bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular Targets for Biological Therapies of Severe Asthma
Authors: Pelaia Corrado , Crimi Claudia , Vatrella Alessandro , Tinello Caterina , Terracciano Rosa , Pelaia Girolamo
Published: November 2020

Asthma is a heterogeneous respiratory disease characterized by usually reversible bronchial obstruction, which is clinically expressed by different phenotypes driven by complex pathobiological mechanisms (endotypes). Within this context, during the last years several molecular effectors and signalling pathways have emerged as suitable targets for biological therapies of severe asthma, refractory to standard treatments. Indeed, various therapeutic antibodies currently allow to intercept at different levels the chain of pathogenic events leading to type 2 (T2) airway inflammation. In addition to pro-allergic immunoglobulin E (IgE), that chronologically represents the first molecule against which an anti-asthma monoclonal antibody (omalizumab) was developed, today other targets are successfully exploited by biological treatments of severe asthma. In particular, pro-eosinophilic interleukin 5 (IL-5) can be targeted by mepolizumab or reslizumab, whereas benralizumab is a selective blocker of IL-5 receptor. Moreover, dupilumab behaves as a dual receptor antagonist of pleiotropic interleukins 4 (IL-4) and 13 (IL-13). Besides these drugs that are already available in medical practice, other biologics are under clinical development such as those targeting innate cytokines, also including the alarmin thymic stromal lymphopoietin (TSLP), which plays a key role in the pathogenesis of type 2 asthma. Therefore, ongoing and future biological therapies are significantly changing the global scenario of severe asthma management. These new therapeutic options make it possible to implement phenotype/endotype-specific treatments, that are delineating personalized approaches precisely addressing the individual traits of asthma pathobiology. Such tailored strategies are thus allowing to successfully target the immune-inflammatory responses underlying uncontrolled T2-high asthma.
Mucosal Immunity in COVID-19: A Neglected but Critical Aspect of SARS-CoV-2 Infection
Authors: Russell Michael W. , Moldoveanu Zina , Ogra Pearay L. , Mestecky Jiri
Published: November 2020

The mucosal immune system is the largest component of the entire immune system, having evolved to provide protection at the main sites of infectious threat: the mucosae. As SARS-CoV-2 initially infects the upper respiratory tract, its first interactions with the immune system must occur predominantly at the respiratory mucosal surfaces, during both inductive and effector phases of the response. However, almost all studies of the immune response in COVID-19 have focused exclusively on serum antibodies and systemic cell-mediated immunity including innate responses. This article proposes that there is a significant role for mucosal immunity and for secretory as well as circulating IgA antibodies in COVID-19, and that it is important to elucidate this in order to comprehend especially the asymptomatic and mild states of the infection, which appear to account for the majority of cases. Moreover, it is possible that mucosal immunity can be exploited for beneficial diagnostic, therapeutic, or prophylactic purposes.
South Adriatic Recipes: Estimating the Vertical Mixing in the Deep Pit
Authors: Cardin Vanessa , Wirth Achim , Khosravi Maziar , Gačić Miroslav
Published: November 2020

The available historical oxygen data show that the deepest part of the South Adriatic Pit remains well-ventilated despite the winter convection reaching only the upper 700 m depth. Here, we show that the evolution of the vertical temperature structure in the deep South Adriatic Pit (dSAP) below the Otranto Strait sill depth (780 m) is described well by continuous diffusion, a continuous forcing by heat fluxes at the upper boundary (Otranto Strait sill depth) and an intermittent forcing by rare (several per decade) deep convective and gravity-current events. The analysis is based on two types of data: (i) 13-year observational data time series (2006–2019) at 750, 900, 1,000, and 1,200 m depths of the temperature from the E2M3A Observatory and (ii) 55 vertical profiles (1985–2019) in the dSAP. The analytical solution of the gravest mode of the heat equation compares well to the temperature profiles, and the numerical integration of the resulting forced heat equation compares favorably to the temporal evolution of the time-series data. The vertical mixing coefficient is obtained with three independent methods. The first is based on a best fit of the long-term evolution by the numerical diffusion-injection model to the 13-year temperature time series in the dSAP. The second is obtained by short-time (daily) turbulent fluctuations and a Prandtl mixing length approximation. The third is based on the zero and first modes of an Empirical Orthogonal Function (EOF) analysis of the time series between 2014 and 2019. All three methods are compared, and a diffusivity of approximately κ = 5 · 10−4m2s−1 is obtained. The eigenmodes of the homogeneous heat equation subject to the present boundary conditions are sine functions. It is shown that the gravest mode typically explains 99.5% of the vertical temperature variability (the first three modes typically explain 99.85%) of the vertical temperature profiles at 1 m resolution. The longest time scale of the dissipative dynamics in the dSAP, associated with the gravest mode, is found to be approximately 5 years. The first mode of the EOF analysis (85%) represents constant heating over the entire depth, and the zero mode is close to the parabolic profile predicted by the heat equation for such forcing. It is shown that the temperature structure is governed by continuous warming at the sill depth and deep convection and gravity current events play less important roles. The simple model presented here allows evaluation of the response of the temperature in the dSAP to different forcings derived from climate change scenarios, as well as feedback on the dynamics in the Adriatic and the Mediterranean Sea.
Impact of Comorbidities and Frailty on Early Shunt Failure in Geriatric Patients With Normal Pressure Hydrocephalus
Authors: Hadjiathanasiou Alexis , Kilinc Fatma , Behmanesh Bedjan , Bernstock Joshua , Güresir Erdem , Heimann Muriel , Konczalla Jürgen , Scharnböck Elisa , Schneider Matthias , Weinhold Leonie , Seifert Volker , Vatter Hartmut , Gessler Florian , Schuss Patrick
Published: November 2020

Background/Aim: Older patients are considered to bear a higher perioperative risk. Since idiopathic normal pressure hydrocephalus (NPH) predominantly concerns older patients, identifying risk factors for early shunt failure for preoperative risk/benefit assessment is indispensable for indication and/or consultation of patients for ventriculoperitoneal shunting (VPS).

Methods: We performed a retrospective study design, including data acquired from two university hospital neurosurgical institutions between 2012 and 2019. Overall, 211 consecutive patients with clinical/radiological signs for NPH who additionally showed alleviation of symptoms after lumbar cerebrospinal fluid (CSF) drainage, received VPS and were included for further analysis. Frailty was measured using the Clinical Frailty Scale (CFS). Main outcome was early shunt failure or post-operative complications within 30 days after initial VPS surgery.

Results: The overall complication rate was 14%. Patient-related complications were observed in 13 patients (6%) and procedure-related complications in 16 patients (8%). Early post-operative complications resulted in a significantly prolonged length of hospital stay 6.9 ± 6.8 vs. 10.8 ± 11.8 days (p = 0.03). Diabetes mellitus with end-organ damage (OR 35.4, 95% CI 6.6 – 189.4, p < 0.0001) as well as preexisting Parkinson's disease were associated with early patient-related post-surgical complications after VPS for NPH.

Conclusions: Patients comorbidities but not frailty were associated with early post-operative patient-related complications in patients suffering NPH. While frailty may deter patients from other (neurosurgical) procedures, VPS surgery might contribute to treating NPH in these patients at a tolerable risk.
Current Perspective: 3D Spheroid Models Utilizing Human-Based Cells for Investigating Metabolism-Dependent Drug-Induced Liver Injury
Authors: Cox Christopher R. , Lynch Stephen , Goldring Christopher , Sharma Parveen
Published: November 2020

Drug-induced liver injury (DILI) remains a leading cause for the withdrawal of approved drugs. This has significant financial implications for pharmaceutical companies, places increasing strain on global health services, and causes harm to patients. For these reasons, it is essential that in-vitro liver models are capable of detecting DILI-positive compounds and their underlying mechanisms, prior to their approval and administration to patients or volunteers in clinical trials. Metabolism-dependent DILI is an important mechanism of drug-induced toxicity, which often involves the CYP450 family of enzymes, and is associated with the production of a chemically reactive metabolite and/or inefficient removal and accumulation of potentially toxic compounds. Unfortunately, many of the traditional in-vitro liver models fall short of their in-vivo counterparts, failing to recapitulate the mature hepatocyte phenotype, becoming metabolically incompetent, and lacking the longevity to investigate and detect metabolism-dependent DILI and those associated with chronic and repeat dosing regimens. Nevertheless, evidence is gathering to indicate that growing cells in 3D formats can increase the complexity of these models, promoting a more mature-hepatocyte phenotype and increasing their longevity, in vitro. This review will discuss the use of 3D in vitro models, namely spheroids, organoids, and perfusion-based systems to establish suitable liver models to investigate metabolism-dependent DILI.
Endobolome, a New Concept for Determining the Influence of Microbiota Disrupting Chemicals (MDC) in Relation to Specific Endocrine Pathogenesis
Authors: Aguilera Margarita , Gálvez-Ontiveros Yolanda , Rivas Ana
Published: November 2020

Endogenous steroid hormones and Endocrine Disrupting Chemicals (EDC) interact with gut microbiota through different pathways. We suggest the use of the term “endobolome” when referring to the group of gut microbiota genes and pathways involved in the metabolism of steroid hormones and EDC. States of dysbiosis and reduced diversity of the gut microbiota may impact and modify the endobolome resulting at long-term in the development of certain pathophysiological conditions. The endobolome might play a central role in the gut microbiota as seen by the amount of potentially endobolome-mediated diseases and thereby it can be considered an useful diagnostic tool and therapeutic target for future functional research strategies that envisage the use of next generation of probiotics. In addition, we propose that EDC and other xenobiotics that alter the gut microbial composition and its metabolic capacities should be categorized into a subgroup termed “microbiota disrupting chemicals” (MDC). This will help to distinguish the role of contaminants from other microbiota natural modifiers such as those contained or released from diet, environment, physical activity and stress. These MDC might have the ability to promote specific changes in the microbiota that can ultimately result in common intestinal and chronic or long-term systemic diseases in the host. The risk of developing certain disorders associated with gut microbiota changes should be established by determining both the effects of the MDC on gut microbiota and the impact of microbiota changes on chemicals metabolism and host susceptibility. In any case, further animal controlled experiments, clinical trials and large epidemiological studies are required in order to establish the concatenated impact of the MDC-microbiota-host health axis.
Induction of the cydAB Operon Encoding the bd Quinol Oxidase Under Respiration-Inhibitory Conditions by the Major cAMP Receptor Protein MSMEG_6189 in Mycobacterium smegmatis
Authors: Ko Eon-Min , Oh Jeong-Il
Published: November 2020

The respiratory electron transport chain (ETC) of Mycobacterium smegmatis is terminated with two terminal oxidases, the aa3 cytochrome c oxidase and the cytochrome bd quinol oxidase. The bd quinol oxidase with a higher binding affinity for O2 than the aa3 oxidase is known to play an important role in aerobic respiration under oxygen-limiting conditions. Using relevant crp1 (MSMEG_6189) and crp2 (MSMEG_0539) mutant strains of M. smegmatis, we demonstrated that Crp1 plays a predominant role in induction of the cydAB operon under ETC-inhibitory conditions. Two Crp-binding sequences were identified upstream of the cydA gene, both of which are necessary for induction of cydAB expression under ETC-inhibitory conditions. The intracellular level of cAMP in M. smegmatis was found to be increased under ETC-inhibitory conditions. The crp2 gene was found to be negatively regulated by Crp1 and Crp2, which appears to lead to significantly low cellular abundance of Crp2 relative to Crp1 in M. smegmatis. Our RNA sequencing analyses suggest that in addition to the SigF partner switching system, Crp1 is involved in induction of gene expression in M. smegmatis exposed to ETC-inhibitory conditions.
A Model of Aerobic and Anaerobic Metabolism of Hydrogen in the Extremophile Acidithiobacillus ferrooxidans
Authors: Kucera Jiri , Lochman Jan , Bouchal Pavel , Pakostova Eva , Mikulasek Kamil , Hedrich Sabrina , Janiczek Oldrich , Mandl Martin , Johnson D. Barrie
Published: November 2020

Hydrogen can serve as an electron donor for chemolithotrophic acidophiles, especially in the deep terrestrial subsurface and geothermal ecosystems. Nevertheless, the current knowledge of hydrogen utilization by mesophilic acidophiles is minimal. A multi-omics analysis was applied on Acidithiobacillus ferrooxidans growing on hydrogen, and a respiratory model was proposed. In the model, [NiFe] hydrogenases oxidize hydrogen to two protons and two electrons. The electrons are used to reduce membrane-soluble ubiquinone to ubiquinol. Genetically associated iron-sulfur proteins mediate electron relay from the hydrogenases to the ubiquinone pool. Under aerobic conditions, reduced ubiquinol transfers electrons to either cytochrome aa3 oxidase via cytochrome bc1 complex and cytochrome c4 or the alternate directly to cytochrome bd oxidase, resulting in proton efflux and reduction of oxygen. Under anaerobic conditions, reduced ubiquinol transfers electrons to outer membrane cytochrome c (ferrireductase) via cytochrome bc1 complex and a cascade of electron transporters (cytochrome c4, cytochrome c552, rusticyanin, and high potential iron-sulfur protein), resulting in proton efflux and reduction of ferric iron. The proton gradient generated by hydrogen oxidation maintains the membrane potential and allows the generation of ATP and NADH. These results further clarify the role of extremophiles in biogeochemical processes and their impact on the composition of the deep terrestrial subsurface.
ED-BioRob: A Neuromorphic Robotic Arm With FPGA-Based Infrastructure for Bio-Inspired Spiking Motor Controllers
Authors: Linares-Barranco Alejandro , Perez-Peña Fernando , Jimenez-Fernandez Angel , Chicca Elisabetta
Published: November 2020

Compared to classic robotics, biological nervous systems respond to stimuli in a fast and efficient way regarding the body motor actions. Decision making, once the sensory information arrives to the brain, is in the order of ms, while the whole process from sensing to movement requires tens of ms. Classic robotic systems usually require complex computational abilities. Key differences between biological systems and robotic machines lie in the way information is coded and transmitted. A neuron is the “basic” element that constitutes biological nervous systems. Neurons communicate in an event-driven way through small currents or ionic pulses (spikes). When neurons are arranged in networks, they allow not only for the processing of sensory information, but also for the actuation over the muscles in the same spiking manner. This paper presents the application of a classic motor control model (proportional-integral-derivative) developed with the biological spike processing principle, including the motor actuation with time enlarged spikes instead of the classic pulse-width-modulation. This closed-loop control model, called spike-based PID controller (sPID), was improved and adapted for a dual FPGA-based system to control the four joints of a bioinspired light robot (BioRob X5), called event-driven BioRob (ED-BioRob). The use of spiking signals allowed the system to achieve a current consumption bellow 1A for the entire 4 DoF working at the same time. Furthermore, the robot joints commands can be received from a population of silicon-neurons running on the Dynap-SE platform. Thus, our proposal aims to bridge the gap between a general purpose processing analog neuromorphic hardware and the spiking actuation of a robotic platform.
Sporadic Creutzfeldt-Jakob Disease and Other Proteinopathies in Comorbidity
Authors: Parobkova Eva , van der Zee Julie , Dillen Lubina , Van Broeckhoven Christine , Rusina Robert , Matej Radoslav
Published: November 2020

Background: Sporadic Creutzfeldt–Jakob disease (sCJD) is the most common type of a group of transmissible spongiform encephalopathies (prion diseases). The etiology of the sporadic form of CJD is still unclear. sCJD can occur in combination with other neurodegenerative diseases, which further complicates the diagnosis. Alzheimer's disease (AD), e.g., is often seen in conjunction with sCJD.

Method: In this study, we performed a systematic analysis of 15 genes related to the most important neurodegenerative diseases - AD, frontotemporal dementia, amyotrophic lateral sclerosis, prion disease, and Parkinson's disease - in a cohort of sCJD and sCJD in comorbidity with AD and primary age-related proteinopathy (PART). A total of 30 neuropathologically verified cases of sCJD with and without additional proteinopathies were included in the study. In addition, we compared microtubule-associated protein tau (MAPT) haplotypes between sCJD patients and patients with sCJD and PART or sCJD and AD. Then we studied the interaction between the Apolipoprotein E gene (APOE) and PRNP in sCJD patients.

Results: We did not find any causal mutations in the neurodegenerative disease genes. We did detect a p.E318G missense variant of uncertain significance (VUS) in PSEN1 in three patients. In PRNP, we also found a previously described non-pathogenic insertion (p.P84_Q91Q).

Conclusion: Our pilot study failed to find any critical differences between pure sCJD and sCJD in conjunction with other comorbid neurodegenerative diseases. Further investigations are needed to better understand this phenomenon.
Myasthenia Gravis: Autoantibody Specificities and Their Role in MG Management
Authors: Lazaridis Konstantinos , Tzartos Socrates J.
Published: November 2020

Myasthenia gravis (MG) is the most common autoimmune disorder affecting the neuromuscular junction, characterized by skeletal muscle weakness and fatigability. It is caused by autoantibodies targeting proteins of the neuromuscular junction; ~85% of MG patients have autoantibodies against the muscle acetylcholine receptor (AChR-MG), whereas about 5% of MG patients have autoantibodies against the muscle specific kinase (MuSK-MG). In the remaining about 10% of patients no autoantibodies can be found with the classical diagnostics for AChR and MuSK antibodies (seronegative MG, SN-MG). Since serological tests are relatively easy and non-invasive for disease diagnosis, the improvement of methods for the detection of known autoantibodies or the discovery of novel autoantibody specificities to diminish SN-MG and to facilitate differential diagnosis of similar diseases, is crucial. Radioimmunoprecipitation assays (RIPA) are the staple for MG antibody detection, but over the past years, using cell-based assays (CBAs) or improved highly sensitive RIPAs, it has been possible to detect autoantibodies in previously SN-MG patients. This led to the identification of more patients with antibodies to the classical antigens AChR and MuSK and to the third MG autoantigen, the low-density lipoprotein receptor-related protein 4 (LRP4), while antibodies against other extracellular or intracellular targets, such as agrin, Kv1.4 potassium channels, collagen Q, titin, the ryanodine receptor and cortactin have been found in some MG patients. Since the autoantigen targeted determines in part the clinical manifestations, prognosis and response to treatment, serological tests are not only indispensable for initial diagnosis, but also for monitoring treatment efficacy. Importantly, knowing the autoantibody profile of MG patients could allow for more efficient personalized therapeutic approaches. Significant progress has been made over the past years toward the development of antigen-specific therapies, targeting only the specific immune cells or autoantibodies involved in the autoimmune response. In this review, we will present the progress made toward the development of novel sensitive autoantibody detection assays, the identification of new MG autoantigens, and the implications for improved antigen-specific therapeutics. These advancements increase our understanding of MG pathology and improve patient quality of life by providing faster, more accurate diagnosis and better disease management.
A Tensor-Based Framework for rs-fMRI Classification and Functional Connectivity Construction
Authors: Noroozi Ali , Rezghi Mansoor
Published: November 2020

Recently, machine learning methods have gained lots of attention from researchers seeking to analyze brain images such as Resting-State Functional Magnetic Resonance Imaging (rs-fMRI) to obtain a deeper understanding of the brain and such related diseases, for example, Alzheimer's disease. Finding the common patterns caused by a brain disorder through analysis of the functional connectivity (FC) network along with discriminating brain diseases from normal controls have long been the two principal goals in studying rs-fMRI data. The majority of FC extraction methods calculate the FC matrix for each subject and then use simple techniques to combine them and obtain a general FC matrix. In addition, the state-of-the-art classification techniques for finding subjects with brain disorders also rely on calculating an FC for each subject, vectorizing, and feeding them to the classifier. Considering these problems and based on multi-dimensional nature of the data, we have come up with a novel tensor framework in which a general FC matrix is obtained without the need to construct an FC matrix for each sample. This framework also allows us to reduce the dimensionality and create a novel discriminant function that rather than using FCs works directly with each sample, avoids vectorization in any step, and uses the test data in the training process without forcing any prior knowledge of its label into the classifier. Extensive experiments using the ADNI dataset demonstrate that our proposed framework effectively boosts the fMRI classification performance and reveals novel connectivity patterns in Alzheimer's disease at its early stages.
Wt1 Positive dB4 Neurons in the Hindbrain Are Crucial for Respiration
Authors: Schnerwitzki Danny , Hayn Christian , Perner Birgit , Englert Christoph
Published: November 2020

Central pattern generator (CPG) networks coordinate the generation of rhythmic activity such as locomotion and respiration. Their development is driven by various transcription factors, one of which is the Wilms tumor protein (Wt1). It is present in dI6 neurons of the mouse spinal cord, and involved in the coordination of locomotion. Here we report about the presence of Wt1 in neurons of the caudoventral medulla oblongata and their impact on respiration. By employing immunohistofluorescence staining, we were able to characterize these Wt1 positive (+) cells as dB4 neurons. The temporal occurrence of Wt1 suggests a role for this transcription factor in the differentiation of dB4 neurons during embryonic and postnatal development. Conditional knockout ofWt1in these cells caused an altered population size of V0 neurons already in the developing hindbrain, leading to a decline in the respiration rate in the adults. Thereby, we confirmed and extended the previously proposed similarity between dB4 neurons in the hindbrain and dI6 neurons of the spinal cord, in terms of development and function. Ablation of Wt1+ dB4 neurons resulted in the death of neonates due to the inability to initiate respiration, suggesting a vital role for Wt1+ dB4 neurons in breathing. These results expand the role of Wt1 in the CNS and show that, in addition to its function in differentiation of dI6 neurons, it also contributes to the development of dB4 neurons in the hindbrain that are critically involved in the regulation of respiration.
Dimensions of Musical Creativity
Authors: Schiavio Andrea , Benedek Mathias
Published: November 2020

Current literature on creative cognition has developed rich conceptual landscapes dedicated to the analysis of both individual and collective forms of creativity. This work has favored the emergence of unifying theories on domain-general creative abilities in which the main experiential, behavioral, computational, and neural aspects involved in everyday creativity are examined and discussed. But while such accounts have gained important analytical leverage for describing the overall conditions and mechanisms through which creativity emerges and operates, they necessarily leave contextual forms of creativity less explored. Among the latter, musical practices have recently drawn the attention of scholars interested in its creative properties as well as in the creative potential of those who engage with them. In the present article, we compare previously posed theories of creativity in musical and non-musical domains to lay the basis of a conceptual framework that mitigates the tension between (i) individual and collective and (ii) domain-general and domain-specific perspectives on creativity. In doing so, we draw from a range of scholarship in music and enactive cognitive science, and propose that creative cognition may be best understood as a process of skillful organism–environment adaptation that one cultivates endlessly. With its focus on embodiment, plurality, and adaptiveness, our account points to a structured unity between living systems and their world, disclosing a variety of novel analytical resources for research and theory across different dimensions of (musical) creativity.
Multiplex Networks to Characterize Seizure Development in Traumatic Brain Injury Patients
Authors: La Rocca Marianna , Garner Rachael , Amoroso Nicola , Lutkenhoff Evan S. , Monti Martin M. , Vespa Paul , Toga Arthur W. , Duncan Dominique
Published: November 2020

Traumatic brain injury (TBI) may cause secondary debilitating problems, such as post-traumatic epilepsy (PTE), which occurs with unprovoked recurrent seizures, months or even years after TBI. Currently, the Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) has been enrolling moderate-severe TBI patients with the goal to identify biomarkers of epileptogenesis that may help to prevent seizure occurrence and better understand the mechanism underlying PTE. In this work, we used a novel complex network approach based on segmenting T1-weighted Magnetic Resonance Imaging (MRI) scans in patches of the same dimension (network nodes) and measured pairwise patch similarities using Pearson's correlation (network connections). This network model allowed us to obtain a series of single and multiplex network metrics to comprehensively analyze the different interactions between brain components and capture structural MRI alterations related to seizure development. We used these complex network features to train a Random Forest (RF) classifier and predict, with an accuracy of 70 and a 95% confidence interval of [67, 73%], which subjects from EpiBioS4Rx have had at least one seizure after a TBI. This complex network approach also allowed the identification of the most informative scales and brain areas for the discrimination between the two clinical groups: seizure-free and seizure-affected subjects, demonstrating to be a promising pilot study which, in the future, may serve to identify and validate biomarkers of PTE.
Competing Risks of Cancer and Non-Cancer Mortality When Accompanied by Lifestyle-Related Factors—A Prospective Cohort Study in Middle-Aged and Older Adults
Authors: Macek Pawel , Biskup Malgorzata , Terek-Derszniak Malgorzata , Manczuk Marta , Krol Halina , Naszydlowska Edyta , Smok-Kalwat Jolanta , Gozdz Stanislaw , Zak Marek
Published: November 2020

Background

The study aimed to identify the association between the lifestyle-related factors and the cancer-specific, or non-cancer-specific mortality, when accompanied by a competing risk. Two statistical methods were applied, i.e., cause-specific hazard (CSH), and sub-distribution hazard ratio (SHR). Their respective key advantages, relative to the actual study design, were addressed, as was overall application potential.

Methods

Source data from 4,584 residents (34.2% men), aged 45–64 years, were processed using two different families of regression models, i.e., CSH and SHR; principal focus upon the impact of lifestyle-related factors on the competing risk of cancer and non-cancer mortality. The results were presented as hazard ratios (HR) with 95% confidence intervals (95% CI).

Results

Age, smoking status, and family history of cancer were found the leading risk factors for cancer death; the risk of non-cancer death higher in the elderly, and smoking individuals. Non-cancer mortality was strongly associated with obesity and hypertension. Moderate to vigorous physical activity decreased the risk of death caused by cancer and non-cancer causes.

Conclusions

Specific, lifestyle-related factors, instrumental in increasing overall, and cancer-specific mortality, are modifiable through health-promoting, individually pursued physical activities. Regular monitoring of such health-awareness boosting pursuits seems viable in terms of public health policy making.
Imperfect Predictors for Lung Cancer Immunotherapy—A Field for Further Research
Authors: Wojas-Krawczyk Kamila , Kubiatowski Tomasz
Published: November 2020

The armamentarium for lung cancer immunotherapy has been strengthened using two groups of monoclonal antibodies: 1) anti-PD-1 antibodies, including pembrolizumab and nivolumab, which block the programmed death 1 receptor on the lymphocyte surface, resulting in increasing activity of these cells, and 2) anti-PD-L1 antibodies, including atezolizumab, durvalumab, and avelumab, which block the ligand for the PD-1 molecule on tumor cells and on tumor-infiltrating immune cells. The effectiveness of both groups of antibodies has been proven in many clinical trials, which translates into positive immunotherapeutic registrations for cancer patients. Regarding the predictive factor, PD-L1 expression on cancer cells is the only biomarker validated in prospective clinical trials used for qualification to immunotherapy in advanced non-small cell lung cancer (NSCLC) patients. However, it is not an ideal one. Unfortunately, no clinical benefits could be noted in patients with high PD-L1 expression on tumor cells against the effectiveness of immunotherapy that may be observed in patients without PD-L1 expression. Furthermore, the mechanism of antitumor immune response is extremely complex, multistage, and depends on many factors. Cancer cells could be recognized by the immune system, provided tumor-specific antigen presentation, and these arise as a result of somatic mutations in tumor cells. Based on novel immunotherapy registration, high tumor mutation burden (TMB) has become an important predictive factor. The intensity of lymphocyte infiltration in tumor tissue may be another predictive factor. The effectiveness of anti-PD-L1 immunotherapy is observed in patients with high expression of genes associated with the effector function of T lymphocytes (i.e., their ability to produce IFN-gamma). This does not end the list of potential factors that become useful in qualification of cancer patients for immunotherapy. There remains a need to search for new and perfect predictive factors for immunotherapy.
The Prognostic Value of Androgen Receptor Splice Variant 7 in Castration-Resistant Prostate Cancer Treated With Novel Hormonal Therapy or Chemotherapy: A Systematic Review and Meta-analysis
Authors: Wang Zhize , Shen Haixiang , Ma Nieying , Li Qinchen , Mao Yeqing , Wang Chaojun , Xie Liping
Published: November 2020

Purpose

This study aimed to evaluate the prognostic role of AR-V7 in terms of prostate-specific antigen (PSA) response, progression-free survival (PFS), and overall survival (OS) in CRPC patients treated with novel hormonal therapy (NHT) (Abiraterone and Enzalutamide) or taxane-based chemotherapy (Docetaxel and Cabazitaxel).

Methods

A comprehensive literature search was conducted on PubMed, Embase, and the Web of Science from inception to February 2020. Studies focusing on the prognostic values of AR-V7 in CRPC patients treated with NHT or chemotherapy were included in our meta-analysis. The OS and PFS were analyzed based on Hazard ratios (HRs) and 95% confidence intervals (CIs). Furthermore, Odds ratios (ORs) and 95% CIs were summarized for the AR-V7 conversion after treatment and the PSA response.

Results

The AR-V7 positive proportion increased significantly after NHT treatment (OR 2.56, 95% CI 1.51–4.32, P<0.001), however, it declined after chemotherapy (OR 0.51, 95% CI 0.28–0.93, P=0.003). AR-V7-positive patients showed a significantly decreased PSA response rate after NHT (OR 0.13, 95% CI 0.09–0.19, P<0.001) but not statistically significant for chemotherapy (OR 0.63, 95% CI 0.40-1.01, P=0.06). Notably, PFS (HR 3.56, 95% CI 2.53–5.01, P<0.001) and OS (HR 4.47, 95% CI 3.03–6.59, P<0.001) were worse in AR-V7-positive ttreated with NHT. Similarly, AR-V7 positivity correlated with poor prognosis after chemotherapy as evidenced by shorter OS (HR 1.98, 95% CI 1.48-2.66, P<0.001) and a significantly shorter PFS (HR 1.35, 95% CI 0.97-1.87, P=0.07).

Conclusion

NHT treatment increased AR-V7 positive proportion whereas chemotherapy decreased it. Moreover, AR-V7 positivity correlated with lower PSA response, poorer PFS, and OS in CRPC treated with NHT, and shorter OS in patients receiving chemotherapy.
MicroRNA Signature in Renal Cell Carcinoma
Authors: Ghafouri-Fard Soudeh , Shirvani-Farsani Zeinab , Branicki Wojciech , Taheri Mohammad
Published: November 2020

Renal cell carcinoma (RCC) includes 2.2% of all diagnosed cancers and 1.8% of cancer-related mortalities. The available biomarkers or screening methods for RCC suffer from lack of sensitivity or high cost, necessitating identification of novel biomarkers that facilitate early diagnosis of this cancer especially in the susceptible individuals. MicroRNAs (miRNAs) have several advantageous properties that potentiate them as biomarkers for cancer detection. Expression profile of miRNAs has been assessed in biological samples from RCC patients. Circulatory or urinary levels of certain miRNAs have been proposed as markers for RCC diagnosis or follow-up. Moreover, expression profile of some miRNAs has been correlated with response to chemotherapy, immunotherapy or targeted therapeutic options such as sunitinib. In the current study, we summarize the results of studies that assessed the application of miRNAs as biomarkers, therapeutic targets or modulators of response to treatment modalities in RCC patients.
Lysine in Combination With Estradiol Promote Dissemination of Estrogen Receptor Positive Breast Cancer via Upregulation of U2AF1 and RPN2 Proteins
Authors: Vazquez Rodriguez Gabriela , Abrahamsson Annelie , Turkina Maria V. , Dabrosin Charlotta
Published: November 2020

The majority of estrogen receptor positive (ER+) breast cancer (BC) maintain the ER at metastatic sites. Despite anti-estrogen therapy, almost 30% of ER+ BC patients relapse. Thus, new therapeutic targets for ER+ BC are needed. Amino acids (AAs) may affect the metastatic capacity by affecting inflammatory cells. Essential AAs (EAAs) cannot be produced by human cells and might therefore be targetable as therapeutics. Here we sampled extracellular EAAs in vivo by microdialysis in human BC. Mass spectrometry-based proteomics was used to identify proteins affected after EAA and estradiol (E2) exposure to BC cells. Proteins relevant for patient survival were identified, knocked down in BC cells, and metastatic capability was determined in vivo in the transgenic zebrafish model. We found that lysine was the most utilized EAA in human ER+BC in vivo. In zebrafish, lysine in presence of E2 increased neutrophil-dependent dissemination of ER+ BC cells via upregulation of U2AF1 and RPN2 proteins, which both correlated with poor prognosis of ER+ BC patients in clinical databases. Knockdown of U2AF1 and RPN2 decreased the expression of several cell-adhesion molecules resulting in diminished dissemination. Dietary lysine or its related metabolic pathways may be useful therapeutic targets in ER+ BC.
The Suppressing Effects of Dkk3 Expression on Aggressiveness and Tumorigenesis of Colorectal Cancer
Authors: Zhao Shuang , Hao Chang-lai , Zhao En-hong , Jiang Hua-mao , Zheng Hua-chuan
Published: November 2020

Dkk3 has been discovered during comparison of immortalized and parental cells. Its expression has been shown to reduce colony formation and induce apoptosis of cancer cells, acting as a tumor suppressor. Herein, we demonstrate that Dkk3 overexpression or protein treatment may inhibit colorectal cancer cell proliferation, migration, and invasion and that they may promote apoptosis and G2 phase arrest with hypoexpression of Bcl-2, cdc25B, cdc25c, N-cadherin, slug, and twist and hyperexpression of Bax and E-cadherin. This effect is consistent with that of recombinant Dkk3 exposure and blocked with anti-Dkk3 antibody. Dkk3 deletion in intestinal cells was not associated with the emergence of epithelial lesions; however, adenoma emerged after sodium desoxycholate treatment. At both mRNA and protein levels, Dkk3 expression was higher in normal than in cancer tissues (p<0.05). Dkk3 mRNA expression was negatively associated with its promoter methylation, growth pattern, differentiation, and favorable prognosis in the patients with colorectal cancer (p<0.05). Dkk3-related signal pathways in colorectal cancer included those of cellular adhesion and migration, melanogenesis, chemokine, Hedgehog, JAK-STAT, TOLL-like receptor, TGF-β, MAPK, and calcium signaling (p<0.05). These findings indicate that Dkk3 expression levels can help assess cancer aggressiveness and patient prognosis. It might also suppress aggressive phenotypes and tumorigenesis as a molecular target in gene therapy.
Vancomycin Prescribing Practices and Therapeutic Drug Monitoring for Critically Ill Neonatal and Pediatric Patients: A Survey of Physicians and Pharmacists in Hong Kong
Authors: Chow Twinny Cheuk Hin , Li Janice Yuen Shun , Wong Jasper Chak Ling , Poon Freddie Man Hong , Lam Hugh Simon , Lam Teddy Tai-ning , Lee Chui Ping , Ewig Celeste Lom-ying , Cheung Yin Ting
Published: November 2020

Background: Deviations from the optimal vancomycin dosing may occur in the neonatal and pediatric population due to inconsistencies in the recommended dosing algorithms. This study aims to collect the expert opinions of clinicians who practice in the neonatal or pediatric intensive care units (NICU/PICUs) of 12 major medical centers in Hong Kong.

Methods: This was a multicenter, cross-sectional study. Eligible physicians and pharmacists completed a structured questionnaire to identify the challenges they encountered when selecting the initial intermittent vancomycin dosing. They also answered questions concerning therapeutic monitoring services (TDM) for vancomycin, including the targeted trough levels for empirical vancomycin regimens administered for complicated and uncomplicated infections.

Results: A total of 23 physicians and 43 pharmacists completed the survey. The top clinical parameters reported as most important for determining the initial vancomycin dosing were renal function (90.9%), post-menstrual/postnatal age (81.8%), body weight (66.7%), and suspected/documented pathogen (53.0%). Respondents reported challenges such as difficulties in determining the optimal initial dose for a targeted level (53.0%), inconsistencies between dosing references (43.9%) and a lack of clear hospital guidelines (27.3%). Half of the pharmacists (48.8%) reported that they had helped to interpret the TDM results and recommend vancomycin dose adjustments in >75% of cases. For methicillin-resistant Staphylococcus aureus infection, physicians, and pharmacists reported target trough levels of ~10–15 and 15–20 mg/L, respectively. For suspected moderate/uncomplicated Gram-positive infections physicians tended to prefer a lower trough range of 5–10 mg/L, while pharmacists preferred a range of 10–15 mg/L.

Conclusions: Our results demonstrate that clinicians used varying vancomycin dosing guidelines in their practices. The multidisciplinary TDM service in Hong Kong can be improved further by establishing a standardized dosing guideline and implementing a well-structured, evidence-based service protocol. Future work includes conducting drug utilization studies to evaluate real-world antimicrobial usage patterns and the impact on tangible clinical outcomes, and developing pharmacokinetic-guided dose calculator for antimicrobials in critically ill neonates and pediatric patients.
Hydrogen Sulfide Attenuates High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease by Inhibiting Apoptosis and Promoting Autophagy via Reactive Oxygen Species/Phosphatidylinositol 3-Kinase/AKT/Mammalian Target of Rapamycin Signaling Pathway
Authors: Wu Dongdong , Zhong Peiyu , Wang Yizhen , Zhang Qianqian , Li Jianmei , Liu Zhengguo , Ji Ailing , Li Yanzhang
Published: November 2020

Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease worldwide. Hydrogen sulfide (H2S) is involved in a wide range of physiological and pathological processes. Nevertheless, the mechanism of action of H2S in NAFLD development has not been fully clarified. Here, the reduced level of H2S was observed in liver cells treated with oleic acid (OA). Administration of H2S increased the proliferation of OA-treated cells. The results showed that H2S decreased apoptosis and promoted autophagy through reactive oxygen species (ROS)-mediated phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) cascade in OA-treated cells. In addition, administration of H2S relieved high-fat diet (HFD)-induced NAFLD via inhibition of apoptosis and promotion of autophagy. These findings suggest that H2S could ameliorate HFD-induced NAFLD by regulating apoptosis and autophagy through ROS/PI3K/AKT/mTOR signaling pathway. Novel H2S-releasing donors may have therapeutic potential for the treatment of NAFLD.
Research Progress on the Interaction Between Autophagy and Energy Homeostasis in Cardiac Remodeling
Authors: Ding Wen , Feng Hong , Li Wen-jing , Liao Hai-han , Tang Qi-zhu
Published: November 2020

Cardiac remodeling is a common pathological process in various heart diseases, such as cardiac hypertrophy, diabetes-associated cardiomyopathy and ischemic heart diseases. The inhibition of cardiac remodeling has been suggested to be a potential strategy for preventing heart failure. However, the mechanisms involved in cardiac remodeling are quite complicated. Recent studies have reported a close correlation between autophagy and energy homeostasis in cardiac remodeling associated with various heart diseases. In this review, we summarize the roles of autophagy and energy homeostasis in cardiac remodeling and discuss the relationship between these two processes in different conditions to identify potential targets and strategies for treating cardiac remodeling by regulating autophagy.
Roles of Endovascular Calyx Related Enzymes in Endothelial Dysfunction and Diabetic Vascular Complications
Authors: Li Zhi , Wu Ning , Wang Jing , Zhang Quanbin
Published: November 2020

In recent years, the number of diabetic patients has rapidly increased. Diabetic vascular complications seriously affect people’s quality of life. Studies found that endothelial dysfunction precedes the vascular complications of diabetes. Endothelial dysfunction is related to glycocalyx degradation on the surface of blood vessels. Heparanase (HPSE), matrix metalloproteinase (MMP), hyaluronidase (HYAL), hyaluronic acid synthase (HAS), and neuraminidase (NEU) are related to glycocalyx degradation. Therefore, we reviewed the relationship between endothelial dysfunction and the vascular complications of diabetes from the perspective of enzymes.
Rationale for COVID-19 Treatment by Nebulized Interferon-β-1b–Literature Review and Personal Preliminary Experience
Authors: Mary Aurélien , Hénaut Lucie , Macq Pierre Yves , Badoux Louise , Cappe Arnaud , Porée Thierry , Eckes Myriam , Dupont Hervé , Brazier Michel
Published: November 2020

The inflammatory response to COVID-19 is specifically associated with an impaired type I interferon (IFN) response and complete blockade of IFN-β secretion. Clinically, nebulization of IFN-α-2b has been historically used in China to treat viral pneumonia associated with SARS-CoV. Very recent data show that the use of inhaled type I IFN is associated with decreased mortality in Chinese COVID-19 patients. However, IFN nebulization is currently not standard in Europe and the United States. Therefore, our group has set up a project aimed to evaluate the possibility to nebulize IFN-β-1b (a drug currently used in Europe to treat multiple sclerosis via subcutaneous injections) and to assess the safety of this new mode of administration in SARS-CoV-2 infected patients. We present here literature data that allowed us to build our hypothesis and to develop collaboration between clinical pharmacists, intensivists and nebulization engineers in order to gain first pre-clinical and clinical experience of IFN-β-1b nebulization. After validation of the nebulization method and verification of droplet size compatible with nebulization, the method has been applied to four intensive care patients treated at our university hospital, for whom none of the COVID-19 therapies initially used in France led to significant clinical improvement. All patients exhibited negative viral carriage and experienced clinical improvement 7–16 days after having initiated nebulized IFN-β-1b inhalation therapy. No side effects were observed. All patients were alive within a 90-days follow-up. Although it is not possible to draw firm conclusions on treatment efficacy based on this case report, our study shows that pulmonary IFN-β-1b administration is feasible, with a good safety profile. This procedure, which presents the advantage of directly targeting the lungs and reducing the risks of systemic side effects, may represent a promising therapeutic strategy for the care of patients with severe COVID-19. However, our preliminary observation requires confirmation by randomized controlled trials.