bluuebunny/crossref_metadata_2025 huggingface dataset:
Features of Cytokine Storm Identified by Distinguishing Clinical Manifestations in COVID-19
Authors: Shen Wei-Xi , Luo Rong-Cheng , Wang Jing-Quan , Chen Zhe-Sheng
Published: May 2021

Coronavirus disease 2019 (COVID-19) is caused by a new coronavirus, namely severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is currently spreading all over the world. In this paper, we developed a practical model for identifying the features of cytokine storm, which is common in acute infectious diseases and harmful manifestation of COVID-19, by distinguishing major and minor clinical events. This model is particularly suitable for identifying febrile and infectious diseases like COVID-19. Based on this model, features of cytokine storm and pathogenesis of COVID-19 have been proposed to be a consequence of the disequilibrated cytokine network resulting from increased biological activity of transforming growth factor-β (TGF-β), which induces certain clinical manifestations such as fatigue, fever, dry cough, pneumonia, abatement and losing of olfactory, and taste senses in some patients. Research and clarification of the pathogenesis of COVID-19 will contribute to precision treatment. Various anti-TGF-β therapies may be explored as potential COVID-19 treatment. This novel model will be helpful in reducing the widespread mortality of COVID-19.
Demolishing the Myth of the Default Human That Is Killing Black Mothers
Authors: Bray Stephanie R. M. , McLemore Monica R.
Published: May 2021

It took a white police officer's knee on George Floyd's neck before white people began to reckon with 400 years of slavery and its aftermath, the effects of which Black people have endured for generations. Monuments are being taken down, flags are being redesigned, and institutions that honored those who denied the humanity of Black people are being renamed. Unfortunately for Sandra Bland, Breonna Taylor, Sha-Asia Washington and countless other Black transgender people including those with capacity for pregnancy, there was no justice even prior to the global pandemic of SARS-Cov-2 or coronavirus; namely racism, violence, and the Black Maternal Health crisis that makes it less likely that Black women will survive pregnancy and childbirth. The purpose of this article is to situate the state of Black people with the capacity for pregnancy in the context of these existing crises to illuminate the myths that racism has perpetuated through science, health services provision and policy. The greatest of these is the myth of a default human that can serve as a standard for the rest of the population. This racist ideal underpins education, provision of care, research, policies, and public health praxis. Demolishing the myth starts with acknowledging that Black people are not the architects of their own destruction: the default standard of whiteness is. The article begins with a historical background on how this myth came to be and elucidates the development and perpetuations of the myth of the default human. Next, we present an evidence based scoping review of the literature to summarize current thinking with specific focus on the Black maternal health crisis, we make policy recommendations and retrofits of upstream public health approaches for existing programs toward health equity. We also situate Black maternal health as part of a reproductive justice frame that centers Black women and birthing people's autonomy and agency. In other words, we use the scoping review to end with reimagining public health policy and provide an actionable roadmap to specifically disrupt the myth of the default human and dismantle racism in education, provision of care, research, policies, and public health praxis.
Social Virtual Reality Platform Comparison and Evaluation Using a Guided Group Walkthrough Method
Authors: Liu Qiaoxi , Steed Anthony
Published: May 2021

As virtual reality (VR) headsets become more commercially accessible, a range of social platforms have been developed that exploit the immersive nature of these systems. There is a growing interest in using these platforms in social and work contexts, but relatively little work into examining the usability choices that have been made. We developed a usability inspection method based on cognitive walkthrough that we call guided group walkthrough. Guided group walkthrough is applied to existing social VR platforms by having a guide walk the participants through a series of abstract social tasks that are common across the platforms. Using this method we compared six social VR platforms for the Oculus Quest. After constructing an appropriate task hierarchy and walkthrough question structure for social VR, we ran several groups of participants through the walkthrough process. We undercover usability challenges that are common across the platforms, identify specific design considerations and comment on the utility of the walkthrough method in this situation.
Hydrological System Complexity Induces a Drought Frequency Paradox
Authors: Buitink Joost , van Hateren Theresa C. , Teuling Adriaan J.
Published: May 2021

Droughts occur as a result of a lack of water compared with normal conditions. Whilst this appears trivial, the exact drought definition of drought is not. Especially as different drought types are present, resulting from the different variables in a hydrological system, each with unique characteristics. We use a common drought definition, the percentile score, and apply the same definition across all drought types, to study whether the actual occurrence of droughts matches the definition. We focus on the data-rich Dutch province of Gelderland, to study droughts from observations across five major components of the terrestrial hydrological cycle. When a percentile threshold of 20% is used as drought definition, corresponding to a mild drought, droughts anywhere in the system occur at least three times more frequently (73% of the time). On the other hand, the situation where drought occurs across all components of the terrestrial hydrological cycle is more than four times less likely than the drought threshold of 20% (namely 5% of the time). This can be attributed by both (1) the different responses across the hydrological system, and (2) the spatial variability present within each component of the hydrological system. With this study, we show the existence of the drought frequently paradox: although droughts are seen and defined as rare from a scientific perspective, when viewed from a societal or operational water management perspective in typical hydrological systems subject to spatial variability and other system complexity, droughts become common, rather than rare. This paradox is a consequence of an inconsistent use of the percentile score drought definition between research and operational water management, and better communication between the two domains is needed in search for a universally accepted drought definition.
Continuous Normothermic Machine Perfusion for Renovation of Extended Criteria Donor Livers Without Recooling in Liver Transplantation: A Pilot Experience
Authors: Chen Zhitao , Hong Xitao , Huang Shanzhou , Wang Tielong , Ma Yihao , Guo Yiwen , Huang Changjun , Zhao Qiang , Guo Zhiyong , He Xiaoshun , Ju Weiqiang , Chen Maogen
Published: May 2021

Background: Ischemia injury affects the recovery of liver allograft function. We propose a novel technique aimed at avoiding a second ischemic injury: transplanting an extended criteria donor (ECD) liver directly under normothermic machine perfusion (NMP) without recooling. We studied two cases to evaluate the efficacy and safety of this technique.

Methods: The perioperative characteristics and postoperative outcomes of two recipients of ECD livers were analyzed. Both transplantations were performed with continuous normothermic machine perfusion without recooling.

Result: In case 1, the cause of donor death was anoxia, and the donor liver had hypernatremia before procurement. The recipient was diagnosed with decompensated cirrhosis. His model for end-stage liver disease (MELD) score was 38. In case 2, the donor liver was from a donor after cardiac death (DCD), and the donor had elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. The recipient was diagnosed with acute hepatic failure. His MELD score was 35. Both donor livers were maintained under NMP and then transplanted without recooling. The peak ALT and AST levels after surgery were 452 and 770 U/L in case 1 and 100 and 592 U/L in case 2. Neither early allograft dysfunction (EAD) nor primary graft non-function (PNF) was present in these two cases.

Conclusion: In conclusion, our results demonstrate that continuous NMP without recooling is efficacious and safe for LT with extended criteria donor livers. Further investigations of this technique will be performed to confirm these promising results.
Relationship Between Pre-operative Blood Glucose Level and Length of Hospital Stay in Patients With Renal Cell Carcinoma Undergoing Laparoscopic Nephrectomy
Authors: He Ting , Zhu Weidong , Wang Chunying , Lu Haowen , Wu Tiange , Pan Kehao , Chen Shuqiu , Xu Bin , Mao Weipu , Li Wei , Chen Ming
Published: May 2021

Purpose: The aim of this study was to assess the effect of pre-operative blood glucose (POBG) levels on the length of stay (LOS) in patients with renal cell carcinoma (RCC) undergoing laparoscopic nephrectomy.

Methods: We collected clinical data on 338 patients with RCC who underwent laparoscopic nephrectomy between 2014 and 2019. Univariate and multivariate logistic regression and dose-response analysis curves of restricted cubic spline function were used to investigate the relationship between POBG and LOS.

Results: According to the level of POBG, we divided the patients into three groups: <4.94 mmol/L group, 4.94 to <7.11 mmol/L group, and ≥7.11 mmol/L group. According to the dose-response analysis curves, we found that the adjusted risk of LOS > 2 weeks and LOS > 3 weeks gradually increased with increasing POBG. In addition, we found that among all patients, patients with POBG levels ≥ 7.11 mmol/L had a 115% higher risk of LOS > 2 weeks than patients with POBG levels <4.94 mmol/L [adjusted odds risk (aOR) 2.15; 95% CI 1.11-4.20; p = 0.024] and patients with POBG levels ≥ 7.11 mmol/L had a 129% higher risk of LOS > 3 weeks than patients with POBG levels <4.94 mmol/L (aOR 2.29; 95% CI 1.16-4.52; p = 0.017). Moreover, similar results were observed in the most subgroups analysis.

Conclusion: We found that in patients with RCC undergoing laparoscopic nephrectomy, higher POBG levels were significantly associated with prolonged LOS.
Engaging Stakeholders in the Design of One Health Surveillance Systems: A Participatory Approach
Authors: Bordier Marion , Goutard Flavie Luce , Antoine-Moussiaux Nicolas , Pham-Duc Phuc , Lailler Renaud , Binot Aurelie
Published: May 2021

Many One Health surveillance systems have proven difficult to enforce and sustain, mainly because of the difficulty of implementing and upholding collaborative efforts for surveillance activities across stakeholders with different values, cultures and interests. We hypothesize that only the early engagement of stakeholders in the development of a One Health surveillance system can create an environment conducive to the emergence of collaborative solutions that are acceptable, accepted and therefore implemented in sustainable manner. To this end, we have designed a socio-technical framework to help stakeholders develop a common vision of their desired surveillance system and to forge the innovation pathway toward it. We implemented the framework in two case studies: the surveillance of antimicrobial resistance in Vietnam and that of Salmonella in France. The socio-technical framework is a participatory and iterative process that consists of four distinct steps implemented during a workshop series: (i) definition of the problem to be addressed, (ii) co-construction of a common representation of the current system, (iii) co-construction of the desired surveillance system, (iv) identification of changes and actions required to progress from the current situation to the desired situation. In both case studies, the process allowed surveillance stakeholders with different professional cultures and expectations regarding One Health surveillance to gain mutual understanding and to reconcile their different perspectives to design the pathway toward their common vision of a desired surveillance system. While the proposed framework is structured around four essential steps, its application can be tailored to the context. Workshop facilitation and representativeness of participants are key for the success of the process. While our approach lays the foundation for the further implementation of the desired One Health surveillance system, it provides no guarantee that the proposed actions will actually be implemented and bring about the required changes. The engagement of stakeholders in a participatory process must be sustained in order to ensure the implementation of co-constructed solutions and evaluate their effectiveness and impacts.
Pigeons as Carriers of Clinically Relevant Multidrug-Resistant Pathogens—A Clinical Case Report and Literature Review
Authors: Chrobak-Chmiel Dorota , Kwiecień Ewelina , Golke Anna , Dolka Beata , Adamczyk Krzysztof , Biegańska Małgorzata J. , Spinu Marina , Binek Marian , Rzewuska Magdalena
Published: May 2021

Pigeons are widespread bird species in urban regions (Columba livia forma urbana) and may carry pathogens with zoonotic potential. In recent years, more and more data indicate that these zoonotic pathogens are multidrug resistant. Our results confirmed that global trend. Three different multidrug-resistant pathogens were isolated from an oral cavity of a racing pigeon with lesions typical for pigeon pox virus infection. Staphylococcus aureus was recognized as methicillin resistant, thus resistant to all beta-lactams. Additionally, it was also resistant to many other classes of antibiotics, namely: aminoglycosides, tetracyclines, phenicols, lincosamides, and macrolides. Escherichia coli showed resistance to all antimicrobials tested, and it was classified as intermediate to amikacin. Moreover, Candida albicans resistant to clotrimazole, natamycin, flucytosine, and amphotericin and intermediate to ketoconazole, nystatin, and econazole was also isolated. This raises the question how pigeons acquire such highly resistant strains. Therefore, more data are needed concerning the resistance to antibiotics in strains from domestic and wild pigeons in Poland. Until the problem is fully understood, it will be challenging to implement adequate planning of any control measures and check their effectiveness.
Community Structure and Systemic Risk of Bank Correlation Networks Based on the U.S. Financial Crisis in 2008
Authors: Huang Yajing , Chen Feng
Published: May 2021

This paper studies the community structure of the bank correlation network in the financial system and analyzes the systemic risk of the community sub-networks. Based on the balance sheet data of U.S. commercial banks from 2008, we establish a bank correlation network for each state according to the banks’ investment portfolio ratio. First, we analyze the community structure of each bank’s correlation network and verify the effectiveness of the community division from the point of view of the importance of nodes. Then, combining the data of failed banks after the 2008 financial crisis, we find that for small communities, the financial systemic risk will appear to have obvious volatility, and it is quite likely to reach an extremely high level. With the increase in the number of nodes in the community, systemic risk will tend towards a stable and low level. Furthermore, if only communities with failed banks are considered, the regression analysis shows that systemic risk and the size of the community almost follow a power law distribution trend. These results reveal the importance of supervising the banking system at the level of community sub-networks, which has certain guiding significance for the stability of the financial system.
Pesticide Usage Is Compromising People’s Health in the United States: Ideas for Reducing Damages
Authors: Centner Terence J.
Published: May 2021

The development of synthetic pesticides has provided new tools for addressing troublesome pests. A review of parts of the registration process for pesticides in the United States identifies an outdated evaluation system that undervalues health damages. Registration fails to adequately consider co-formulants and effects of exposure to multiple chemicals. Frustration with failures to protect people and property from damages accompanying pesticide usage has led injured plaintiffs to resort to tort lawsuits to secure relief. However, litigation involves compensating injured persons after they are injured rather than preventing injury. A more proactive approach would be to prevent situations that injure people. This paper offers four ideas to reduce health damages accompanying pesticide usage. Slight adjustments to pesticide registration requirements can offer greater protection for people’s health.
New Technology for Desert Locust Control
Authors: Matthews Graham A.
Published: May 2021

Locust outbreaks usually begin in remote unpopulated areas following higher than average rainfall. The need to survey such areas has suggested that unmanned aerial vehicles (UAVs), often referred to as drones, might be a suitable means of surveying areas with suitable detection devices to survey areas and detect important locust concentrations. This would facilitate determining where sprays need to be applied at this early stage and would minimise the risk of swarms developing and migrating to feed on large areas of crops. Ideally, a drone could also spray groups of hoppers and adults at this stage. To date, tests have shown limitations in their use to apply sprays, although it has been suggested that using a fleet of drones might be possible. The use of biopesticide in these areas has the advantage of being more environmentally acceptable as the spray has no adverse impact on birds.
Effects of Ridge Tillage and Straw Mulching on Cultivation the Fresh Faba Beans
Authors: Li Bo , Chen Xinyu , Shi Xiaoxu , Liu Jian , Wei Yafeng , Xiong Fei
Published: May 2021

Ridge tillage is an effective agronomic practice and a miniature precision agriculture; however, its effects on the growth of faba beans (Vicia faba L.) are poorly understood. This study aimed to determine the effect of ridge tillage and straw mulching on the root growth, nutrient accumulation and yield of faba beans. Field experiments were conducted during 2016 and 2017 cropping seasons and comprised four treatments: ridge tillage without any mulching (RT), flat tillage without any mulch (FT), flat tillage with rice straw mulched on the ridge tillage (FTRSM) and ridge tillage with rice straw mulched on the ridge tillage (RTRSM). The RT and RTRSM increased soil temperature and decreased soil humidity and improved soil total nitrogen, total phosphorus, available potassium and organic matter. RT and RTRSM increased the root length density, root surface area, root diameter and root activity of faba beans at flowering and harvest periods. The RT and RTRSM also increased the nitrogen, phosphorus, potassium absorption and the yield of faba beans. These results indicated that ridge tillage and straw mulching affect faba bean growth by improving soil moisture conditions and providing good air permeability and effective soil nutrition supply. This study provides a theoretical basis for the high yield cultivation improvement of faba beans.
Effects of Apigenin and Astragalus Polysaccharide on the Cryopreservation of Bull Semen
Authors: Wang Hongtao , Lu Ping , Yuan Chongshan , Zhao Jing , Liu Hongyu , Lu Wenfa , Wang Jun
Published: May 2021

The purpose of this study was to determine the effects of apigenin and astragalus polysaccharides on the cryopreservation of bovine semen. Apigenin, astragalus polysaccharides, or their combination were added to a frozen diluent of bovine semen. Afterwards, Computer Assisted Semen Analysis (CASA), membrane functionality, acrosome integrity, mitochondrial integrity, CAT, SOD, GSH-Px, MDA, and ROS detection were conducted. The results showed that adding 0.2 mmol/L AP or 0.5 mg/mL APS could improve the quality of frozen sperm. Compared to 0.2 mmol/L AP alone, the combination of 0.2 mmol/L AP and 0.3 mg/mL APS significantly increased the total motility (TM), average path distance (DAP), straight line distance (DSL), average path velocity (VAP), curvilinear velocity (VCL), wobble (WOB), and sperm CAT and SOD levels (p < 0.05), while reducing the ROS and MDA levels (p < 0.05). These results indicated that the addition of 0.2 mmol/L AP or 0.5 mg/mL APS alone has a protective effect on the freezing of bovine semen. Compared to the addition of 0.2 mmol/L AP, a combination of 0.2 mmol/L AP and 0.3 mg/mL APS could further improve the quality of frozen semen.
Characterisation of Extreme Precipitation Events in the Pyrenees: From the Local to the Synoptic Scale
Authors: Lemus-Canovas Marc , Lopez-Bustins Joan Albert , Martín-Vide Javier , Halifa-Marin Amar , Insua-Costa Damián , Martinez-Artigas Joan , Trapero Laura , Serrano-Notivoli Roberto , Cuadrat José María
Published: May 2021

Mountain systems within the Mediterranean region, e.g., the Pyrenees, are very sensitive to climate change. In the present study, we quantified the magnitude of extreme precipitation events and the number of days with torrential precipitation (daily precipitation ≥ 100 mm) in all the rain gauges available in the Pyrenees for the 1981–2015 period, analyzing the contribution of the synoptic scale in this type of event. The easternmost (under Mediterranean influence) and north-westernmost (under Atlantic influence) areas of the Pyrenees registered the highest number of torrential events. The heaviest events are expected in the eastern part, i.e., 400 mm day−1 for a return period of 200 years. Northerly advections over the Iberian Peninsula, which present a low zonal index, i.e., implying a stronger meridional component, give rise to torrential events over the western Pyrenees; and easterly advections favour extreme precipitation over the eastern Pyrenees. The air mass travels a long way, from the east coast of North America, bringing heavy rainfall to the western Pyrenees. In the case of the torrential events over the eastern Pyrenees, the trajectory of the air mass causing the events in these areas is very short and originates in the Mediterranean Basin. The North Atlantic Oscillation (NAO) index has no influence upon the occurrence of torrential events in the Pyrenees, but these events are closely related to certain Mediterranean teleconnections such as the Western Mediterranean Oscillation (WeMO).
Source Apportionment and Health Risk Assessment of Metal Elements in PM2.5 in Central Liaoning’s Urban Agglomeration
Authors: Guo Qingyuan , Li Liming , Zhao Xueyan , Yin Baohui , Liu Yingying , Wang Xiaoli , Yang Wen , Geng Chunmei , Wang Xinhua , Bai Zhipeng
Published: May 2021

To better understand the source and health risk of metal elements in PM2.5, a field study was conducted from May to December 2018 in the central region of the Liaoning province, China, including the cities of Shenyang, Anshan, Fushun, Benxi, Yingkou, Liaoyang, and Tieling. 24 metal elements (Na, K, V, Cr, Mn, Co, Ni, Cu, Zn, As, Mo, Cd, Sn, Sb, Pb, Bi, Al, Sr, Mg, Ti, Ca, Fe, Ba, and Si) in PM2.5 were measured by ICP-MS and ICP-OES. They presented obvious seasonal variations, with the highest levels in winter and lowest in summer for all seven cities. The sum of 24 elements were ranged from to in these cities. The element mass concentration ratio was the highest in Yingkou in the spring (26.15%), and the lowest in Tieling in winter (3.63%). The highest values of elements in PM2.5 were mostly found in Anshan and Fushun among the studied cities. Positive matrix factorization (PMF) modelling revealed that coal combustion, industry, traffic emission, soil dust, biomass burning, and road dust were the main sources of measured elements in all cities except for Yingkou. In Yingkou, the primary sources were identified as coal combustion, metal smelting, traffic emission, soil dust, and sea salt. Health risk assessment suggested that Mn had non-carcinogenic risks for both adults and children. As for Cr, As, and Cd, there was carcinogenic risks for adults and children in most cities. This study provides a clearer understanding of the regional pollution status of industrial urban agglomeration.
Polish Adaptation of the Social Communication Questionnaire (SCQ) and Female Autism Phenotype: An Investigation of Potentially Sex-Biased Items in the Screening Assessment and Their Impact on Scores
Authors: Rynkiewicz Agnieszka , Szura Magdalena , Bernaciak Daria , Kozak Anna , Karwowska Magdalena
Published: May 2021

Standardized screening assessments and sex differences in autism spectrum disorder (ASD) are still under-explored in Poland. This study investigated the differences between Polish ASD females and males based on the responses provided by parents/caregivers to a Polish adaptation of the Social Communication Questionnaire, SCQ Lifetime and SCQ Current. The study included 90 ASD participants from Mental Health Services and Autism Clinics in Poland with no intellectual disability and no profound communication difficulties. Parents provided information on the SCQ items which were compared under three domains of the Autism Diagnostic Interview-Revised (ADI-R). Four SCQ items with the examples were investigated. No significant differences were found between the two sexes in the three domains. The repetitive use of objects declined with age in ASD males. Although the findings of the present study did not reveal substantial gender biases in the Polish adaptation of the SCQ, it is necessary to take into account potential gender differences in the clinical presentation of ASD and in the adaptation of screening and diagnostic tools.
High Serum PD-L1 Levels Are Associated with Poor Survival in Urothelial Cancer Patients Treated with Chemotherapy and Immune Checkpoint Inhibitor Therapy
Authors: Krafft Ulrich , Olah Csilla , Reis Henning , Kesch Claudia , Darr Christopher , Grünwald Viktor , Tschirdewahn Stephan , Hadaschik Boris , Horvath Orsolya , Kenessey Istvan , Nyirady Peter , Varadi Melinda , Modos Orsolya , Csizmarik Anita , Szarvas Tibor
Published: May 2021

Serum PD-L1 (sPD-L1) levels are associated with prognosis in various tumors but has not yet been investigated in advanced bladder cancer. We assessed pretreatment serum samples from 83 BC patients who received platinum chemotherapy and from 12 patients who underwent immune checkpoint inhibitor (ICI) therapy. In addition, on-treatment samples from further therapy cycles were collected during chemotherapy (n = 58) and ICI therapy (n = 11). Serum PD-L1 levels were determined using ELISA. High baseline sPD-L1 levels were associated with worse ECOG status (p = 0.007) and shorter overall survival for both chemotherapy- and ICI-treated patients (p = 0.002 and p = 0.040, respectively). Multivariate analysis revealed high baseline sPD-L1 level as an independent predictor of poor survival for platinum-treated patients (p = 0.002). A correlation analysis between serum concentrations of PD-L1 and matrix metalloprotease-7 (MMP-7)—a protease which was recently found to cleave PD-L1—revealed a positive correlation (p = 0.001). No significant sPD-L1 changes were detected during chemotherapy, while in contrast we found a strong, 25-fold increase in sPD-L1 levels during atezolizumab treatment. In conclusion, our work demonstrates that pretreatment sPD-L1 levels are associated with a poor prognosis of BC patients undergoing platinum and ICI therapy. Future research should prospectively address the value of sPD-L1 in predicting treatment response.
MARCH8 Suppresses Tumor Metastasis and Mediates Degradation of STAT3 and CD44 in Breast Cancer Cells
Authors: Chen Wenjing , Patel Dhwani , Jia Yuzhi , Yu Zihao , Liu Xia , Shi Hengliang , Liu Huiping
Published: May 2021

Protein stability is largely regulated by post-translational modifications, such as ubiquitination, which is mediated by ubiquitin-activating enzyme E1, ubiquitin-conjugating enzyme E2, and ubiquitin ligase E3 with substrate specificity. Membrane-associated RING-CH (MARCH) proteins represent one novel family of transmembrane E3 ligases which target glycoproteins for lysosomal destruction. While most of the MARCH family members are known to degrade membrane proteins in immune cells, their tumor-intrinsic role is largely unknown. In this study, we found that the expression of one MARCH family member, MARCH8, is specifically downregulated in breast cancer tissues and positively correlated with breast cancer survival rate according to bioinformatic analysis of The Cancer Genomic Atlas (TCGA) dataset. MARCH8 protein expression was also lower in a variety of human breast cancer cell lines in comparison to immortalized human mammary epithelial MCF-12A cells. Restoration of MARCH8 expression induced apoptosis in human breast cancer cell lines MDA-MB-231 and BT549. Stable expression of MARCH8 inhibited tumorigenesis and lung metastases of MDA-MB-231 cells in mice. Moreover, we discovered that the breast cancer stem-cell marker and metastasis driver CD44, a membrane protein, interacts with MARCH8 and is one of the glycoprotein targets subject to MARCH8-dependent lysosomal degradation. Unexpectedly, we identified a nonmembrane protein, signal transducer and transcription activator 3 (STAT3), as another essential ubiquitination target of MARCH8, whose degradation through the proteasome pathway is responsible for the proapoptotic changes mediated by MARCH8. These findings highlight a novel tumor-suppressing function of MARCH8 in targeting both membrane and nonmembrane protein targets required for the survival and metastasis of breast cancer cells.
Impact of the rs1024611 Polymorphism of CCL2 on the Pathophysiology and Outcome of Primary Myelofibrosis
Authors: Masselli Elena , Carubbi Cecilia , Pozzi Giulia , Percesepe Antonio , Campanelli Rita , Villani Laura , Gobbi Giuliana , Bonomini Sabrina , Roti Giovanni , Rosti Vittorio , Massa Margherita , Barosi Giovanni , Vitale Marco
Published: May 2021

Single nucleotide polymorphisms (SNPs) can modify the individual pro-inflammatory background and may therefore have relevant implications in the MPN setting, typified by aberrant cytokine production. In a cohort of 773 primary myelofibrosis (PMF), we determined the contribution of the rs1024611 SNP of CCL2—one of the most potent immunomodulatory chemokines—to the clinical and biological characteristics of the disease, demonstrating that male subjects carrying the homozygous genotype G/G had an increased risk of PMF and that, among PMF patients, the G/G genotype is an independent prognostic factor for reduced overall survival. Functional characterization of the SNP and the CCL2-CCR2 axis in PMF showed that i) homozygous PMF cells are the highest chemokine producers as compared to the other genotypes; ii) PMF CD34+ cells are a selective target of CCL2, since they uniquely express CCR2 (CCL2 receptor); iii) activation of the CCL2-CCR2 axis boosts pro-survival signals induced by driver mutations via Akt phosphorylation; iv) ruxolitinib effectively counteracts CCL2 production and down-regulates CCR2 expression in PMF cells. In conclusion, the identification of the role of the CCL2/CCR2 chemokine system in PMF adds a novel element to the pathophysiological picture of the disease, with clinical and therapeutic implications.
HPV Strain Predicts Severity of Juvenile-Onset Recurrent Respiratory Papillomatosis with Implications for Disease Screening
Authors: Bedard Mary C. , de Alarcon Alessandro , Kou Yann-Fuu , Lee David , Sestito Alexandra , Duggins Angela L. , Brusadelli Marion , Lane Adam , Wikenheiser-Brokamp Kathryn A. , Wells Susanne I. , Smith David F.
Published: May 2021

Juvenile-onset recurrent respiratory papillomatosis (JoRRP) is the most common benign neoplasm of the larynx in children, presenting with significant variation in clinical course and potential for progression to malignancy. Since JoRRP is driven by human papillomavirus (HPV), we evaluated viral factors in a prospective cohort to identify predictive factors of disease severity. Twenty children with JoRRP undergoing routine debridement of papillomas were recruited and followed for ≥1 year. Demographical features, clinical severity scores, and surgeries over time were tabulated. Biopsies were used to establish a tissue bank and primary cell cultures for HPV6 vs. HPV11 genotyping and evaluation of viral gene expression. We found that patients with HPV11+ disease had an earlier age at disease onset, higher frequency of surgeries, increased number of lifetime surgeries, and were more likely to progress to malignancy. However, the amplitude of viral E6/E7 gene expression did not account for increased disease severity in HPV11+ patients. Determination of HPV strain is not routinely performed in the standard of care for JoRRP patients; we demonstrate the utility and feasibility of HPV genotyping using RNA-ISH for screening of HPV11+ disease as a biomarker for disease severity and progression in JoRRP patients.
Transformational Role of Medical Imaging in (Radiation) Oncology
Authors: Coolens Catherine , Gwilliam Matt N. , Alcaide-Leon Paula , de Freitas Faria Isabella Maria , Ynoe de Moraes Fabio
Published: May 2021

Onboard, real-time, imaging techniques, from the original megavoltage planar imaging devices, to the emerging combined MRI-Linear Accelerators, have brought a huge transformation in the ability to deliver targeted radiation therapies. Each generation of these technologies enables lethal doses of radiation to be delivered to target volumes with progressively more accuracy and thus allows shrinking of necessary geometric margins, leading to reduced toxicities. Alongside these improvements in treatment delivery, advances in medical imaging, e.g., PET, and MRI, have also allowed target volumes themselves to be better defined. The development of functional and molecular imaging is now driving a conceptually larger step transformation to both better understand the cancer target and disease to be treated, as well as how tumors respond to treatment. A biological description of the tumor microenvironment is now accepted as an essential component of how to personalize and adapt treatment. This applies not only to radiation oncology but extends widely in cancer management from surgical oncology planning and interventional radiology, to evaluation of targeted drug delivery efficacy in medical oncology/immunotherapy. Here, we will discuss the role and requirements of functional and metabolic imaging techniques in the context of brain tumors and metastases to reliably provide multi-parametric imaging biomarkers of the tumor microenvironment.
AR Splicing Variants and Resistance to AR Targeting Agents
Authors: Kanayama Mayuko , Lu Changxue , Luo Jun , Antonarakis Emmanuel S.
Published: May 2021

Over the past decade, advances in prostate cancer research have led to discovery and development of novel biomarkers and effective treatments. As treatment options diversify, it is critical to further develop and use optimal biomarkers for the purpose of maximizing treatment benefit and minimizing unwanted adverse effects. Because most treatments for prostate cancer target androgen receptor (AR) signaling, aberrations affecting this drug target are likely to emerge following the development of castration-resistant prostate cancer (CRPC), and it is conceivable that such aberrations may play a role in drug resistance. Among the many AR aberrations, we and others have been studying androgen receptor splice variants (AR-Vs), especially AR-V7, and have conducted preclinical and clinical studies to develop and validate the clinical utility of AR-V7 as a prognostic and potential predictive biomarker. In this review, we first describe mechanisms of AR-V generation, regulation and their functions from a molecular perspective. We then discuss AR-Vs from a clinical perspective, focusing on the significance of AR-Vs detected in different types of human specimens and AR-Vs as potential therapeutic targets.
A Circulating Exosome RNA Signature Is a Potential Diagnostic Marker for Pancreatic Cancer, a Systematic Study
Authors: Wu Yixing , Zeng Hongmei , Yu Qing , Huang Huatian , Fervers Beatrice , Chen Zhe-Sheng , Lu Lingeng
Published: May 2021

Several exosome proteins, miRNAs and KRAS mutations have been investigated in the hope of carrying out the early detection of pancreatic cancer with high sensitivity and specificity, but they have proven to be insufficient. Exosome RNAs, however, have not been extensively evaluated in the diagnosis of pancreatic cancer. The purpose of this study was to investigate the potential of circulating exosome RNAs in pancreatic cancer detection. By retrieving RNA-seq data from publicly accessed databases, differential expression and random-effects meta-analyses were performed. The results showed that pancreatic cancer had a distinct circulating exosome RNA signature in healthy individuals, and that the top 10 candidate exosome RNAs could distinguish patients from healthy individuals with an area under the curve (AUC) of 1.0. Three (HIST2H2AA3, LUZP6 and HLA-DRA) of the 10 genes in exosomes had similar differential patterns to those in tumor tissues based on RNA-seq data. In the validation dataset, the levels of these three genes in exosomes displayed good performance in distinguishing cancer from both chronic pancreatitis (AUC = 0.815) and healthy controls (AUC = 0.8558), whereas a slight difference existed between chronic pancreatitis and healthy controls (AUC = 0.586). Of the three genes, the level of HIST2H2AA3 was positively associated with KRAS status. However, there was no significant difference in the levels of the three genes across the disease stages (stages I–IV). These findings indicate that circulating exosome RNAs have a potential early detection value in pancreatic cancer, and that a distinct exosome RNA signature exists in distinguishing pancreatic cancer from healthy individuals.
Inhibition of DNA Repair in Combination with Temozolomide or Dianhydrogalactiol Overcomes Temozolomide-Resistant Glioma Cells
Authors: Ohba Shigeo , Yamashiro Kei , Hirose Yuichi
Published: May 2021

Resistance to temozolomide and intratumoral heterogeneity contribute to the poor prognosis of glioma. The mechanisms of temozolomide resistance can vary within a heterogeneous tumor. Temozolomide adds a methyl group to DNA. The primary cytotoxic lesion, O6-methylguanine, mispairs with thymine, leading to a futile DNA mismatch repair cycle, formation of double-strand breaks, and eventual cell death when O6-methylguanine DNA methyltransferase (MGMT) is absent. N7-methylguanine and N3-methyladenine are repaired by base excision repair (BER). The study aim was to elucidate temozolomide resistance mechanisms and identify methods to overcome temozolomide resistance in glioma. Several temozolomide-resistant clones were analyzed. Increased homologous recombination and mismatch repair system deficiencies contributed to temozolomide resistance. Inhibition of homologous recombination resensitized resistant cells with high homologous recombination efficiency. For the mismatch repair-deficient cells, inhibition of BER by PARP inhibitor potentiated temozolomide-induced cytotoxicity. Dianhydrogalactiol is a bifunctional DNA-targeting agent that forms N7-alkylguanine and inter-strand DNA crosslinks. Dianhydrogalactiol reduced the proliferation of cells independent of MGMT and mismatch repair, inducing DNA double-strand breaks and apoptosis in temozolomide-resistant cells. Further, inhibition of chk1 or homologous recombination enhanced dianhydrogalactiol-induced cytotoxicity in the cells. Selecting treatments most appropriate to the types of resistance mechanisms can potentially improve the prognosis of glioma.
Paradigm Change in First-Line Treatment of Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma
Authors: Borcoman Edith , Marret Gregoire , Le Tourneau Christophe
Published: May 2021

Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR) in combination with platinum-based chemotherapy has been for the decade standard of care for the treatment of head and neck squamous cell carcinomas (HNSCC) patients in the first-line recurrent and/or metastatic setting. The KEYNOTE-048 trial published last year established a new paradigm in this setting with the demonstration that immunotherapy should be given either alone or in combination with chemotherapy. Indeed, pembrolizumab, an antiprogrammed cell death 1 (PD-1) immune checkpoint inhibitor, improved overall survival as compared to the EXTREME regimen in patients expressing PD-L1 in the tumor microenvironment, which represents a large majority of the patient population. In this review, we will decipher this important change of paradigm in the first-line treatment of recurrent and/or metastatic HNSCC, and discuss associated challenges.
The DEAD/DEAH Box Helicase, DDX11, Is Essential for the Survival of Advanced Clear Cell Renal Cell Carcinoma and Is a Determinant of PARP Inhibitor Sensitivity
Authors: Park Jee Soo , Lee Myung Eun , Jang Won Sik , Rha Koon Ho , Lee Seung Hwan , Lee Jongsoo , Ham Won Sik
Published: May 2021

Genes associated with the DEAD-box helicase DDX11 are significant biomarkers of aggressive renal cell carcinoma (RCC), but their molecular function is poorly understood. We analyzed the molecular pathways through which DDX11 is involved in RCC cell survival and poly (ADP-ribose) polymerase (PARP) inhibitor sensitivity. Immunohistochemistry and immunoblotting determined DDX11 expression in normal kidney tissues, benign renal tumors, and RCC tissues and cell lines. Quantitative polymerase chain reaction validated the downregulation of DDX11 in response to transfection with DDX11-specific small interfering RNA. Proliferation analysis and apoptosis assays were performed to determine the impact of DDX11 knockdown on RCC cells, and the relevant effects of sunitinib, olaparib, and sunitinib plus olaparib were evaluated. DDX11 was upregulated in high-grade, advanced RCC compared to low-grade, localized RCC, and DDX11 was not expressed in normal kidney tissues or benign renal tumors. DDX11 knockdown resulted in the inhibition of RCC cell proliferation, segregation defects, and rapid apoptosis. DDX11-deficient RCC cells exhibited significantly increased sensitivity to olaparib compared to sunitinib alone or sunitinib plus olaparib combination treatments. Moreover, DDX11 could determine PARP inhibitor sensitivity in RCC. DDX11 could serve as a novel therapeutic biomarker for RCC patients who are refractory to conventional targeted therapies and immunotherapies.
Challenging, Accurate and Feasible: CAF-1 as a Tumour Proliferation Marker of Diagnostic and Prognostic Value
Authors: Sykaras Alexandros G. , Pergaris Alexandros , Theocharis Stamatios
Published: May 2021

The discovery of novel biomarkers of diagnostic, prognostic, and therapeutic value is a major challenge of current cancer research. The assessment of tumour cell proliferative capacity is pivotal for grading and clinical decision-making, highlighting the importance of proliferation markers as diagnostic and prognostic tools. Currently, the immunohistochemical analysis of Ki-67 expression levels is routinely used in clinical settings to assess tumour proliferation. Inasmuch as the function of Ki-67 is not fully understood and its evaluation lacks standardization, there is interest in chromatin regulator proteins as alternative proliferation markers of clinical value. Here, we review recent evidence demonstrating that chromatin assembly factor 1 (CAF-1), a histone chaperone selectively expressed in cycling cells, is a proliferation marker of clinical value. CAF-1 expression, when evaluated by immunocytochemistry in breast cancer cytology smears and immunohistochemistry in cancer biopsies from several tissues, strongly correlates with the expression of Ki-67 and other proliferation markers. Notably, CAF-1 expression is upregulated in almost all cancers, and CAF-1 overexpression is significantly associated, in most cancer types, with high histological tumour grade, advanced stage, recurrence, metastasis, and decreased patient survival. These findings suggest that CAF-1 is a robust, reproducible, and feasible proliferation marker of prognostic importance. CAF-1 may represent an attractive alternative or complementary to Ki-67 for cancer stratification and clinical guidance.
Effects of Cancer, Chemotherapy, and Cytokines on Subjective and Objective Cognitive Functioning Among Patients with Breast Cancer
Authors: Chen Vincent Chin-Hung , Lin Chin-Kuo , Hsiao Han-Pin , Tzang Bor-Show , Hsu Yen-Hsuan , Wu Shu-I , Stewart Robert
Published: May 2021

Background: We aimed to investigate the associations of breast cancer (BC) and cancer-related chemotherapies with cytokine levels, and cognitive function. Methods: We evaluated subjective and objective cognitive function in BC patients before chemotherapy and 3~9 months after the completion of chemotherapy. Healthy volunteers without cancer were also compared as control group. Interleukins (IL) 2, 4, 5, 6, 10, 12p70, 13, 17A, 1β, IFNγ, and TNFα were measured. Associations of cancer status, chemotherapy and cytokine levels with subjective and objective cognitive impairments were analyzed using a regression model, adjusting for covariates, including IQ and psychological distress. Results: After adjustment, poorer performance in semantic verbal fluency was found in the post-chemotherapy subgroup compared to controls (p = 0.011, η2 = 0.070); whereas pre-chemotherapy patients scored higher in subjective cognitive perception. Higher IL-13 was associated with lower semantic verbal fluency in the post-chemotherapy subgroup. Higher IL-10 was associated with better perceived cognitive abilities in the pre-chemotherapy and control groups; while IL-5 and IL-13 were associated with lower perceived cognitive abilities in pre-chemotherapy and control groups. Our findings from mediation analysis further suggest that verbal fluency might be affected by cancer status, although mediated by anxiety. Conclusions: Our findings suggest that verbal fluency might be affected by cancer status, although mediated by anxiety. Different cytokines and their interactions may have different roles of neuroinflammation or neuroprotection that need further research.
Borate Anion Dopant Inducing Oxygen Vacancies over Co3O4 Nanocages for Enhanced Oxygen Evolution
Authors: Liu Xuetao , Liu Heng , He Guangling , Zhu Yanlin , Xiao Jiamin , Han Lei
Published: May 2021

The rational design of cost effective and highly efficient oxygen evolution reaction (OER) catalysts plays an extremely important role in promoting the commercial applications of electrochemical water splitting. Herein we reported a sacrificial template strategy for the preparation of borate anion doped Co3O4@ZIF-67 nanocages assembled with nanosheets (B-Co3O4@ZIF-67) by hydrothermal boronation of zeolitic imidazolate framework-67 (ZIF-67). During the preparation process, two different kinds of borate anion sources were found to regulate the morphological structures by tuning the etching rate between ZIF precursors and the borate anion. Moreover, borate anion doping was also found to induce oxygen vacancy defects, which is beneficial for modulating the electronic structure and accelerating electron transport. Meanwhile, the resultant B-Co3O4@ZIF-67 nanocages possess a large specific surface area, which is beneficial for the mass transfer of the electrolyte and exposing more catalytic active sites. Benefiting from the advantages above, the resultant B-Co3O4@ZIF-67 nanocages exhibit impressive OER performance with a small overpotential of 334 mV, a current density of 10 mA cm−2, a small Tafel slope of 73.88 mV dec−1, as well as long-term durability in an alkaline electrolyte.