrhaging.
A Design-Based Model of the Aortic Valve for Fluid-Structure Interaction
Authors: Alexander D. Kaiser, Rohan Shad, William Hiesinger, Alison L. Marsden
Date: 2020-10-05 00:00:00

This paper presents a new method for modeling the mechanics of the aortic valve, and simulates its interaction with blood. As much as possible, the model construction is based on first principles, but such that the model is consistent with experimental observations. We require that tension in the leaflets must support a pressure, then derive a system of partial differential equations governing its mechanical equilibrium. The solution to these differential equations is referred to as the predicted loaded configuration; it includes the loaded leaflet geometry, fiber orientations and tensions needed to support the prescribed load. From this configuration, we derive a reference configuration and constitutive law. In fluid-structure interaction simulations with the immersed boundary method, the model seals reliably under physiological pressures, and opens freely over multiple cardiac cycles. Further, model closure is robust to extreme hypo- and hypertensive pressures. Then, exploiting the unique features of this model construction, we conduct experiments on reference configurations, constitutive laws, and gross morphology. These experiments suggest the following conclusions, which are directly applicable to the design of prosthetic aortic valves. (i) The loaded geometry, tensions and tangent moduli primarily determine model function. (ii) Alterations to the reference configuration have little effect if the predicted loaded configuration is identical. (iii) The leaflets must have sufficiently nonlinear material response to function over a variety of pressures. (iv) Valve performance is highly sensitive to free edge length and leaflet height. For future use, our aortic valve modeling framework offers flexibility in patient-specific models of cardiac flow.
Alpha-1 adrenergic receptor antagonists to prevent hyperinflammation and death from lower respiratory tract infection
Authors: Allison Koenecke, Michael Powell, Ruoxuan Xiong, Zhu Shen, Nicole Fischer, Sakibul Huq, Adham M. Khalafallah, Marco Trevisan, Pär Sparen, Juan J Carrero, Akihiko Nishimura, Brian Caffo, Elizabeth A. Stuart, Renyuan Bai, Verena Staedtke, David L. Thomas, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein, Shibin Zhou, Chetan Bettegowda, Maximilian F. Konig, Brett Mensh, Joshua T. Vogelstein, Susan Athey
Date: 2020-04-21 00:00:00

In severe viral pneumonia, including Coronavirus disease 2019 (COVID-19), the viral replication phase is often followed by hyperinflammation, which can lead to acute respiratory distress syndrome, multi-organ failure, and death. We previously demonstrated that alpha-1 adrenergic receptor ($\alpha_1$-AR) antagonists can prevent hyperinflammation and death in mice. Here, we conducted retrospective analyses in two cohorts of patients with acute respiratory distress (ARD, n=18,547) and three cohorts with pneumonia (n=400,907). Federated across two ARD cohorts, we find that patients exposed to $\alpha_1$-AR antagonists, as compared to unexposed patients, had a 34% relative risk reduction for mechanical ventilation and death (OR=0.70, p=0.021). We replicated these methods on three pneumonia cohorts, all with similar effects on both outcomes. All results were robust to sensitivity analyses. These results highlight the urgent need for prospective trials testing whether prophylactic use of $\alpha_1$-AR antagonists ameliorates lower respiratory tract infection-associated hyperinflammation and death, as observed in COVID-19.
Pneumonia after bacterial or viral infection preceded or followed by radiation exposure -- a reanalysis of older radiobiological data and implications for low dose radiotherapy for COVID-19 pneumonia
Authors: Mark P Little, Wei zhang, Roy van Dusen, Nobuyuki Hamada
Date: 2020-08-06 00:00:00
Tasks: Systematic Literature Review

Currently, there are 14 ongoing clinical studies on low dose radiotherapy (LDRT) for COVID-19 pneumonia. An underlying assumption is that irradiation of about 1 Gy is effective at ameliorating viral pneumonia. Its rationale, however, relies on early human case series or animal studies mostly obtained in the pre-antibiotic era, where rigorous statistical analyses were not performed. It therefore remains unclear whether those early data support such assumptions. With standard statistical survival models, and based on a systematic literature review, we re-analyzed 14 radiobiological animal datasets in which animals received mostly fractionated doses of radiation before or after bacterial/viral inoculation, and assessing various health endpoints (mortality, pneumonia morbidity). In most datasets absorbed doses did not exceed 7 Gy. Various different model systems and types of challenging infection are considered. For 7 studies that evaluated post-inoculation radiation exposure (more relevant to LDRT for COVID-19 pneumonia) the results are heterogeneous, with 2 studies showing a significant increase (p<0.001) and another showing a significant decrease (p<0.001) in mortality associated with radiation exposure. For pre-inoculation exposure the results are also heterogeneous, with 6 datasets showing a significant increase (p<0.01) in mortality risk associated with radiation exposure and the other 2 showing a significant decrease (p<0.05) in mortality risk. Collectively, these data do not provide clear support for reductions in morbidity or mortality associated with post-infection radiation exposure. For pre-infection radiation exposure the inconsistency of direction of effect makes this body of data difficult to interpret. Nevertheless, one must be cautious about adducing evidence from the published reports of these old animal datasets.
Integrodifference master equation describing actively growing blood vessels in angiogenesis
Authors: L. L. Bonilla, M. Carretero, F. Terragni
Date: 2020-09-02 00:00:00

We study a system of particles in a two-dimensional geometry that move according to a reinforced random walk with transition probabilities dependent on the solutions of reaction-diffusion equations for the underlying fields. A birth process and a history-dependent killing process are also considered. This system models tumor-induced angiogenesis, the process of formation of blood vessels induced by a growth factor released by a tumor. Particles represent vessel tip cells, whose trajectories constitute the growing vessel network. New vessels appear and may fuse with existing ones during their evolution. Thus, the system is described by tracking the density of active tips, calculated as an ensemble average over many realizations of the stochastic process. Such density satisfies a novel discrete master equation with source and sink terms. The sink term is proportional to a space-dependent and suitably fitted killing coefficient. Results are illustrated studying two influential angiogenesis models.
A mathematical study of the influence of hypoxia and acidity on the evolutionary dynamics of cancer
Authors: Giada Fiandaca, Marcello Delitala, Tommaso Lorenzi
Date: 2020-09-01 00:00:00

Hypoxia and acidity act as environmental stressors promoting selection for cancer cells with a more aggressive phenotype. As a result, a deeper theoretical understanding of the spatio-temporal processes that drive the adaptation of tumour cells to hypoxic and acidic microenvironments may open up new avenues of research in oncology and cancer treatment. We present a mathematical model to study the influence of hypoxia and acidity on the evolutionary dynamics of cancer cells in vascularised tumours. The model is formulated as a system of partial integro-differential equations that describe the phenotypic evolution of cancer cells in response to dynamic variations in the spatial distribution of three abiotic factors that are key players in tumour metabolism: oxygen, glucose and lactate. The results of numerical simulations of a calibrated version of the model based on real data recapitulate the eco-evolutionary spatial dynamics of tumour cells and their adaptation to hypoxic and acidic microenvironments. Moreover, such results demonstrate how nonlinear interactions between tumour cells and abiotic factors can lead to the formation of environmental gradients which select for cells with phenotypic characteristics that vary with distance from intra-tumour blood vessels, thus promoting the emergence of intra-tumour phenotypic heterogeneity. Finally, our theoretical findings reconcile the conclusions of earlier studies by showing that the order in which resistance to hypoxia and resistance to acidity arise in tumours depend on the ways in which oxygen and lactate act as environmental stressors in the evolutionary dynamics of cancer cells.
Single Cell Transcriptome Research in Human Placenta
Authors: Hui Li, Qianhui Huang, Yu Liu, Lana X Garmire
Date: 2020-08-07 00:00:00

Human placenta is a complex and heterogeneous organ interfacing between the mother and the fetus that supports fetal development. Alterations to placental structural components are associated with various pregnancy complications. To reveal the heterogeneity among various placenta cell types in normal and diseased placentas, as well as elucidate molecular interactions within a population of placental cells, a new genomics technology called single cell RNA-Seq (or scRNA-seq) has been employed in the last couple of years. Here we review the principles of scRNA-seq technology, and summarize the recent human placenta studies at scRNA-seq level across gestational ages as well as in pregnancy complications such as preterm birth and preeclampsia. We list the computational analysis platforms and resources available for the public use. Lastly, we discuss the future areas of interest for placenta single cell studies, as well as the data analytics needed to accomplish them.
SARS-CoV-2 mortality in blacks and temperature-sensitivity to an angiotensin-2 receptor blocker
Authors: Donald R. Forsdyke
Date: 2020-04-30 00:00:00
Tasks: Blocking, Negation, Sensitivity

Tropical climates provoke adaptations in skin pigmentation and in mechanisms controlling the volume, salt-content and pressure of body fluids. For many whose distant ancestors moved to temperate climes, these adaptations proved harmful: pigmentation decreased by natural selection and susceptibility to hypertension emerged. Now an added risk is lung inflammation from coronavirus that may be furthered by innate immune differences. Hypertension and coronavirus have in common angiotensin converting enzyme 2 (ACE2), which decreases blood pressure and mediates virus entry. In keeping with less detailed studies, a long-term case-report shows that decreased blood pressure induced by blocking a primary angiotensin receptor is supplemented, above critical blocker dosage, by a further temperature-dependent fall, likely mediated by ACE2 and secondary angiotensin receptors. Temperature-dependence suggests a linkage with tropical heritage and an influence of blockers on the progress of coronavirus infections. Positive therapeutic results should result from negation of host pro-inflammatory effects mediated by the primary angiotensin receptor and concomitant promotion of countervailing anti-inflammatory effects mediated by ACE2 through other receptors. These effects may involve innate immune system components (lectin complement pathway, NAD metabolome). Black vulnerability - more likely based on physiological than on socioeconomic differences - provides an important clue that may guide treatments.
Histopathology of Third Trimester Placenta from SARS-CoV-2-Positive Women
Authors: Mai He, Priya Skaria, Kasey Kreutz, Ling Chen, Ian Hagemann, Ebony B. Carter, Indira U. Mysorekar, D Michael Nelson, John Pfeifer, Louis P. Dehner
Date: 2020-08-05 00:00:00

Background: This study aims to investigate whether maternal SARS-CoV-2 status affect placental pathology. Methods: A retrospective case-control study was conducted by reviewing charts and slides of placentas between April 1 to July 24, 2020. Clinical history of COVID-19 were searched in Pathology Database (CoPath). Controls were matched with SARS-CoV-2-negative women with singleton deliveries in the 3rd-trimester. Individual and group, pathological features were extracted from placental pathology reports. Results: Twenty-one 3rd-trimester, placentas from SARS-CoV-2-positive women were identified and compared to 20 placentas from SARS-CoV-2-negative women. There were no significant differences in individual or group gross or microscopic pathological features between the groups. Within the SARS-CoV-2+ group, there are no differences between symptomatic and asymptomatic women. Conclusion: Placentas from SARS-CoV-2-positive women do not demonstrate a specific pathological pattern. Pregnancy complicated with COVID-19 during the 3rd trimester does not have a demonstrable effect on placental structure and pathology.