bluuebunny/crossref_metadata_2025 huggingface dataset:
Larval Fish Assemblage Structure at Coastal Fronts and the Influence of Environmental Variability
Authors: Pattrick Paula , Weidberg Nicolas , Goschen Wayne S. , Jackson Jennifer M. , McQuaid Christopher D. , Porri Francesca
Published: May 2021

Within the coastal zone, oceanographic features, such as fronts, can have major effects on the abundance and distribution of larval fish. We investigated the effects of fronts on larval fish assemblages by jointly collecting physical (ADCP and CTD) and biological (larvae) data in the nearshore waters of the south coast of South Africa, on four separate neap-tide occasions. Accumulation of fish larvae at predominantly internal wave-associated fronts was observed, with higher larval densities inshore of and within the front than farther offshore. On each occasion, larvae of coastal species with pelagic eggs (Mugillidae and Sparidae) were numerically dominant at the front itself, while inshore of the front, larvae of coastal species with benthic eggs (Gobiesocidae and Gobiidae) were more abundant. Offshore catches mainly comprised Engraulidae (pelagic species with pelagic eggs) larvae, which were generally restricted to the bottom, where current velocities were onshore on each occasion. On the occasion when fast (>100 cm/s) currents prevailed, however, accumulation of the larvae of coastal species occurred offshore of the front, and larvae were mixed throughout the water column. Thus, larval occurrence at these coastal frontal systems was strongly affected by the degree of mixing by currents, which on most occasions resulted in onshore retention. The results underline the importance of frontal systems in determining the nearshore distributions of fish larvae, particularly by retaining coastal fish species in the inshore region. The environmental variability observed at these frontal systems has potential implications for larval connectivity of fish populations.
Polymorphisms of Antigen-Presenting Machinery Genes in Non-Small Cell Lung Cancer: Different Impact on Disease Risk and Clinical Parameters in Smokers and Never-Smokers
Authors: Wiśniewski Andrzej , Sobczyński Maciej , Pawełczyk Konrad , Porębska Irena , Jasek Monika , Wagner Marta , Niepiekło-Miniewska Wanda , Kowal Aneta , Dubis Joanna , Jędruchniewicz Natalia , Kuśnierczyk Piotr
Published: May 2021

Lung cancer is strongly associated with cigarette smoking; nevertheless some never-smokers develop cancer. Immune eradication of cancer cells is dependent on polymorphisms of HLA class I molecules and antigen-processing machinery (APM) components. We have already published highly significant associations of single nucleotide polymorphisms (SNPs) of the ERAP1 gene with non-small cell lung cancer (NSCLC) in Chinese, but not in Polish populations. However, the smoking status of participants was not known in the previous study. Here, we compared the distribution of APM polymorphic variants in larger cohorts of Polish patients with NSCLC and controls, stratified according to their smoking status. We found significant but opposite associations in never-smokers and in smokers of all tested SNPs (rs26653, rs2287987, rs30187, and rs27044) but one (rs26618) in ERAP1. No significant associations were seen in other genes. Haplotype analysis indicated that the distribution of many ERAP1/2 haplotypes is opposite, depending on smoking status. Additionally, haplotypic combination of low activity ERAP1 and the lack of an active form of ERAP2 seems to favor the disease in never-smokers. We also revealed interesting associations of some APM polymorphisms with: age at diagnosis (ERAP1 rs26653), disease stage (ERAP1 rs27044, PSMB9 rs17587), overall survival (ERAP1 rs30187), and response to chemotherapy (ERAP1 rs27044). The results presented here may suggest the important role for ERAP1 in the anti-cancer response, which is different in smokers versus never-smokers, depending to some extent on the presence of ERAP2, and affecting NSCLC clinical course.
The Potential Role of the Intestinal Micromilieu and Individual Microbes in the Immunobiology of Chimeric Antigen Receptor T-Cell Therapy
Authors: Schubert Maria-Luisa , Rohrbach Roman , Schmitt Michael , Stein-Thoeringer Christoph K.
Published: May 2021

Cellular immunotherapy with chimeric antigen receptor (CAR)-T cells (CARTs) represents a breakthrough in the treatment of hematologic malignancies. CARTs are genetically engineered hybrid receptors that combine antigen-specificity of monoclonal antibodies with T cell function to direct patient-derived T cells to kill malignant cells expressing the target (tumor) antigen. CARTs have been introduced into clinical medicine as CD19-targeted CARTs for refractory and relapsed B cell malignancies. Despite high initial response rates, current CART therapies are limited by a long-term loss of antitumor efficacy, the occurrence of toxicities, and the lack of biomarkers for predicting therapy and toxicity outcomes. In the past decade, the gut microbiome of mammals has been extensively studied and evidence is accumulating that human health, apart from our own genome, largely depends on microbes that are living in and on the human body. The microbiome encompasses more than 1000 bacterial species who collectively encode a metagenome that guides multifaceted, bidirectional host-microbiome interactions, primarily through the action of microbial metabolites. Increasing knowledge has been accumulated on the role of the gut microbiome in T cell-driven anticancer immunotherapy. It has been shown that antibiotics, dietary components and gut microbes reciprocally affect the efficacy and toxicity of allogeneic hematopoietic cell transplantation (allo HCT) as the prototype of T cell-based immunotherapy for hematologic malignancies, and that microbiome diversity metrics can predict clinical outcomes of allo HCTs. In this review, we will provide a comprehensive overview of the principles of CD19-CART immunotherapy and major aspects of the gut microbiome and its modulators that impact antitumor T cell transfer therapies. We will outline i) the extrinsic and intrinsic variables that can contribute to the complex interaction of the gut microbiome and host in CART immunotherapy, including ii) antibiotic administration affecting loss of colonization resistance, expansion of pathobionts and disturbed mucosal and immunological homeostasis, and ii) the role of specific gut commensals and their microbial virulence factors in host immunity and inflammation. Although the role of the gut microbiome in CART immunotherapy has only been marginally explored so far, this review may open a new chapter and views on putative connections and mechanisms.
The GIMAP Family Proteins: An Incomplete Puzzle
Authors: Limoges Marc-André , Cloutier Maryse , Nandi Madhuparna , Ilangumaran Subburaj , Ramanathan Sheela
Published: May 2021

Overview: Long-term survival of T lymphocytes in quiescent state is essential to maintain their cell numbers in secondary lymphoid organs and in peripheral circulation. In the BioBreeding diabetes-prone strain of rats (BB-DP), loss of functional GIMAP5 (GTPase of the immune associated nucleotide binding protein 5) results in profound peripheral T lymphopenia. This discovery heralded the identification of a new family of proteins initially called Immune-associated nucleotide binding protein (IAN) family. In this review we will use ‘GIMAP’ to refer to this family of proteins. Recent studies suggest that GIMAP proteins may interact with each other and also be involved in the movement of the cellular cargo along the cytoskeletal network. Here we will summarize the current knowledge on the characteristics and functions of GIMAP family of proteins.
Sponge-Associated Polychaetes: Not a Random Assemblage
Authors: Goren Liron , Idan Tal , Shefer Sigal , Ilan Micha
Published: May 2021

Polychaetes are among the most common marine organisms, and in many habitats they dominate both in species richness and abundance. They are often found in association with other organisms. Specifically, sponges with their complex three-dimensional internal architecture, are known to host a great diversity of polychaetes. Due to the fact that a large number of sponge-associated polychaete species are known to be common on other substrates, most studies agree that they represent an opportunistic part of the sponge-inhabiting assemblage, without any selection of species tightly associated with sponges. The current study aimed to shed light on polychaetes affinity to sponges. We applied Clarke and Warwick’s taxonomic distinctness indices and test for random assembly, to a dataset compiled of 13 publications that provided polychaete species lists from massive-sponges across the Mediterranean Sea, and compared them with benthic-polychaete species lists from all of the Mediterranean and its zoogeographical regions. These indices are considered to be independent of sampling efforts and setting, and can be applied on presence/absence data, making it possible to compare data from multiple studies. We further compared the trophic structure of sponge-associated polychaetes between the Mediterranean’s zoogeographical regions. Our results show that the trophic structure of the sponge-associated polychaete community, was found to be stable across the entire Mediterranean Sea. Moreover, randomization tests showed that at almost all observational scales (e.g., study, region, Mediterranean) the phylogenetic diversity is not assembled at random, and that sponge-associated polychaete communities are composed of taxonomically related species. These results support the statement that polychaete assemblages inhabiting sponges are not a transient facultative assembly of species, but rather stable, diverse and specialized communities which are well adapted for life in this habitat.
Deformation and Fracture Behavior of Sandwiched Copper Foam Brazed Joint Using Amorphous Copper–Tin–Nickel–Phosphorus Filler
Authors: Mohd Zahri Nur Amirah , Yusof Farazila , Badruddin Irfan Anjum , Haseeb A. S. Md. Abdul , Sukiman Nazatul Liana , Kamangar Sarfaraz
Published: May 2021

Utilization of open-cell metal foams in functional applications such as in energy absorption, noise absorber, heat insulator, and lightweight panels is trending in many industrial applications. The development of reliable joining technologies for sandwiched metal foams is crucial for thermal application and one of the techniques used is brazing process. In the current work, copper foam was sandwiched between a copper plate using amorphous filler of Cu-9.7Sn-5.7Ni-7.0P (Cu: copper, Sn: tin, Ni: nickel, and P: phosphorus) via brazing technique. The shear test was conducted on the brazed joint interface of copper/copper foam, while the compressive test was carried out on the brazed sample. Microstructures of the copper substrate surface obtained from the shear fracture of brazed copper/copper foam show the tear region and cleavage fractures. The stress–strain curve of shear and compressive strength explains the deformation behavior of the brazed sample.
Dysprosium Oxide-Supported CaO for Thermochemical Energy Storage
Authors: Fedunik-Hofman Larissa , Bayon Alicia , Gao Xiang , Tricoli Antonio , Donne Scott W.
Published: May 2021

A novel CaO-based material supported with Ca3Al2O6 and Dy2O3 was found to show excellent performance as a thermochemical energy storage material for use in solar thermal power plants. It retains a carbonation conversion capacity of 82.7% for a period of 40 cycles, as well as exothermic heats of reaction of 582.2 kJ kg−1, up to seven times greater than other materials found in the literature. The improved performance was attributed to the greater prevention of sintering and retention of high surface area by the addition of two inert supports: Ca3Al2O6 and Dy2O3. Long-term effectiveness of the novel material was also evaluated by using a sintering model. It retains an energy storage utilization of 6.2 kg kWh−1 after 30 years of cycling, while commercial limestone would require 81 tons kWh−1 equivalent. Limestone requires replacement every six thermal cycles, making it impractical for real thermochemical energy storage implementation. The extra cost associated with the addition of supports in this CaO-based material is justified by the long-term durability, which would imply a reduction in the overall capital and operational expenditure of the plant.
Microstructure-Dependent Rate Theory Model of Radiation-Induced Segregation in Binary Alloys
Authors: Hu Shenyang , Li Yulan , Burkes Douglas , Senor David J.
Published: May 2021

Conventional rate theory often uses the mean field concept to describe the effect of inhomogeneous microstructures on the evolution of radiation induced defect and solute/fission product segregation. However, the spatial and temporal evolution of defects and solutes determines the formation and spatial distribution of radiation-induced second phase such as precipitates and gas bubbles/voids, especially in materials with complicated microstructures and subject to high dose radiation. In this work, a microstructure-dependent model of radiation-induced segregation (RIS) has been developed to investigate the effect of inhomogeneous thermodynamic and kinetics properties of defects on diffusion and accumulations of solute A in AB binary alloys. Four independent concentrations: atom A, interstitial A, interstitial B, and vacancy on [A, B] sublattice are used as field variables to describe temporal and spatial distribution and evolution of defects and solute A. The independent concentrations of interstitial A and interstitial B allow to describe their different generation rates, thermodynamic and kinetic properties, and release the assumptions of interstitial generation and sink strength used in the conventional rate theory. Microstructure and concentration dependent chemical potentials of defects are used to calculate the driving forces of defect diffusions. With the model, the effects of defect chemical potentials and mobilities on the RIS in polycrystalline AB model alloys have been simulated. The results demonstrated the model capability in predicting defect evolution in materials with inhomogeneous thermodynamic and kinetic properties of defects. The model can be extended to materials with complicated microstructures such as a wide range of grain size distribution, coating structure and multiphases as well as radiation-induced precipitation subject to severe radiation damage.
Disease Activity Indices in Rheumatoid Arthritis: Comparative Performance to Detect Changes in Function, IL-6 Levels, and Radiographic Progression
Authors: Rodriguez-García Sebastián C. , Montes Nuria , Ivorra-Cortes José , Triguero-Martinez Ana , Rodriguez-Rodriguez Luis , Castrejón Isabel , Carmona Loreto , González-Álvaro Isidoro
Published: May 2021

Objective:To compare the capacity of various disease activity indices to evaluate changes in function, IL-6 levels, and radiographic progression in early and established rheumatoid arthritis (RA).

Methods:Secondary data analysis of a clinical trial assessing the efficacy of tocilizumab in patients with established RA (ACT-RAY) and a longitudinal prospective register of early arthritis (PEARL). Targeted outcomes were changes in physical function, measured with the health assessment questionnaire (HAQ), IL-6 serum levels, and radiographic progression. The “Hospital Universitario La Princesa Index” (HUPI), DAS28 using erythrocyte sedimentation rate and SDAI were the disease activity indices compared. Models adjusted for age and sex were fitted for each outcome and index and ranked based on theR2parameter and the quasi-likelihood under the independence model criterion.

Results:Data from 8,090 visits (550 patients) from ACT-RAY and 775 visits (534 patients) from PEARL were analyzed. The best performing models for HAQ were the HUPI (R2= 0.351) and SDAI ones (R2= 0.329). For serum IL-6 levels, the SDAI (R2= 0.208) followed by the HUPI model (R2= 0.205). For radiographic progression in ACT-RAY, the HUPI (R2= 0.034) and the DAS28 models (R2= 0.026) performed best whereas the DAS28 (R2= 0.030) and HUPI models (R2= 0.023) did so in PEARL.

Conclusions:HUPI outperformed other indices identifying changes in HAQ and radiographic progression and performed similarly to SDAI for IL-6 serum levels.
Intrauterine Growth Restriction Promotes Postnatal Airway Hyperresponsiveness Independent of Allergic Disease
Authors: Kalotas Jack O. , Wang Carolyn J. , Noble Peter B. , Wang Kimberley C. W.
Published: May 2021

Introduction: Intrauterine growth restriction (IUGR) is associated with asthma. Murine models of IUGR have altered airway responsiveness in the absence of any inflammatory exposure. Given that a primary feature of asthma is airway inflammation, IUGR-affected individuals may develop more substantial respiratory impairment if subsequently exposed to an allergen. This study used a maternal hypoxia-induced mouse model of IUGR to determine the combined effects of IUGR and allergy on airway responsiveness.

Methods: Pregnant BALB/c mice were housed under hypoxic conditions (10.5% O2) from gestational day (GD) 11-GD 17.5 (IUGR group; term = GD 21). Following hypoxic exposure, mice were returned to a normoxic environment (21% O2). A second group of pregnant mice were housed under normoxic conditions throughout pregnancy (Control). All offspring were sensitized to ovalbumin (OVA) and assigned to one of four treatment groups: Control – normoxic and saline challenge; IUGR – hypoxic and saline challenge; Allergy – normoxic and OVA challenge; and IUGR + Allergy – hypoxic and OVA challenge. At 8 weeks of age, and 24 h post-aerosol challenge, mice were tracheostomised for methacholine challenge and assessment of lung mechanics by the forced oscillation technique, and lungs subsequently fixed for morphometry.

Results: IUGR offspring were lighter than Control at birth and in adulthood. Both Allergy and IUGR independently increased airway resistance after methacholine challenge. The IUGR group also exhibited an exaggerated increase in tissue damping and elastance after methacholine challenge compared with Control. However, there was no incremental effect on airway responsiveness in the combined IUGR + Allergy group. There was no impact of IUGR or Allergy on airway structure and no effect of sex on any outcome.

Conclusion: IUGR and aeroallergen independently increased bronchoconstrictor response, but when combined the pathophysiology was not worsened. Findings suggest that an association between IUGR and asthma is mediated by baseline airway responsiveness rather than susceptibility to allergen.
Bioactive Molecules of Tea as Potential Inhibitors for RNA-Dependent RNA Polymerase of SARS-CoV-2
Authors: Bhardwaj Vijay Kumar , Singh Rahul , Sharma Jatin , Rajendran Vidya , Purohit Rituraj , Kumar Sanjay
Published: May 2021

The coronavirus disease (COVID-19), a worldwide pandemic, is caused by the severe acute respiratory syndrome-corona virus-2 (SARS-CoV-2). At this moment in time, there are no specific therapeutics available to combat COVID-19. Drug repurposing and identification of naturally available bioactive molecules to target SARS-CoV-2 are among the key strategies to tackle the notorious virus. The enzyme RNA-dependent RNA polymerase (RdRp) performs a pivotal role in replicating the virus. RdRp is a prime target for Remdesivir and other nucleotides analog-based antiviral drugs. In this study, we showed three bioactive molecules from tea (epicatechin-3,5-di-O-gallate, epigallocatechin-3,5-di-O-gallate, and epigallocatechin-3,4-di-O-gallate) that showed better interaction with critical residues present at the catalytic center and the NTP entry channel of RdRp than antiviral drugs Remdesivir and Favipiravir. Our computational approach to identify these molecules included molecular docking studies, followed by robust molecular dynamics simulations. All the three molecules are readily available in tea and could be made accessible along with other medications to treat COVID-19 patients. However, these results require validation by furtherin vitroandin vivostudies.
Metatranscriptome Library Preparation Influences Analyses of Viral Community Activity During a Brown Tide Bloom
Authors: Gann Eric R. , Kang Yoonja , Dyhrman Sonya T. , Gobler Christopher J. , Wilhelm Steven W.
Published: May 2021

There is growing interest in the use of metatranscriptomics to study virus community dynamics. We used RNA samples collected from harmful brown tides caused by the eukaryotic alga Aureococcus anophagefferens within New York (United States) estuaries and in the process observed how preprocessing of libraries by either selection for polyadenylation or reduction in ribosomal RNA (rRNA) influenced virus community analyses. As expected, more reads mapped to the A. anophagefferens genome in polyadenylation-selected libraries compared to the rRNA-reduced libraries, with reads mapped in each sample correlating to one another regardless of preprocessing of libraries. Yet, this trend was not seen for reads mapping to the Aureococcus anophagefferens Virus (AaV), where significantly more reads (approximately two orders of magnitude) were mapped to the AaV genome in the rRNA-reduced libraries. In the rRNA-reduced libraries, there was a strong and significant correlation between reads mappings to AaV and A. anophagefferens. Overall, polyadenylation-selected libraries produced fewer viral contigs, fewer reads mapped to viral contigs, and different proportions across viral realms and families, compared to their rRNA-reduced pairs. This study provides evidence that libraries generated by rRNA reduction and not selected for polyadenylation are more appropriate for quantitative characterization of viral communities in aquatic ecosystems by metatranscriptomics.
Potent Molecular Feature-based Neutralizing Monoclonal Antibodies as Promising Therapeutics Against SARS-CoV-2 Infection
Authors: Kombe Kombe Arnaud John , Zahid Ayesha , Mohammed Ahmed , Shi Ronghua , Jin Tengchuan
Published: May 2021

The 2019–2020 winter was marked by the emergence of a new coronavirus (SARS-CoV-2) related disease (COVID-19), which started in Wuhan, China. Its high human-to-human transmission ability led to a worldwide spread within few weeks and has caused substantial human loss. Mechanical antiviral control approach, drug repositioning, and use of COVID-19 convalescent plasmas (CPs) were the first line strategies utilized to mitigate the viral spread, yet insufficient. The urgent need to contain this deadly pandemic has led searchers and pharmaceutical companies to develop vaccines. However, not all vaccines manufactured are safe. Besides, an alternative and effective treatment option for such an infectious disease would include pure anti-viral neutralizing monoclonal antibodies (NmAbs), which can block the virus at specific molecular targets from entering cells by inhibiting virus-cell structural complex formation, with more safety and efficiency than the CP. Indeed, there is a lot of molecular evidence about the protector effect and the use of molecular feature-based NmAbs as promising therapeutics to contain COVID-19. Thus, from the scientific publication database screening, we here retrieved antibody-related papers and summarized the repertory of characterized NmAbs against SARS-CoV-2, their molecular neutralization mechanisms, and their immunotherapeutic pros and cons. About 500 anti-SARS-CoV-2 NmAbs, characterized through competitive binding assays and neutralization efficacy, were reported at the writing time (January 2021). All NmAbs bind respectively to SARS-CoV-2 S and exhibit high molecular neutralizing effects against wild-type and/or pseudotyped virus. Overall, we defined six NmAb groups blocking SARS-CoV-2 through different molecular neutralization mechanisms, from which five potential neutralization sites on SARS-CoV-2 S protein are described. Therefore, more efforts are needed to develop NmAbs-based cocktails to mitigate COVID-19.
Cortical Structural Connectivity Alterations and Potential Pathogenesis in Mid-Stage Sporadic Parkinson’s Disease
Authors: Deng Xia , Liu Zheng , Kang Qin , Lu Lin , Zhu Yu , Xu Renshi
Published: May 2021

Many clinical symptoms of sporadic Parkinson’s disease (sPD) cannot be completely explained by a lesion of the simple typical extrapyramidal circuit between the striatum and substantia nigra. Therefore, this study aimed to explore the new potential damaged pathogenesis of other brain regions associated with the multiple and complex clinical symptoms of sPD through magnetic resonance imaging (MRI). A total of 65 patients with mid-stage sPD and 35 healthy controls were recruited in this study. Cortical structural connectivity was assessed by seed-based analysis using the vertex-based morphology of MRI. Seven different clusters in the brain regions of cortical thickness thinning derived from the regression analysis using brain size as covariates between sPD and control were selected as seeds. Results showed that the significant alteration of cortical structural connectivity mainly occurred in the bilateral frontal orbital, opercular, triangular, precentral, rectus, supplementary-motor, temporal pole, angular, Heschl, parietal, supramarginal, postcentral, precuneus, occipital, lingual, cuneus, Rolandic-opercular, cingulum, parahippocampal, calcarine, olfactory, insula, paracentral-lobule, and fusiform regions at the mid-stage of sPD. These findings suggested that the extensive alteration of cortical structural connectivity is one of possible pathogenesis resulting in the multiple and complex clinical symptoms in sPD.
A Modified Treatment Through Point-to-Point Coil Embolization for Direct Carotid Cavernous to Fistula: A Single-Center Result
Authors: Zhang Zihuan , Liu Jiaqiang , Zhang Bingbing , Zhou Mengliang , Zhao Xintong , Li Zhenbao
Published: May 2021

This study aims to assess the safety and efficacy of the modified treatment through point-to-point coil embolization of direct carotid cavernous fistula (dCCF), and evaluate the long-term outcome of patients who underwent the above treatment. A total of 18 patients who suffered from dCCF (a total of 19 fistulas) between January 2013 to May 2020 were analyzed. Among these patients, 14 patients were treated through point-to-point coil embolization of the fistula, while four patients were treated through combined endovascular embolization (coils, a balloon, Onyx, and/or a stent). The number of coils that filled the fistulas was counted. The primary outcome was defined by post-operative digital subtraction angiography (DSA) or the signs after the recanalization of dCCFs during the follow-up period. For patients with dCCF who underwent point-to-point coil embolization, a minimum of three coils and a maximum of 16 coils were used for these 14 fistula patients, and an average of 7.9 coils were used for each fistula, but none of the fistulas was recanalized. Furthermore, two pseudoaneurysms were observed as a result of the compression of the coils. However, none of these 14 patients presented with signs of recanalization of fistulas or cranial paralysis. The procedure applied for the present study was shown to be a safe, economical and efficacious treatment approach for dCCFs through the point-to-point coil embolization of the fistula.
Comparisons Between Serum Levels of Hepcidin and Leptin in Male College-Level Endurance Runners and Sprinters
Authors: Nirengi Shinsuke , Taniguchi Hirokazu , Ishibashi Aya , Fujibayashi Mami , Akiyama Nao , Kotani Kazuhiko , Ishihara Kengo , Sakane Naoki
Published: May 2021

Background: Hepcidin-25 is a 25 amino acid hepatokine and a key regulator of iron metabolism related to iron deficiency anemia. Recent studies have suggested that an elevated hepcidin level is correlated with low energy availability. Leptin is an appetite-suppressing adipokine and has been reported to stimulate hepcidin production in animals and cultured cells. While leptin is modulated by exercise, it is known that endurance runners and sprinters practice different types of exercise. This study investigated and compared the relationships between hepcidin and leptin levels, iron status, and body fat to understand better the risk of iron deficiency anemia in endurance runners and sprinters.

Methods: Thirty-six male college track and field athletes (15 endurance runners and 21 sprinters) were recruited for this study. Dietary intake, body composition, and blood levels of ferritin, hepcidin-25, leptin, and adiponectin were measured. Correlations between hepcidin levels and ferritin, body fat, leptin, and adiponectin were evaluated using Pearson's correlation coefficient for each group.

Results: The endurance runners had lower hepcidin levels and higher leptin and adiponectin levels compared with sprinters. Ferritin was positively correlated with hepcidin-25 levels in both the endurance and sprinter groups. A positive correlation was observed between hepcidin-25 and body fat or leptin levels only in sprinters.

Conclusion: This is the first study investigating the relationship between blood levels of hepcidin and leptin in athletes. The positive correlation between hepcidin-25 and leptin was observed in sprinters but not endurance runners.
Assessing the Contribution of Relative Macrophage Frequencies to Subcutaneous Adipose Tissue
Authors: Kalafati Marianthi , Lenz Michael , Ertaylan Gökhan , Arts Ilja C. W. , Evelo Chris T. , van Greevenbroek Marleen M. J. , Blaak Ellen E. , Adriaens Michiel , Kutmon Martina
Published: May 2021

Background: Macrophages play an important role in regulating adipose tissue function, while their frequencies in adipose tissue vary between individuals. Adipose tissue infiltration by high frequencies of macrophages has been linked to changes in adipokine levels and low-grade inflammation, frequently associated with the progression of obesity. The objective of this project was to assess the contribution of relative macrophage frequencies to the overall subcutaneous adipose tissue gene expression using publicly available datasets.

Methods: Seven publicly available microarray gene expression datasets from human subcutaneous adipose tissue biopsies (n = 519) were used together with TissueDecoder to determine the adipose tissue cell-type composition of each sample. We divided the subjects in four groups based on their relative macrophage frequencies. Differential gene expression analysis between the high and low relative macrophage frequencies groups was performed, adjusting for sex and study. Finally, biological processes were identified using pathway enrichment and network analysis.

Results: We observed lower frequencies of adipocytes and higher frequencies of adipose stem cells in individuals characterized by high macrophage frequencies. We additionally studied whether, within subcutaneous adipose tissue, interindividual differences in the relative frequencies of macrophages were reflected in transcriptional differences in metabolic and inflammatory pathways. Adipose tissue of individuals with high macrophage frequencies had a higher expression of genes involved in complement activation, chemotaxis, focal adhesion, and oxidative stress. Similarly, we observed a lower expression of genes involved in lipid metabolism, fatty acid synthesis, and oxidation and mitochondrial respiration.

Conclusion: We present an approach that combines publicly available subcutaneous adipose tissue gene expression datasets with a deconvolution algorithm to calculate subcutaneous adipose tissue cell-type composition. The results showed the expected increased inflammation gene expression profile accompanied by decreased gene expression in pathways related to lipid metabolism and mitochondrial respiration in subcutaneous adipose tissue in individuals characterized by high macrophage frequencies. This approach demonstrates the hidden strength of reusing publicly available data to gain cell-type-specific insights into adipose tissue function.
Ketogenic Metabolic Therapy, Without Chemo or Radiation, for the Long-Term Management of IDH1-Mutant Glioblastoma: An 80-Month Follow-Up Case Report
Authors: Seyfried Thomas N. , Shivane Aditya G. , Kalamian Miriam , Maroon Joseph C. , Mukherjee Purna , Zuccoli Giulio
Published: May 2021

Background: Successful treatment of glioblastoma (GBM) remains futile despite decades of intense research. GBM is similar to most other malignant cancers in requiring glucose and glutamine for growth, regardless of histological or genetic heterogeneity. Ketogenic metabolic therapy (KMT) is a non-toxic nutritional intervention for cancer management. We report the case of a 32-year-old man who presented in 2014 with seizures and a right frontal lobe tumor on MRI. The tumor cells were immunoreactive with antibodies to the IDH1 (R132H) mutation, P53 (patchy), MIB-1 index (4–6%), and absent ATRX protein expression. DNA analysis showed no evidence of methylation of the MGMT gene promoter. The presence of prominent microvascular proliferation and areas of necrosis were consistent with an IDH-mutant glioblastoma (WHO Grade 4).

Methods: The patient refused standard of care (SOC) and steroid medication after initial diagnosis, but was knowledgeable and self-motivated enough to consume a low-carbohydrate ketogenic diet consisting mostly of saturated fats, minimal vegetables, and a variety of meats. The patient used the glucose ketone index calculator to maintain his Glucose Ketone Index (GKI) near 2.0 without body weight loss.

Results: The tumor continued to grow slowly without expected vasogenic edema until 2017, when the patient opted for surgical debulking. The enhancing area, centered in the inferior frontal gyrus, was surgically excised. The pathology specimen confirmed IDH1-mutant GBM. Following surgery, the patient continued with a self-administered ketogenic diet to maintain low GKI values, indicative of therapeutic ketosis. At the time of this report (May 2021), the patient remains alive with a good quality of life, except for occasional seizures. MRI continues to show slow interval progression of the tumor.

Conclusion: This is the first report of confirmed IDH1-mutant GBM treated with KMT and surgical debulking without chemo- or radiotherapy. The long-term survival of this patient, now at 80 months, could be due in part to a therapeutic metabolic synergy between KMT and the IDH1 mutation that simultaneously target the glycolysis and glutaminolysis pathways that are essential for GBM growth. Further studies are needed to determine if this non-toxic therapeutic strategy could be effective in providing long-term management for other GBM patients with or without IDH mutations.
Agreement of Single-Frequency Electrical Bioimpedance in the Evaluation of Fat Free Mass and Fat Mass in Peritoneal Dialysis Patients
Authors: Reis Nayrana Soares do Carmo , Vaninni Francieli Cristina Delatim , Silva Maryanne Zilli Canedo , de Oliveira Rogério Carvalho , Reis Fabrício Moreira , Costa Fabiana Lourenço , Martin Luis Cuadrado , Barretti Pasqual
Published: May 2021

Background: Protein-energy wasting is related to impairment of quality of life and lower survival of end-stage kidney disease (ESKD) patients. The evaluation of body composition, especially fat free mass (FFM) and fat mass (FM), is important for the prediction of outcomes in these individuals. The aim of this study was to compare the FFM and FM measurements obtained by single-frequency bioimpedance (SF-BIA) and by a multiple frequency bioimpedance (MF-BIA) device, using dual energy X-ray absorptiometry (DXA) peritoneal dialysis (PD) patients.

Methods: This was a cross-sectional study involving adult patients undergoing regular PD, in which we performed SF-BIA, MF-BIA, and DXA at the same visit. To compare the bioimpedance values with DXA, we used: Person correlation (r), intraclass correlation coefficient (ICC), and Bland-Altman concordance analysis.

Results: The sample consisted of 50 patients in the PD, with mean age of 55.1 ± 16.3 years. Both bioimpedance methods showed a strong correlation (r > 0.7) and excellent reproducibility (ICC > 0.75) compared to DXA. According to the Bland-Altman diagram, SF-BIA showed agreement in body compartment measurements, with no proportionality bias (p > 0.05), without systematic bias for FFM (−0.5 ± 4.9, 95% CI −1.8 to 0.9, p = 0.506), and for FM (0.3 ± 4.6, p = 0.543). MF-BIA did not present a proportionality bias for the FFM, but it underestimated this body compartment by 2.5 ± 5.4 kg (p = 0.002). In addition, MF-BIA presented proportionality bias for FM.

Conclusion: SF-BIA was a more accurate assessing method than MBIA for FFM and FM measurements in PD patients. Because it is a low-cost, non-evaluator-dependent measurement and has less systematic bias, it can also be recommended for fat mass and free-fat mass evaluation in PD patients.
The Efficacy and Safety of Hypofractionated Radiation Therapy With Tomotherapy for Advanced or Recurrent Hepatocellular Carcinoma
Authors: Shen Jie , Yan Jing , Zhu Sihui , Kong Weiwei , Zou Zhengyun , Liu Juan , Li Shuangshuang , Liu Baorui
Published: May 2021

The effects of radiotherapy on hepatocellular carcinoma (HCC) still remain to be further proved. The dose of radiotherapy is generally 2Gy*25f. In the current study, we prospectively investigated the clinical outcomes of advanced or recurrent HCC patients who received hypofractionated radiotherapy at a dose of 5Gy*10f with tomotherapy. A study involving hypofractionated radiotherapy (5Gy*10f) based on TOMO was conducted in HCC patients with Child-Pugh grade A or B who were unsuitable candidates for resection or radiofrequency ablation or with residual disease after transarterial chemoembolization (TACE). The prescription dose was 50 grays in 10 fractions. From Sep. 2016 and Dec. 2017, 65 patents were evaluated with a median follow-up of 24 months (range: 7–41 months). 10 patients were treatment-naïve (failure to undergo surgery or intervention due to the presence of a portal or portal branch tumor thrombus), 15 patients were treated for residual HCC after TACE as salvage therapy, and 40 cases were treated for recurrent HCC. The median overalls survival (OS) of these patients was 18 months. Among them, 27 patients classified as BCLC stage B had a median OS of 22 months. Moreover, 28 patients classified as BCLC stage C had a median OS of 14 months. None of the patients experienced recurrence in the area of radiotherapy. The local control rate of primary tumor at 3 months, 6 months, 1 year and 2 years was 100%. The 3-month survival rate was 100%, the 6-month survival rate was 100%, the 1-year survival rate was 75.4%, and the 2-year survival rate was 43%. In addition, 14 patients had the opportunity to continue the treatment of PD-1 antibody after the disease progression, and their prognosis was not surprisingly better compared with the patients who did not receive PD-1 antibody treatment (NR vs. 15 months, P=0.04). No serious side effect was found in all patients during and after radiotherapy. Hypofractionated radiotherapy (5Gy*10f) based on TOMO achieved high local control rate and OS with tolerable toxicities for HCC patients. TOMO therapy could be used to effectively against HCC in treatment-naive, intrahepatic failure, residual disease, and recurrent settings.
Identification of Genes Related to Immune Infiltration in the Tumor Microenvironment of Cutaneous Melanoma
Authors: Qin Rujia , Peng Wen , Wang Xuemin , Li Chunyan , Xi Yan , Zhong Zhaoming , Sun Chuanzheng
Published: May 2021

Cutaneous melanoma (CM) is the leading cause of skin cancer deaths and is typically diagnosed at an advanced stage, resulting in a poor prognosis. The tumor microenvironment (TME) plays a significant role in tumorigenesis and CM progression, but the dynamic regulation of immune and stromal components is not yet fully understood. In the present study, we quantified the ratio between immune and stromal components and the proportion of tumor-infiltrating immune cells (TICs), based on the ESTIMATE and CIBERSORT computational methods, in 471 cases of skin CM (SKCM) obtained from The Cancer Genome Atlas (TCGA) database. Differentially expressed genes (DEGs) were analyzed by univariate Cox regression analysis, least absolute shrinkage, and selection operator (LASSO) regression analysis, and multivariate Cox regression analysis to identify prognosis-related genes. The developed prognosis model contains ten genes, which are all vital for patient prognosis. The areas under the curve (AUC) values for the developed prognostic model at 1, 3, 5, and 10 years were 0.832, 0.831, 0.880, and 0.857 in the training dataset, respectively. The GSE54467 dataset was used as a validation set to determine the predictive ability of the prognostic signature. Protein–protein interaction (PPI) analysis and weighted gene co-expression network analysis (WGCNA) were used to verify “real” hub genes closely related to the TME. These hub genes were verified for differential expression by immunohistochemistry (IHC) analyses. In conclusion, this study might provide potential diagnostic and prognostic biomarkers for CM.
Computertomography-Based Prediction of Complete Response Following Neoadjuvant Chemoradiotherapy of Locally Advanced Rectal Cancer
Authors: Maslova Marina , Herden Heinz , Schork Karin , Turewicz Michael , Eisenacher Martin , Schroers Roland , Baraniskin Alexander , Mika Thomas
Published: May 2021

Therapeutic strategies for patients with locally advanced rectal cancer (LARC) who are achieving a pathological complete response (pCR) after neoadjuvant radio-chemotherapy (neoCRT) are being increasingly investigated. Recent trials challenge the current standard therapy of total mesorectal excision (TME). For some patients, the treatment strategy of “watch-and-wait” seems a preferable procedure. The key factor in determining individual treatment strategies following neoCRT is the precise evaluation of the tumor response. Contrast-enhanced computer tomography (ceCT) has proven its ability to discriminate benign and malign lesions in multiple cancers. In this study, we retrospectively analyzed the ceCT based density of LARC in 30 patients, undergoing neoCRT followed by TME. We compared the tumors´ pre- and post-neoCRT density and correlated the results to the amount of residual vital tumor cells in the resected tissue. Overall, the density decreased after neoCRT, with the highest decrease in patients achieving pCR. Densitometry demonstrated a specificity of 88% and sensitivity of 68% in predicting pCR. Thus, we claim that ceCT based densitometry is a useful tool in identifying patients with LARC who may benefit from a “watch-and-wait” strategy and suggest further prospective studies.
Case Report: Rechallenge With BRAF and MEK Inhibitors in Metastatic Melanoma: A Further Therapeutic Option in Salvage Setting?
Authors: Stagno Anna , Vari Sabrina , Annovazzi Alessio , Anelli Vincenzo , Russillo Michelangelo , Cognetti Francesco , Ferraresi Virginia
Published: May 2021

Background

The combination of BRAF and MEK inhibitors represents the standard of care treatment for patients with metastatic BRAF-mutated melanoma, notwithstanding the high frequency of emergent resistance. Moreover, therapeutic options outside clinical trials are scarce when patients have progressed after both targeted therapy and therapy with immune checkpoint inhibitors. In this article, we report our experience with targeted therapy rechallenging with BRAF and MEK inhibitors in patients with metastatic BRAF-mutated melanoma after progression with kinase inhibitors and immunotherapy.

Methods

Four patients with metastatic BRAF-mutated melanoma were rechallenged with BRAF and MEK inhibitors after progression with targeted therapy and subsequent immunotherapy (checkpoint inhibitors).

Results

Two patients (one of them was heavily pretreated) had partial response over 36 months (with local treatment on oligoprogression disease) and 10 months, respectively. A third patient with multisite visceral disease and high serum levels of lactate dehydrogenase had a short-lived clinical benefit rapidly followed by massive progression of disease (early progressor). The fourth patient, currently on treatment with BRAF/MEK inhibitors, is showing a clinical benefit and radiological stable disease over 3 months of therapy. Adverse events were manageable, similar to those reported during the first targeted therapy; the treatment was better tolerated at rechallenge compared with the first treatment by two out of four patients.
GRK6 Depletion Induces HIF Activity in Lung Adenocarcinoma
Authors: Yao Sumei , Ertay Ayse , Zhou Yilu , Yao Liudi , Hill Charlotte , Chen Jinliang , Guan Yangbo , Sun Hui , Ewing Rob M. , Liu Yifei , Lv Xuedong , Wang Yihua
Published: May 2021

G protein-coupled receptor kinase 6 (GRK6) is expressed in various tissues and is involved in the development of several diseases including lung cancer. We previously reported that GRK6 is down-regulated in lung adenocarcinoma patients, which induces cell invasion and metastasis. However, further understanding of the role of GRK6 in lung adenocarcinoma is required. Here we explored the functional consequence of GRK6 inhibition in lung epithelial cells. Analysis of TCGA data was coupled with RNA sequencing (RNA-seq) in alveolar epithelial type II (ATII) cells following depletion of GRK6 with RNA interference (RNAi). Findings were validated in ATII cells followed by tissue microarray analysis. Pathway analysis suggested that one of the Hallmark pathways enriched upon GRK6 inhibition is ‘Hallmark_Hypoxia’ (FDR = 0.014). We demonstrated that GRK6 depletion induces HIF1α (hypoxia-inducible factor 1 alpha) levels and activity in ATII cells. The findings were further confirmed in lung adenocarcinoma samples, in which GRK6 expression levels negatively and positively correlate with HIF1α expression (P = 0.015) and VHL expression (P < 0.0001), respectively. Mechanistically, we showed the impact of GRK6 on HIF activity could be achieved via regulation of VHL levels. Taken together, targeting the HIF pathway may provide new strategies for therapy in GRK6-depleted lung adenocarcinoma patients.
Multiparametric MRI Features Predict the SYP Gene Expression in Low-Grade Glioma Patients: A Machine Learning-Based Radiomics Analysis
Authors: Xiao Zheng , Yao Shun , Wang Zong-ming , Zhu Di-min , Bie Ya-nan , Zhang Shi-zhong , Chen Wen-li
Published: May 2021

Purpose

Synaptophysin (SYP) gene expression levels correlate with the survival rate of glioma patients. This study aimed to explore the feasibility of applying a multiparametric magnetic resonance imaging (MRI) radiomics model composed of a convolutional neural network to predict the SYP gene expression in patients with glioma.

Method

Using the TCGA database, we examined 614 patients diagnosed with glioma. First, the relationship between the SYP gene expression level and outcome of survival rate was investigated using partial correlation analysis. Then, 7266 patches were extracted from each of the 108 low-grade glioma patients who had available multiparametric MRI scans, which included preoperative T1-weighted images (T1WI), T2-weighted images (T2WI), and contrast-enhanced T1WI images in the TCIA database. Finally, a radiomics features-based model was built using a convolutional neural network (ConvNet), which can perform autonomous learning classification using a ROC curve, accuracy, recall rate, sensitivity, and specificity as evaluation indicators.

Results

The expression level of SYP decreased with the increase in the tumor grade. With regard to grade II, grade III, and general patients, those with higher SYP expression levels had better survival rates. However, the SYP expression level did not show any significant association with the outcome in Level IV patients.

Conclusion

Our multiparametric MRI radiomics model constructed using ConvNet showed good performance in predicting the SYP gene expression level and prognosis in low-grade glioma patients.