bluuebunny/crossref_metadata_2025 huggingface dataset:
Understanding the Impact of Uterine Fibroids on Human Endometrium Function
Authors: Navarro Antonia , Bariani Maria Victoria , Yang Qiwei , Al-Hendy Ayman
Published: May 2021

Uterine fibroids (leiomyomas) are the most common benign gynecological tumors in women of reproductive age worldwide. They cause heavy menstrual bleeding, usually leading to severe anemia, pelvic pain/pressure, infertility, and other debilitating morbidities. Fibroids are believed to be monoclonal tumors arising from the myometrium, and recent studies have demonstrated that fibroids actively influence the endometrium globally. Studies suggest a direct relationship between the number of fibroids removed and fertility problems. In this review, our objective was to provide a complete overview of the origin of uterine fibroids and the molecular pathways and processes implicated in their development and growth, which can directly affect the function of a healthy endometrium. One of the most common characteristics of fibroids is the excessive production of extracellular matrix (ECM) components, which contributes to the stiffness and expansion of fibroids. ECM may serve as a reservoir of profibrotic growth factors such as the transforming growth factor β (TGF-β) and a modulator of their availability and actions. Fibroids also elicit mechanotransduction changes that result in decreased uterine wall contractility and increased myometrium rigidity, which affect normal biological uterine functions such as menstrual bleeding, receptivity, and implantation. Changes in the microRNA (miRNA) expression in fibroids and myometrial cells appear to modulate the TGF-β pathways and the expression of regulators of ECM production. Taken together, these findings demonstrate an interaction among the ECM components, TGF-β family signaling, miRNAs, and the endometrial vascular system. Targeting these components will be fundamental to developing novel pharmacotherapies that not only treat uterine fibroids but also restore normal endometrial function.
In vivo Functional Genomics for Undiagnosed Patients: The Impact of Small GTPases Signaling Dysregulation at Pan-Embryo Developmental Scale
Authors: Lauri Antonella , Fasano Giulia , Venditti Martina , Dallapiccola Bruno , Tartaglia Marco
Published: May 2021

While individually rare, disorders affecting development collectively represent a substantial clinical, psychological, and socioeconomic burden to patients, families, and society. Insights into the molecular mechanisms underlying these disorders are required to speed up diagnosis, improve counseling, and optimize management toward targeted therapies. Genome sequencing is now unveiling previously unexplored genetic variations in undiagnosed patients, which require functional validation and mechanistic understanding, particularly when dealing with novel nosologic entities. Functional perturbations of key regulators acting on signals’ intersections of evolutionarily conserved pathways in these pathological conditions hinder the fine balance between various developmental inputs governing morphogenesis and homeostasis. However, the distinct mechanisms by which these hubs orchestrate pathways to ensure the developmental coordinates are poorly understood. Integrative functional genomics implementing quantitative in vivo models of embryogenesis with subcellular precision in whole organisms contribute to answering these questions. Here, we review the current knowledge on genes and mechanisms critically involved in developmental syndromes and pediatric cancers, revealed by genomic sequencing and in vivo models such as insects, worms and fish. We focus on the monomeric GTPases of the RAS superfamily and their influence on crucial developmental signals and processes. We next discuss the effectiveness of exponentially growing functional assays employing tractable models to identify regulatory crossroads. Unprecedented sophistications are now possible in zebrafish, i.e., genome editing with single-nucleotide precision, nanoimaging, highly resolved recording of multiple small molecules activity, and simultaneous monitoring of brain circuits and complex behavioral response. These assets permit accurate real-time reporting of dynamic small GTPases-controlled processes in entire organisms, owning the potential to tackle rare disease mechanisms.
Stromal Cells Underlining the Paths From Autoimmunity, Inflammation to Cancer With Roles Beyond Structural and Nutritional Support
Authors: Honan Amanda M. , Chen Zhibin
Published: May 2021

Stromal cells provide structural support and nutrients in secondary lymphoid organs and non-lymphoid tissues. However, accumulating evidence suggests that a complex relationship exists between stromal cells and immune cells. Interactions between immune cells and stromal cells have been shown to influence the pathology of both autoimmunity and cancer. This review examines the heterogeneity of stromal cells within the lymph node and non-lymphoid tissues during both homeostatic and inflammatory conditions, in particular autoimmunity and cancer, with the goal of better understanding the complex and apparently paradoxical relationship between these two classes of diseases. The review surveys potential novel mechanisms involving the interactions between stromal cells and immune cells which may contribute to the development, pathology and underlying connection between autoimmunity and cancer, including potential pathways from autoimmune inflammation to either “hot” or “cold” tumors. These interactions may provide some insights to explain the rising incidence of both autoimmunity and cancer in young women in industrialized countries and have the potential to be exploited in the development of new interventions for preventions and treatments of both autoimmune diseases and cancer.
Characterization of DNA Methylation and Screening of Epigenetic Markers in Polycystic Ovary Syndrome
Authors: Cao Pengbo , Yang Wanting , Wang Peijun , Li Xihe , Nashun Buhe
Published: May 2021

Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine and metabolic disorder in women, which is characterized by androgen excess, ovulation dysfunction, and polycystic ovary. Although the etiology of PCOS is largely unknown, many studies suggest that aberrant DNA methylation is an important contributing factor for its pathological changes. In this study, we investigated DNA methylation characteristics and their impact on gene expression in granulosa cells obtained from PCOS patients. Transcriptome analysis found that differentially expressed genes were mainly enriched in pathways of insulin resistance, fat cell differentiation, and steroid metabolism in PCOS. Overall DNA methylation level in granulosa cells was reduced in PCOS, and the first introns were found to be the major genomic regions that were hypomethylated in PCOS. Integrated analysis of transcriptome, DNA methylation, and miRNAs in ovarian granulosa cells revealed a DNA methylation and miRNA coregulated network and identified key candidate genes for pathogenesis of PCOS, including BMP4, ETS1, and IRS1. Our study shed more light on epigenetic mechanism of PCOS and provided valuable reference for its diagnosis and treatment.
Electrochemiluminescence at 3D Printed Titanium Electrodes
Authors: Douman Samantha F. , De Eguilaz Miren Ruiz , Cumba Loanda R. , Beirne Stephen , Wallace Gordon G. , Yue Zhilian , Iwuoha Emmanuel I. , Forster Robert J.
Published: May 2021

The fabrication and electrochemical properties of a 3D printed titanium electrode array are described. The array comprises 25 round cylinders (0.015 cm radius, 0.3 cm high) that are evenly separated on a 0.48 × 0.48 cm square porous base (total geometric area of 1.32 cm2). The electrochemically active surface area consists of fused titanium particles and exhibits a large roughness factor ≈17. In acidic, oxygenated solution, the available potential window is from ~-0.3 to +1.2 V. The voltammetric response of ferrocyanide is quasi-reversible arising from slow heterogeneous electron transfer due to the presence of a native/oxidatively formed oxide. Unlike other metal electrodes, both [Ru(bpy)3]1+ and [Ru(bpy)3]3+ can be created in aqueous solutions which enables electrochemiluminescence to be generated by an annihilation mechanism. Depositing a thin gold layer significantly increases the standard heterogeneous electron transfer rate constant, ko, by a factor of ~80 to a value of 8.0 ± 0.4 × 10−3 cm s−1 and the voltammetry of ferrocyanide becomes reversible. The titanium and gold coated arrays generate electrochemiluminescence using tri-propyl amine as a co-reactant. However, the intensity of the gold-coated array is between 30 (high scan rate) and 100-fold (slow scan rates) higher at the gold coated arrays. Moreover, while the voltammetry of the luminophore is dominated by semi-infinite linear diffusion, the ECL response is significantly influenced by radial diffusion to the individual microcylinders of the array.
Dengue Virus Infection in Sub-Saharan Africa Between 2010 and 2020: A Systematic Review and Meta-Analysis
Authors: Eltom Khalid , Enan Khalid , El Hussein Abdel Rahim M. , Elkhidir Isam M.
Published: May 2021

Dengue virus (DENV) infection has garnered a global interest in the past few decades. Nevertheless, its epidemiology in certain developing and low-income regions remains poorly understood, due to the absence of comprehensive surveillance and reporting systems. This systematic review and meta-analysis aimed to determine the prevalence of DENV infection in the population of Sub-Saharan Africa using DENV infection markers, and to track any changes in its prevalence during the past ten years. It was conducted in accordance with the PRISMA guidelines, targeting the literature available at MEDLINE/PubMed, ScienceDirect, Cochrane library and Google Scholar. All articles published in English language between January 2010 and June 2020 were screened for eligibility. Random effects model was used to calculate the pooled prevalence of all infection markers. The Inconsistency Index (I2) was used to assess the level of heterogeneity between studies. Subgroup analysis according to country and time-frame of studies was conducted to provide possible explanations to substantial heterogeneity. The critical appraisal tool for prevalence studies designed by the Joanna Briggs Institute (JBI) was used to assess the risk of bias in all included studies. A total of 84 articles, covering 21 countries, were included in this review. Quantitative meta-analysis estimated a pooled IgG prevalence of 25% (95% CI: 21-29%, I2 = 99%), a pooled IgM prevalence of 10% (95% CI: 9-11%, I2 = 98%) and a pooled DENV RNA prevalence of 14% (95% CI: 12-16%, I2 = 99%). Evidence for possible publication bias was also found in all three meta-analyses. Subgroup analysis according to the time of sample collection was performed to closely track the changing prevalence of DENV infection markers between 2010 and 2019. This meta-analysis estimates a high prevalence of DENV infection in Sub-Saharan Africa. More cost-efficient vector control strategies should be designed and implemented in order to adapt to the low-resource nature of this region.
Governing Net Zero Carbon Removals to Avoid Entrenching Inequities
Authors: Healey Peter , Scholes Robert , Lefale Penehuro , Yanda Pius
Published: May 2021

Climate change embeds inequities and risks reinforcing these in policies for climate change remediation. In particular, with policies designed to achieve “net zero” carbon dioxide, offsets may be considered inequitable if seen to avoid or delay gross emission reductions; offsets to emissions through technologically mature methods of carbon dioxide removals (CDR) require natural resources at scales threatening food security; knowledge of the potential of immature CDR is largely a global north monopoly; and CDR in particular environments is ill-understood and its implications for development unexamined. The use of CDR to contribute to robust progress toward Paris climate goals requires global agreement on simultaneously reducing emissions and enhancing removals, equity in burden sharing, and an interdisciplinary effort led by individual jurisdictions and focused on the co-development of technologies and governance to create CDR portfolios matched to local needs.
Don't Trust Your Eyes: Image Manipulation in the Age of DeepFakes
Authors: Langguth Johannes , Pogorelov Konstantin , Brenner Stefan , Filkuková Petra , Schroeder Daniel Thilo
Published: May 2021

We review the phenomenon of deepfakes, a novel technology enabling inexpensive manipulation of video material through the use of artificial intelligence, in the context of today’s wider discussion on fake news. We discuss the foundation as well as recent developments of the technology, as well as the differences from earlier manipulation techniques and investigate technical countermeasures. While the threat of deepfake videos with substantial political impact has been widely discussed in recent years, so far, the political impact of the technology has been limited. We investigate reasons for this and extrapolate the types of deepfake videos we are likely to see in the future.
Relationship Between Different Risk Factor Patterns and Follow-Up Outcomes in Patients With ST-Segment Elevation Myocardial Infarction
Authors: Chen Si , Che Qianzi , Zheng Qiwen , Zhang Yan , Jia Jia , Wu Yiqun , Huo Yong , Chen Dafang
Published: May 2021

Objective: Few studies have been concerned with the combined influences of the presence of multiple risk factors on follow-up outcomes in AMI patients. Our study aimed to identify risk factor patterns that may be associated with 1-year survival in male patients with ST-segment elevation myocardial infarction (STEMI).

Methods: Data were from the China STEMI Care Project Phase 2 (CSCAP-2) collected between 2015 and 2018. A total of 15,675 male STEMI patients were enrolled in this study. Risk factor patterns were characterized using latent class analysis (LCA) according to seven risk factors. Associations between risk factor patterns and follow-up outcomes, including the incidence of major adverse cardiovascular and cerebrovascular events (MACCE) and all-cause death, were investigated by Cox proportional hazard regression analysis.

Results: We obtained four risk factor patterns as “young and middle-aged with low levels of multimorbidity,” “middle-aged with overweight,” “middle-aged and elderly with normal weight,” and “elderly with high multimorbidity.” Four patterns had significant differences in event-free survival (P < 0.001). As compared with the patients of “young and middle-aged with low levels of multimorbidity” pattern, the risk of incidence of MACCE and all-cause death were increased in patients of “middle-aged with overweight” pattern (All-cause death: HR = 1.70, 95% CI:1.29~2.23; MACCE: HR = 1.49, 95% CI:1.29~1.72), “middle-aged and elderly with normal weight” pattern (All-cause death: HR = 3.04, 95% CI: 2.33~3.98; MACCE: HR = 1.82, 95% CI: 1.56~2.12), and “elderly with high multimorbidity” pattern (All-cause death: HR = 5.78, 95% CI: 4.49~7.42; MACCE: HR = 2.67, 95% CI: 2.31~3.10).

Conclusions: By adopting a Latent Class Analysis Approach, STEMI patients can be characterized into four risk factor patterns with significantly different prognosis. The data is useful for the improvement of community health management in each specific subgroup of patients, which indicates a particular risk factor pattern.
A Need for Updating the Research Agenda for Cleft Lip and Palate and Extending the Cleft Team Model to Dental Medicine
Authors: Vieira Alexandre R.
Published: May 2021

Care for individuals born with cleft lip and palate is done by a team approach, including dental medicine. However, oral health is not integrated in other situations that affect overall health. This perspective essay makes the case for a universal team approach, having dental medicine integrated regardless of the overall health issue, much like how cleft lip and palate is managed. Furthermore, future research agenda on the etiology of cleft lip and palate in particular will need to be adjusted for a major roadblock: the lack of more sophisticated clinical descriptions for the cases ascertained at birth.
Blowout Morphometrics and Mass Balances
Authors: Baird Thomas R. , Bristow Charles S. , Luo Wanyin , Du Erji , Bryant Robert G. , Mitchell Thomas M. , Vermeesch Pieter
Published: May 2021

The Gonghe Basin on the Qinghai-Tibet Plateau has a cold, arid climate and has suffered severe land degradation. Climate change as well as anthropogenic activities including overgrazing have resulted in widespread blowout development and the formation of some of Earth’s largest blowouts. The blowouts are part of an aeolian dominated landscape that passes from deflation zone to grass covered plain, and then through blowouts of increasing size and complexity to transverse barchanoid dunes that are migrating into the valley of the Yellow River. A combination of structure-from-motion (SfM) optical drone mapping, ground-penetrating radar (GPR) and soil pits are used to investigate blowout scour hollows and depositional lobes. Comparisons of the volumes of sediment removed from the scour hollows with the volumes of sediment deposited within adjacent lobes varies between sites. The lobe volume is invariably less than the volume of the scour hollow. This can, in part, be attributed to aeolian reworking of the lobe, distributing sand further downwind and uplifting of dust. However, much of the difference in volumes between the scour and lobe can be attributed to the measurement technique, particularly where GPR was employed to calculate lobe volumes. The wavelength of the GPR limits its ability to resolve thin layers of sand resulting in an underestimate of the deposited sand at the margins of a lobe where the sand thickness is equal to, or less than, the wavelength of the GPR. For thin sand layers, beneath the resolution of the GPR, soil pits suggest a closer match between the volume of sand eroded from the scour and the volume of the lobe, albeit with large measurement uncertainty. We put forth two hypotheses to explain the spatio-temporal evolution of the blowout dune field. The downwind increase in blowout dune size could either reflect a downwind propagation of aeolian instability; or it could result from an upwind propagation of the instability, which started at the highest points in the landscape and has subsequently migrated in a northwesterly direction, towards lower elevations. Recent optically stimulated luminescence dating appear to support the latter hypothesis.
Origin and Paleoenvironmental Significance of the Old Red Sand Along the Southeast Coast of China
Authors: Fan Qingbin , Liao Jie , Li Yan , Ye Wei , Wang Tao , Feng Xiao
Published: May 2021

The “Old Red Sand” (ORS) along the southeast coast of China is of significant paleoclimatic and paleoenvironmental significance. However, its provenance remains controversial. In this study, grain size characteristics and quartz grain surface microtextures were analyzed to study the origin and paleoenvironmental significance of the ORS, the results show that the grain size of the ORS show typical aeolian features, the quartz grain surface microtextures of the ORS show both aeolian features and subaqueous environments characteristics. Combined with the latest OSL dating data, we suggest that the ORS was coastal aeolian sand dunes developed since the last interglacial period. The formation of the ORS was restricted jointly by climate changes of the coastal area and the distance from the shoreline that resulted from sea level changes.
Reconstruction of Cultivated Land in the Northeast Margin of Qinghai–Tibetan Plateau and Anthropogenic Impacts on Palaeo-Environment During the Mid-Holocene
Authors: Wende Zhuoma , Hou Guangliang , Gao Jingyi , Chen Xiaoliang , Jin Sunmei , Lancuo Zhuoma
Published: May 2021

The study of past global change is paramount to comprehending the present and future, as well as to better understand the mechanisms and influences of human–land interactions in a given region. The northeastern margin of the Qinghai–Tibetan Plateau has complex natural environments, sensitive to global change, and renowned for its long history of human occupancy. This makes it an ideal region for the study of anthropogenic impacts on the paleo-natural environment. This paper reconstructed the prehistoric temporal and spatial distribution of cultivated lands on the northeast margin of Qinghai–Tibetan Plateau, and analyzed the Dianziping pollen assemblage to disclose the anthropogenic impacts on the paleo-environment. The results demonstrated that around 4.3–4.0 cal ka BP, the rapid development of the Majiayao culture boosted the population to approximately 39,200 people, over 460 km2 of the land area was converted to cropland, concomitantly, evidence of tree pollen decreased significantly. This marked the earliest identification of anthropogenic impacts on vegetation through agricultural activity in this region. At 4.0–3.6 cal ka BP, the population appeared to have diminished in conjunction with the cultivated land area. Nevertheless, forested areas continued to decrease, primarily due to adverse climatic conditions, but, anthropogenic activities played an undeniable role. Dianziping profile demonstrated the existence of natural forest in the Hehuang Valley during Qijia cultural Period. There was also evidence for the occurrence of regional fire events, suggesting large-scale burning of land cover in the area. This further illustrates anthropogenic impacts. At 3.6–2.6 cal ka BP, populations reached approximately 61,300 people, coinciding with the peak of cropland expansion. Consequently, more of the natural vegetation were converted to crops, and the superimposed influences of farming and grazing aggravated the process of deforestation and vegetation succession. Likewise, deforestation during the historical period can be explained, mostly by human driven causes with limited influence from climatic factors. The extensive exploitation of forest and expansion of cropland consequently resulted in extensive land deterioration, leaving the region with forest islands scattered in less populated, mountainous regions.
The Role of Brown Adipose Tissue Dysfunction in the Development of Cardiovascular Disease
Authors: Chen Hong-Jin , Meng Ting , Gao Ping-Jin , Ruan Cheng-Chao
Published: May 2021

Brown adipose tissue (BAT), consisted of brown adipocytes and stromal vascular fraction, which includes endothelial cells, lymphocytes, fibroblasts and stem cells, plays a vital role in regulating cardiovascular health and diseases. As a thermogenic organ, BAT can influence body through strengthening energy expenditure by promoting glucose and lipid metabolism. In addition, BAT is also an endocrine organ which is able to secret adipokines in an autocrine and/or paracrine fashion. BAT plays a protective role in cardiovascular system through attenuating cardiac remodeling and suppressing inflammatory response. In this review, we summarize the advances from the discovery of BAT to the present and provide an overview on the role of BAT dysfunction in cardiovascular diseases.
Restoring Nature at Lower Food Production Costs
Authors: Vittis Yiorgos , Folberth Christian , Bundle Sophie-Charlotte , Obersteiner Michael
Published: May 2021

Growing competition for land, water and energy call for global strategies ensuring affordable food production at minimum environmental impacts. Economic modelling studies suggest trade-off relationships between environmental sustainability and food prices. However, evidence based on empirical cost-functions supporting such trade-offs remains scarce at the global level. Here, based on cost engineering modelling, we show that optimised spatial allocation of 10 major crops, would reduce current costs of agricultural production by approximately 40% while improving environmental performance. Although production inputs per unit of output increase at local scales, a reduction of cultivated land of 50% overcompensates the slightly higher field-scale costs enabling improved overall cost-effectiveness. Our results suggest that long-run food prices are bound to continue to decrease under strong environmental policies. Policies supporting sustainability transitions in the land sector should focus on managing local barriers to the implementation of high-yield regenerative agricultural practices delivering multiple regional and global public goods.
PiggyBac-Generated CAR19-T Cells Plus Lenalidomide Cause Durable Complete Remission of Triple-Hit Refractory/Relapsed DLBCL: A Case Report
Authors: Li Chenggong , Sun Yan , Wang Jing , Tang Lu , Jiang Huiwen , Guo Tao , Liu Lin , Wu Yaohui , Ai Lisha , Xia Linghui , Wu Jianjun , Lin Zhicai , Qian Qijun , Hu Yu , Mei Heng
Published: May 2021

MYC/BCL2/BCL6 triple-hit lymphoma (THL) is an uncommon subset of high-grade B-cell lymphoma with aggressive clinical behavior and poor prognosis. TP53 mutation is an independently poor progonistic indicator in patients with THL, hence novel therapeutic strategies are needed for these patients. CD19-directed chimeric antigen receptor(CAR19)-T cell therapy has shown promising efficacy for relapsed/refractory diffuse large B cell lymphoma (RR DLBCL), but the majority of CAR19-T cell products to date have been manufactured using viral vectors. PiggyBac transposon system, with an inclination to memory T cells, offers a more convenient and economical alternative for transgene delivery. We herein report the first case of triple-hit RR DLBCL with TP53 mutation who was treated with piggyBac-generated CAR19-T cells and accompanied by grade 2 cytokine release syndrome. The patient obtained a complete remission (CR) in the 2nd month post-infusion and demanded maintenance therapy. Whether maintenance therapy is favorable and how to administrate it after CAR-T cell infusion remain controversial. Preclinical studies demonstrated that lenalidomide could enhance antitumor activity of CAR19-T cells. Therefore, we pioneered oral lenalidomide after CAR19-T therapy in the patient from the 4th month, and he discontinued after one cycle due to side effects. The patient has still kept sustained CR for over 24 months. Our case have firstly demonstrated the feasibility, preliminary safety and efficacy of piggyBac-produced CAR19-T cell therapy in triple-hit lymphoma. The innovative combination with lenalidomide warrants further investigation. Our findings shed new light on the possible solutions to improve short-term relapse after CAR19-T cell therapy in RR DLBCL. ChiCTR, number ChiCTR1800018111.
A Multi-Omics Analysis of Mucosal-Associated-Invariant T Cells Reveals Key Drivers of Distinct Modes of Activation
Authors: Schubert Kristin , Karkossa Isabel , Schor Jana , Engelmann Beatrice , Steinheuer Lisa Maria , Bruns Tony , Rolle-Kampczyk Ulrike , Hackermüller Jörg , von Bergen Martin
Published: May 2021

The function of mucosal-associated invariant T (MAIT) cells highly depends on the mode of activation, either by recognition of bacterial metabolitesviatheir T cell receptor (TCR) or in a TCR-independent mannerviacytokines. The underlying molecular mechanisms are not entirely understood. To define the activation of MAIT cells on the molecular level, we applied a multi-omics approach with untargeted transcriptomics, proteomics and metabolomics. Transcriptomic analysis ofE. coli- and TCR-activated MAIT cells showed a distinct transcriptional reprogramming, including altered pathways, transcription factors and effector molecules. We validated the consequences of this reprogramming on the phenotype by proteomics and metabolomics. Thus, and to distinguish between TCR-dependent and -independent activation, MAIT cells were stimulated with IL12/IL18, anti-CD3/CD28 or both. Only a combination of both led to full activation of MAIT cells, comparable to activation byE. coli. Using an integrated network-based approach, we identified key drivers of the distinct modes of activation, including cytokines and transcription factors, as well as negative feedback regulators like TWIST1 or LAG3. Taken together, we present novel insights into the biological function of MAIT cells, which may represent a basis for therapeutic approaches to target MAIT cells in pathological conditions.
Colorectal Carcinoma Affected Patients Are Significantly Poor Responders Against the Oncogenic JC Polyomavirus
Authors: Torreggiani Elena , Bononi Ilaria , Pietrobon Silvia , Mazzoni Elisa , Guerra Giovanni , Feo Carlo , Martini Fernanda , Tognon Mauro
Published: May 2021

Background

Many investigations reported the association between human tumors and JCPyV, a polyomavirus with oncogenic potential. The association has been supported by studies that found JCPyV footprints in CRC and gliomas of different types. Indeed, JCPyV footprints including its nucleic acids and Tag oncoprotein have been revealed in CRC tissues.

Methods

Herein, sera from colorectal carcinoma (CRC) affected patients and healthy individuals (HS), employed as control, were analysed for immunoglobulin G (IgG) antibodies against specific JCPyV viral capsid protein 1 (VP1) antigens. The investigation was carried out employing an innovative immunological assay. Indeed, an indirect enzyme-linked immunosorbent assay (ELISA) with JCPyV VP1 mimotopes was used. JCPyV VP1 mimotopes consisted of synthetic peptides mimicking VP1 epitopes.

Results

Sera from CRC affected patients, evaluated using indirect ELISAs with synthetic mimotopes, showed a significant lower prevalence of IgG antibodies against JCPyV VP1 mimotopes (26%) compared to HS (51%), p<0.005. These data were confirmed by another method, the hemagglutination inhibition (HAI) assay. Altogether these results, i.e. the prevalence of serum IgG antibodies against JCPyV VP1 mimotopes from patients with CRC is approximately 50% lower than in HS, are of interest.

Discussion

Our data suggest that patients with CRC are significantly poor responders against JCPyV VP1 antigens. It is possible that CRC patients are affected by a specific immunological deregulation. This immunological dysfunction, revelled in CRC patients, may account for their predisposition to the colorectal carcinoma onset.
Enhancement of the Tolerogenic Phenotype in the Liver by ImmTOR Nanoparticles
Authors: Ilyinskii Petr O. , Roy Christopher J. , LePrevost Julie , Rizzo Gina L. , Kishimoto Takashi Kei
Published: May 2021

ImmTOR biodegradable nanoparticles encapsulating rapamycin have been shown to induce a durable tolerogenic immune response to co-administered biologics and gene therapy vectors. Prior mechanism of action studies have demonstrated selective biodistribution of ImmTOR to the spleen and liver following intravenous (IV) administration. In the spleen, ImmTOR has been shown to induce tolerogenic dendritic cells and antigen-specific regulatory T cells and inhibit antigen-specific B cell activation. Splenectomy of mice resulted in partial but incomplete abrogation of the tolerogenic immune response induced by ImmTOR. Here we investigated the ability of ImmTOR to enhance the tolerogenic environment in the liver. All the major resident populations of liver cells, including liver sinusoidal endothelial cells (LSECs), Kupffer cells (KC), stellate cells (SC), and hepatocytes, actively took up fluorescent-labeled ImmTOR particles, which resulted in downregulation of MHC class II and co-stimulatory molecules and upregulation of the PD-L1 checkpoint molecule. The LSEC, known to play an important role in hepatic tolerance induction, emerged as a key target cell for ImmTOR. LSEC isolated from ImmTOR treated mice inhibited antigen-specific activation of ovalbumin-specific OT-II T cells. The tolerogenic environment led to a multi-pronged modulation of hepatic T cell populations, resulting in an increase in T cells with a regulatory phenotype, upregulation of PD-1 on CD4+and CD8+T cells, and the emergence of a large population of CD4–CD8–(double negative) T cells. ImmTOR treatment protected mice in a concanavalin A-induced model of acute hepatitis, as evidenced by reduced production of inflammatory cytokines, infiltrate of activated leukocytes, and tissue necrosis. Modulation of T cell phenotype was seen to a lesser extent after administration by empty nanoparticles, but not free rapamycin. The upregulation of PD-1, but not the appearance of double negative T cells, was inhibited by antibodies against PD-L1 or CTLA-4. These results suggest that the liver may contribute to the tolerogenic properties of ImmTOR treatment.
Identification of an Autoantibody Against ErbB-3-Binding Protein-1 in the Sera of Patients With Chronic Hepatitis B Virus Infection
Authors: Jiang Li , Niu Wei , Zheng Qian , Meng Gang , Chen Xiaoling , Zhang Mengjun , Deng Guohong , Mao Qing , Wang Li
Published: May 2021

Background

Studies have shown that autoimmune response contributes to chronic hepatitis B (CHB) development.

Aim

This study aimed to identify autoantibodies in the sera of patients with CHB and to investigate the association of autoimmune response with disease severity in CHB.

Methods

Proteins from human liver carcinoma cell line HepG2 were separated by two-dimensional electrophoresis. The candidate autoantigens were recognized by serum autoantibodies from Chinese CHB patients. Immunohistochemical staining was performed to determine the hepatic expression of the autoantigen in CHB patients with different inflammatory grades. Enzyme-linked immunosorbent assay (ELISA) was conducted to measure the prevalence and the levels of serum autoantibody in CHB patients with different disease severity. Flow cytometry analysis was carried out to assess the autoreactive T cell response in the peripheral circulation of CHB patients.

Results

ErbB-3-binding protein-1 (EBP-1) was identified as an autoantigen of serum autoantibodies in CBP patients. EBP-1 protein expression was upregulated in the liver of CHB patients with high-grade hepatic inflammation. The prevalence and levels of serum anti-EBP1 IgG were significantly increased in CHB patients with severe diseases compared with those with mild or moderate diseases, but none was detectable in the healthy controls. EBP-1 peptides induced proinflammatory cytokine expression in CD4+ T cells from CHB patients.

Conclusion

Our results demonstrate the presence of an autoantibody against EBP-1 in the sera as well as EBP-1-reactive T cells in the peripheral blood of CHB patient. EBP-1-induced autoimmune response is positively associated with the disease severity, suggesting that EBP-1-induced autoimmune response possibly contributes to progressive liver failure.
Connective Tissue Growth Factor Is Overexpressed in Explant Lung Tissue and Broncho-Alveolar Lavage in Transplant-Related Pulmonary Fibrosis
Authors: Vanstapel Arno , Goldschmeding Roel , Broekhuizen Roel , Nguyen Tri , Sacreas Annelore , Kaes Janne , Heigl Tobias , Verleden Stijn E. , De Zutter Alexandra , Verleden Geert , Weynand Birgit , Verbeken Erik , Ceulemans Laurens J. , Van Raemdonck Dirk E. , Neyrinck Arne P. , Schoemans Helene M. , Vanaudenaerde Bart M. , Vos Robin
Published: May 2021

Background

Connective tissue growth factor (CTGF) is an important mediator in several fibrotic diseases, including lung fibrosis. We investigated CTGF-expression in chronic lung allograft dysfunction (CLAD) and pulmonary graft-versus-host disease (GVHD).

Materials and Methods

CTGF expression was assessed by quantitative real-time polymerase chain reaction (qPCR) and immunohistochemistry in end-stage CLAD explant lung tissue (bronchiolitis obliterans syndrome (BOS), n=20; restrictive allograft syndrome (RAS), n=20), pulmonary GHVD (n=9). Unused donor lungs served as control group (n=20). Next, 60 matched lung transplant recipients (BOS, n=20; RAS, n=20; stable lung transplant recipients, n=20) were included for analysis of CTGF protein levels in plasma and broncho-alveolar lavage (BAL) fluid at 3 months post-transplant, 1 year post-transplant, at CLAD diagnosis or 2 years post-transplant in stable patients.

Results

qPCR revealed an overall significant difference in the relative content of CTGF mRNA in BOS, RAS and pulmonary GVHD vs. controls (p=0.014). Immunohistochemistry showed a significant higher percentage and intensity of CTGF-positive respiratory epithelial cells in BOS, RAS and pulmonary GVHD patients vs. controls (p<0.0001). BAL CTGF protein levels were significantly higher at 3 months post-transplant in future RAS vs. stable or BOS (p=0.028). At CLAD diagnosis, BAL protein content was significantly increased in RAS patients vs. stable (p=0.0007) and BOS patients (p=0.042). CTGF plasma values were similar in BOS, RAS, and stable patients (p=0.74).

Conclusions

Lung CTGF-expression is increased in end-stage CLAD and pulmonary GVHD; and higher CTGF-levels are present in BAL of RAS patients at CLAD diagnosis. Our results suggest a potential role for CTGF in CLAD, especially RAS, and pulmonary GVHD.
Immunomics-Guided Antigen Discovery for Praziquantel-Induced Vaccination in Urogenital Human Schistosomiasis
Authors: Pearson Mark S. , Tedla Bemnet A. , Becker Luke , Nakajima Rie , Jasinskas Al , Mduluza Takafira , Mutapi Francisca , Oeuvray Claude , Greco Beatrice , Sotillo Javier , Felgner Philip L. , Loukas Alex
Published: May 2021

Despite the enormous morbidity attributed to schistosomiasis, there is still no vaccine to combat the disease for the hundreds of millions of infected people. The anthelmintic drug, praziquantel, is the mainstay treatment option, although its molecular mechanism of action remains poorly defined. Praziquantel treatment damages the outermost surface of the parasite, the tegument, liberating surface antigens from dying worms that invoke a robust immune response which in some subjects results in immunologic resistance to reinfection. Herein we term this phenomenon Drug-Induced Vaccination (DIV). To identify the antigenic targets of DIV antibodies in urogenital schistosomiasis, we constructed a recombinant proteome array consisting of approximately 1,000 proteins informed by various secretome datasets including validated proteomes and bioinformatic predictions. Arrays were screened with sera from human subjects treated with praziquantel and shown 18 months later to be either reinfected (chronically infected subjects, CI) or resistant to reinfection (DIV). IgG responses to numerous antigens were significantly elevated in DIV compared to CI subjects, and indeed IgG responses to some antigens were completely undetectable in CI subjects but robustly recognized by DIV subjects. One antigen in particular, a cystatin cysteine protease inhibitor stood out as a unique target of DIV IgG, so recombinant cystatin was produced, and its vaccine efficacy assessed in a heterologous Schistosoma mansoni mouse challenge model. While there was no significant impact of vaccination with adjuvanted cystatin on adult worm numbers, highly significant reductions in liver egg burdens (45-55%, P<0.0001) and intestinal egg burdens (50-54%, P<0.0003) were achieved in mice vaccinated with cystatin in two independent trials. This study has revealed numerous antigens that are targets of DIV antibodies in urogenital schistosomiasis and offer promise as subunit vaccine targets for a drug-linked vaccination approach to controlling schistosomiasis.
Autophagy as a Target for Drug Development Of Skin Infection Caused by Mycobacteria
Authors: Bittencourt Tamiris Lameira , da Silva Prata Rhana Berto , de Andrade Silva Bruno Jorge , de Mattos Barbosa Mayara Garcia , Dalcolmo Margareth Pretti , Pinheiro Roberta Olmo
Published: May 2021

Pathogenic mycobacteria species may subvert the innate immune mechanisms and can modulate the activation of cells that cause disease in the skin. Cutaneous mycobacterial infection may present different clinical presentations and it is associated with stigma, deformity, and disability. The understanding of the immunopathogenic mechanisms related to mycobacterial infection in human skin is of pivotal importance to identify targets for new therapeutic strategies. The occurrence of reactional episodes and relapse in leprosy patients, the emergence of resistant mycobacteria strains, and the absence of effective drugs to treat mycobacterial cutaneous infection increased the interest in the development of therapies based on repurposed drugs against mycobacteria. The mechanism of action of many of these therapies evaluated is linked to the activation of autophagy. Autophagy is an evolutionary conserved lysosomal degradation pathway that has been associated with the control of the mycobacterial bacillary load. Here, we review the role of autophagy in the pathogenesis of cutaneous mycobacterial infection and discuss the perspectives of autophagy as a target for drug development and repurposing against cutaneous mycobacterial infection.
When the Good Syndrome Goes Bad: A Systematic Literature Review
Authors: Shi Yiyun , Wang Chen
Published: May 2021

Background

Good syndrome is a rare adult-onset immunodeficiency characterized by thymoma and hypogammaglobulinemia. Its clinical manifestations are highly heterogeneous, ranging from various infections to autoimmunity.

Objective

This study was to summarize patient characteristics, identify prognostic factors and define clinical subgroups of Good syndrome.

Methods

A systematic literature review was conducted to include patients with Good syndrome identified in PubMed, Embase and Cochrane databases between January 2010 and November 2020. Logistic and Cox regressions were used to identify prognostic factors impacting outcomes. Clinical subgroups were defined by multiple correspondence analysis and unsupervised hierarchical clustering. A decision tree was constructed to characterize the subgroup placement of cases.

Results

Of 162 patients included in the current study, the median age at diagnosis was 58 years and 51% were male. Type AB was the most common histological subtype of thymoma, and infections as well as concurrent autoimmune disorders were identified in 92.6% and 51.2% patients, respectively. Laboratory workup showed typical findings of combined immunodeficiency. Thymoma status (odds ratio [OR] 4.157, confidence interval [CI] 1.219-14.177, p = 0.023), infections related to cellular immunity defects (OR 3.324, 95% CI 1.100-10.046, p = 0.033), infections of sinopulmonary tract (OR 14.351, 95% CI 2.525-81.576, p = 0.003), central nerve system (OR 6.403, 95% CI 1.205-34.027, p = 0.029) as well as bloodstream (OR 6.917, 95% CI 1.519-31.505, p = 0.012) were independent prognostic factors. The 10-year overall survival was 53.7%. Cluster analysis revealed three clinical subgroups with distinct characteristics and prognosis (cluster 1, infections related to cellular immunity defects; cluster 2, infections related to other immunity defects; cluster 3, infections related to humoral and phagocytic immunity defects). A decision tree using infection types (related to humoral and cellular immunity defects) could place patients into corresponding clusters with an overall correct prediction of 72.2%.

Conclusions

Infection type and site were the main prognostic factors impacting survival of patients with Good syndrome. We identified three subgroups within Good syndrome associated with distinct clinical features, which may facilitate the study of underlying pathogenesis as well as development of targeted therapy.
Characterization of Firebrands Released From Different Burning Tree Species
Authors: Almeida Miguel , Porto Leonardo , Viegas Domingos
Published: May 2021

The number, dimensions, and initial velocity of the firebrands released from burning Quercus suber, Eucalyptus globulus, Quercus robur, and Pinus pinaster trees were analyzed in laboratory experiments using a particle image velocimetry system. Additionally, the flame height, tree mass decay, vertical flow velocity, and temperature at the top of the trees were measured during the experiments. The relationship between the various parameters was analyzed and a good connection was found. The specimens burnt were mostly young trees, so large particles (e.g., pine cones, thick trunk barks, branches) were not included in this study as they were not present. Actually, the firebrands produced in the laboratory tests, mainly burning leaves, had a cross-sectional area of <1,600 mm2, having the potential to cause short distance spotting (up to tens of meters). Quercus trees are often considered to have a lower fire risk than eucalyptus or pine trees. However, in this study, Quercus suber and Quercus robur were the species that produced more firebrands, both in terms of number and total volume. The tests with Quercus suber were the only ones using specimens from an adult tree, confirming the great importance of the age of trees in the propensity to release firebrands. The results obtained with Quercus robur confirmed the high tendency of this species to originate spot fires at a short distance. Thus, these results are of great relevance to afforestation plans and to evaluating the risk of the presence of these species in wildland–urban interface areas.
Pathergy Phenomenon
Authors: Ergun Tulin
Published: May 2021

Skin pathergy reaction (SPR) is a hyperreactivity response to needle induced trauma which is characterized by a papule or pustule formation, 24–48 h after sterile-needle prick. It is affected by a wide array of factors, including the physical properties of the needles being used, number of pricks and disease related factors such as male gender, active disease. There is a great variation in reactivity among different populations with very low positivity rate in regions of low prevalence like Northern Europe, and higher prevalance mainly in communities living along the historical Silk Road, like Turkey, China and Middle Eastern countries. SPR is not constant during the disease course, has lost its sensitivity over decades and can be positive in various disorders including Sweet's syndrome, pyoderma gangrenosum, Crohn's diesease, A20 haploinsufficiency, deficiency of IL-1-receptor antagonist and few others. Nevertheless, it is a criteria included into many currently used diagnostic or classification criteria for Behçet's disease. Although, not being fully uncovered yet, available data points to the activation of both innate and adaptive immune system with an inflammatory response mediated by polymorphonuclears and T-cells. In addition to its utility in diagnosis of Behçet's Disease, SPR may serve as a model for investigating the inflammatory pathways involved in the etiopathogenesis of this complex disease.
Multi-Atlas MRI-Based Striatum Segmentation for 123I-FP-CIT SPECT (DAT-SPECT) Compared With the Bolt Method and SPECT-Atlas-Based Segmentation Method Toward the Accurate Diagnosis of Parkinson's Disease/Syndrome
Authors: Sohara Koji , Sekine Tetsuro , Tateno Amane , Mizumura Sunao , Suda Masaya , Sakayori Takeshi , Okubo Yoshiro , Kumita Shin-ichiro
Published: May 2021

Aims: This study aimed to analyze the performance of multi-atlas MRI-based parcellation for 123I-FP-CIT SPECT (DAT-SPECT) in healthy volunteers. The proposed method was compared with the SPECT-atlas-based and Bolt methods. 18F-FE-PE2I-PET (DAT-PET) was used as a reference.

Methods: Thirty healthy subjects underwent DAT-SPECT, DAT-PET, and 3D-T1WI-MRI. We calculated the striatum uptake ratio (SUR/SBR), caudate uptake ratio (CUR), and putamen uptake ratio (PUR) for DAT-SPECT using the multi-atlas MRI-based method, SPECT-atlas-based method, and Bolt method. In the multi-atlas MRI-based method, the cerebellum, occipital cortex, and whole-brain were used as reference regions. The correlation of age with DAT-SPECT activity and the correlations of SUR/SBR, CUR, and PUR between DAT-SPECT and DAT-PET were calculated by each of the three methods.

Results: The correlation between age and SUR/SBR for DAT-SPECT based on the multi-atlas MRI-based method was comparable to that based on the SPECT-atlas-based method (r = −0.441 to −0.496 vs. −0.488). The highest correlation between DAT-SPECT and DAT-PET was observed using the multi-atlas MRI-based method with the occipital lobe defined as the reference region compared with the SPECT-atlas-based and Bolt methods (SUR, CUR, and PUR: 0.687, 0.723, and 0.676 vs. 0.698, 0.660, and 0.616 vs. 0.655).

Conclusion: Multi-atlas MRI-based parcellation with the occipital lobe defined as the reference region was at least comparable to the clinical methods.