bluuebunny/crossref_metadata_2025 huggingface dataset:
Maternal Smoking Leads to Larger Cleft Palate Defects
Authors: Lacerda Rosa Helena Wanderley , Furtado Paulo Germano Cavalcanti , Vieira Alexandre Rezende
Published: January 2021

Background: Oral clefts are birth defects that affect 500–1,000 livebirths depending on the geographic area. Maternal smoking increases the risk of stillbirths, prematurity, low birth weight, and oral clefts.

Methods: In this case series, we measured the cleft palate defect of 10 children born from mothers who smoked during pregnancy and compared with measurements of 36 children born from mothers who did not smoke.

Results: Palate defects tended to be larger in the group that the mother smoked during pregnancy.

Conclusion: Smoking during pregnancy aggravates the size of the cleft defect in the palate.
Activity and Stability of Oxides During Oxygen Evolution Reaction‐‐‐From Mechanistic Controversies Toward Relevant Electrocatalytic Descriptors
Authors: Zeradjanin Aleksandar R. , Masa Justus , Spanos Ioannis , Schlögl Robert
Published: January 2021

Plotting the roadmap of future “renewable energy highway” requires drastic technological advancement of devices like electrolyzers and fuel cells. Technological breakthrough is practically impossible without advanced fundamental understanding of interfacial energy conversion processes, including electrocatalytic water splitting. Particularly challenging is the oxygen evolution reaction which imposes high demands on the long-term activity of electrocatalysts and electrode support materials. To cross the “Rubicon” and in a deterministic manner claim that we developed principles of rational catalyst design, we need first to comprehend the determinants of electrocatalytic activity as well as character of their time evolution. How reliable are reported activity and stability trends, could we interrelate activity and stability, and how meaningful that relation really is are some of the important questions that have to be tackled in building of a more comprehensive view on critically important anodic oxygen evolution.
Assessment of Subsampling Strategies in Microspectroscopy of Environmental Microplastic Samples
Authors: Brandt Josef , Fischer Franziska , Kanaki Elisavet , Enders Kristina , Labrenz Matthias , Fischer Dieter
Published: January 2021

The analysis of environmental occurrence of microplastic (MP) particles has gained notable attention within the past decade. An effective risk assessment of MP litter requires elucidating sources of MP particles, their pathways of distribution and, ultimately, sinks. Therefore, sampling has to be done in high frequency, both spatially and temporally, resulting in a high number of samples to analyze. Microspectroscopy techniques, such as FTIR imaging or Raman particle measurements allow an accurate analysis of MP particles regarding their chemical classification and size. However, these methods are time-consuming, which gives motivation to establish subsampling protocols that require measuring less particles, while still obtaining reliable results. The challenge regarding the subsampling of environmental MP samples lies in the heterogeneity of MP types and the relatively low numbers of target particles. Herein, we present a comprehensive assessment of different proposed subsampling methods on a selection of real-world samples from different environmental compartments. The methods are analyzed and compared with respect to resulting MP count errors, which eventually allows giving recommendations for staying within acceptable error margins. Our results are based on measurements with Raman microspectroscopy, but are applicable to any other analysis technique. We show that the subsampling-errors are mainly due to statistical counting errors (i.e., extrapolation from low numbers) and only in edge cases additionally impacted by inhomogeneous distribution of particles on the filters. Keeping the subsampling-errors low can mainly be realized by increasing the fraction of MP particles in the samples.
Identification of Key Modules and Hub Genes of Annulus Fibrosus in Intervertebral Disc Degeneration
Authors: Wang Hantao , Liu Wenhui , Yu Bo , Yu Xiaosheng , Chen Bin
Published: January 2021

Background: Intervertebral disc degeneration impairs the quality of patients lives. Even though there has been development of many therapeutic strategies, most of them remain unsatisfactory due to the limited understanding of the mechanisms that underlie the intervertebral disc degeneration.

Questions/purposes: This study is meant to identify the key modules and hub genes related to the annulus fibrosus in intervertebral disc degeneration (IDD) through: (1) constructing a weighted gene co-expression network; (2) identifying key modules and hub genes; (3) verifying the relationships of key modules and hub genes with IDD; and (4) confirming the expression pattern of hub genes in clinical samples.

Methods: The Gene Expression Omnibus provided 24 sets of annulus fibrosus microarray data. Differentially expressed genes between the annulus fibrosus of degenerative and non-degenerative intervertebral disc samples have gone through the Gene Ontology (GO) and pathway analysis. The construction of a gene network and classification of genes into different modules were conducted through performing Weighted Gene Co-expression Network Analysis. The identification of modules and hub genes that were most related to intervertebral disc degeneration was proceeded. In order to verify the relationships of the module and hub genes with intervertebral disc degeneration, Ingenuity Pathway Analysis was operated. Clinical samples were adopted to help verify the hub gene expression profile.

Results: One thousand one hundred ninety differentially expressed genes were identified. Terms and pathways associated with intervertebral disc degeneration were presented by GO and pathway analysis. The construction of a Weighted Gene Coexpression Network was completed and clustering differentially expressed genes into four modules was also achieved. The module with the lowest P-value and the highest absolute correlation coefficient was selected and its relationship with intervertebral disc degeneration was confirmed by Ingenuity Pathway Analysis. The identification of hub genes and the confirmation of their expression profile were also realized.

Conclusions: This study generated a comprehensive overview of the gene networks underlying annulus fibrosus in intervertebral disc degeneration.

Clinical Relevance: Modules and hub genes identified in this study are highly associated with intervertebral disc degeneration, and may serve as potential therapeutic targets for intervertebral disc degeneration.
Decitabine Induces Change of Biological Traits in Myelodysplastic Syndromes via FOXO1 Activation
Authors: Zhang Zheng , Jia Yan , Xv Feng , Song Lu-xi , Shi Lei , Guo Juan , Chang Chun-kang
Published: January 2021

Decitabine (DAC) is considered to be a profound global DNA demethylation, which can induce the re-expression of silenced tumor suppressor genes. Little is known about the function of tumor suppressor gene FOXO1 in myelodysplastic syndromes (MDS). To address this issue, the study firstly investigated differentially expressed genes (DEGs) for DAC treatment in MDS cell lines, then explored the role of FOXO1 through silencing its expression before DAC treatment in MDS. The results showed that FOXO1 exists in a hyperphosphorylated, inactive form in MDS-L cells. DAC treatment both induces FOXO1 expression and reactivates the protein in its low phosphorylation level. Additionally, the results also demonstrated that this FOXO1 activation is responsible for the DAC-induced apoptosis, cell cycle arrest, antigen differentiation, and immunoregulation in MDS-L cells. We also demonstrated DAC-induced FOXO1 activation upregulates anti-tumor immune response in higher-risk MDS specimens. Collectively, these results suggest that DAC induces FOXO1 activation, which plays an important role in anti-MDS tumors.
Emerging Technologies for Genome-Wide Profiling of DNA Breakage
Authors: Rybin Matthew J. , Ramic Melina , Ricciardi Natalie R. , Kapranov Philipp , Wahlestedt Claes , Zeier Zane
Published: January 2021

Genome instability is associated with myriad human diseases and is a well-known feature of both cancer and neurodegenerative disease. Until recently, the ability to assess DNA damage—the principal driver of genome instability—was limited to relatively imprecise methods or restricted to studying predefined genomic regions. Recently, new techniques for detecting DNA double strand breaks (DSBs) and single strand breaks (SSBs) with next-generation sequencing on a genome-wide scale with single nucleotide resolution have emerged. With these new tools, efforts are underway to define the “breakome” in normal aging and disease. Here, we compare the relative strengths and weaknesses of these technologies and their potential application to studying neurodegenerative diseases.
Identification of Functional lncRNAs Associated With Ovarian Endometriosis Based on a ceRNA Network
Authors: Bai Jian , Wang Bo , Wang Tian , Ren Wu
Published: January 2021

Background

Endometriosis is a common gynecological disease affecting women of reproductive age; however, the mechanisms underlying this condition are not fully clear. The aim of this study was to identify functional long non-coding RNAs (lncRNAs) associated with ovarian endometriosis for potential use as biomarkers and therapeutic targets.

Methods

RNA-seq profiles of paired ectopic (EC) and eutopic (EU) endometrial samples from patients with ovarian endometriosis were downloaded from the publicly available Gene Expression Omnibus (GEO) database. Bioinformatics algorithms were used to construct a network of ovarian endometriosis-related competing endogenous RNAs (ceRNAs) and to detect functional lncRNAs.

Results

A total of 4,213 mRNAs, 1,474 lncRNAs, and 221 miRNAs were identified as being differentially expressed between EC and EU samples, and an ovarian endometriosis-related ceRNA network was constructed through analysis of these differentially expressed RNAs. H19 and GS1-358P8.4 were identified as key ovarian endometriosis-related lncRNAs through topological feature analysis, and RP11-96D1.10 was identified using a random walk with restart algorithm.

Conclusion

Based on bioinformatics analysis of a ceRNA network, we identified the lncRNAs H19, GS1-358P8.4, and RP11-96D1.10 as being strongly associated with ovarian endometriosis. These three lncRNAs hold potential as targets for medical therapy and as diagnostic biomarkers. Further studies are needed to elucidate the detailed biological function of these lncRNAs in the pathogenesis of endometriosis.
The Complex Role of Regulatory T Cells in Immunity and Aging
Authors: Rocamora-Reverte Lourdes , Melzer Franz Leonard , Würzner Reinhard , Weinberger Birgit
Published: January 2021

The immune system is a tightly regulated network which allows the development of defense mechanisms against foreign antigens and tolerance toward self-antigens. Regulatory T cells (Treg) contribute to immune homeostasis by maintaining unresponsiveness to self-antigens and suppressing exaggerated immune responses. Dysregulation of any of these processes can lead to serious consequences. Classically, Treg cell functions have been described in CD4+T cells, but other immune cells also harbour the capacity to modulate immune responses. Regulatory functions have been described for different CD8+T cell subsets, as well as other T cells such as γδT cells or NKT cells. In this review we describe the diverse populations of Treg cells and their role in different scenarios. Special attention is paid to the aging process, which is characterized by an altered composition of immune cells. Treg cells can contribute to the development of various age-related diseases but they are poorly characterized in aged individuals. The huge diversity of cells that display immune modulatory functions and the lack of universal markers to identify Treg make the expanding field of Treg research complex and challenging. There are still many open questions that need to be answered to solve the enigma of regulatory T cells.
High-Sensitivity Refractive Index Sensor Based on a Cascaded Core-Offset and Macrobending Single-Mode Fiber Interferometer
Authors: Teng Chuanxin , Zhu Yongjie , Yu Fangda , Deng Shijie , Yuan Libo , Zheng Jie , Cheng Yu
Published: January 2021

A high-sensitivity Mach–Zehnder interferometer (MZI) based on the cascaded core-offset and macrobending fiber structure is proposed for refractive index (RI) measurement. The core-offset structure makes the fiber core mode couple to the cladding modes, and some of them recouple back to the fiber core at the macrobending structure forming a model interference effect. The liquid RI can be measured by monitoring the spectral shift of the modal interference. The RI sensing performances for the interferometers with different macrobending radii and core offsets are investigated experimentally. Experimental results show that when the core offset is 2 μm and the macrobending radius is 5.5 mm, the sensitivity can reach 699.95 nm/RIU for the RI of 1.43. The temperature dependence for the proposed sensor is also tested, and a temperature sensitivity of 0.112 nm/°C is obtained.
Directional Control of Rayleigh Wave Propagation in an Elastic Lattice by Gyroscopic Effects
Authors: Nieves M. J. , Carta G. , Pagneux V. , Brun M.
Published: January 2021

We discuss the propagation of Rayleigh waves at the boundary of a semi-infinite elastic lattice connected to a system of gyroscopic spinners. We present the derivation of the analytical solution of the equations governing the system when the lattice is subjected to a force acting on the boundary. We show that the analytical results are in excellent agreement with the outcomes of independent finite element simulations. In addition, we investigate the influence of the load direction, frequency and gyroscopic properties of the model on the dynamic behavior of the micro-structured medium. The main result is that the response of the forced discrete system is not symmetric with respect to the point of application of the force when the effect of the gyroscopic spinners is taken into account. Accordingly, the gyroscopic lattice represents an important example of a non-reciprocal medium. Hence, it can be used in practical applications to split the energy coming from an external source into different contributions, propagating in different directions.
Setal Field Transects, Evolutionary Transitions and Gecko–Anole Convergence Provide Insights Into the Fundamentals of Form and Function of the Digital Adhesive System of Lizards
Authors: Russell Anthony P. , Garner Austin M.
Published: January 2021

Recent years have witnessed a multitude of studies focusing on gekkotan adhesion. Intense interest in this phenomenon was triggered by the discovery of the manner and magnitude of the forces generated by the hair-like filaments (setae) on the toe pads and inspired the development of the next generation of smart, reversible synthetic adhesives. Most studies pursuing these goals have concentrated on the generalized form and properties of gekkotan setae outlined in those key early studies, resulting in the fabrication of synthetic filaments of uniform dimensions. Although there are over 1,800 species of extant geckos, and hundreds of species of anoles (a separate lizard lineage that has convergently evolved adhesive toe pads), most investigations have used relatively few species as the source of basic information, the Tokay gecko (Gekko gecko) being the most prominent among these. Such exemplar taxa generally exhibit structurally intricate setae and morphologically complex configurations of the adhesive apparatus. Setal structure taken to be characteristic of these taxa is generally reported by singular statements of maximal length, diameter, density and branching pattern. Contemporaneous work focusing on the configuration of setae at locations across the toe pads and upon the evolutionary origin of adhesively competent digits in anoles and specific lineages of geckos, however, has revealed extensive variation of setal structure within individuals, information about how setae may have arisen from non-adhesive filamentous precursors, and how newly adhesively competent digits have been integrated into pre-existing patterns of locomotor mechanics and kinematics. Such observations provide insights into what is minimally necessary for adhesively competent digits to function and reveal the simplest configuration of components that make this possible. We contend that information gleaned from such studies will assist those seeking to employ the principles of fibrillar-based adhesion, as exemplified by lizards, for bio-inspired applications.
“Push and Pull”: Biomechanics of the Pollination Apparatus of Oncidium spp.
Authors: Thielen Marc , Voigt Dagmar , Gallenmüller Friederike , Speck Thomas , Gorb Stanislav
Published: January 2021

Comprising ca. 28,000, species the Orchidaceae constitute one of the most species-rich plant families. Orchids differ from other monocotyledons i.a., in the formation of so-called pollinaria, which are entities consisting of pollen grains aggregated into compact pollinia and accessory structures, a viscidium and mostly also a pollinium stalk. The viscidium releases an adhesive material that attaches the pollinarium to a pollinator. Pollinaria are part of a complex pollination apparatus that enables the orchids to colonize niches in which only a few individuals of the respective pollinator occur infrequently. Because the aggregated pollen grains are removed from the flower at once, the development of a mechanical barrier ensuring that only suitable pollinators are able to access the flowers and more importantly to remove the pollen are important selective traits. In this paper we describe the functional morphology of the pollination apparatus in two orchid species,Oncidium wentworthianumandO. otogaya, by experimentally mimicking the pollination process. Furthermore, we analyzed the mechanical resistance of this apparatus by means of force measurements and showed that it most probably constitutes a hierarchical two-stage barrier. The first stage consists of the presence of the anther cap that not only protects the pollinia, but also serves to prevent premature removal of young and unripe pollinaria from the flower. As soon as the pollinaria are ripe, the anther cap sheds and the second stage of the mechanical barrier takes effect, a severable bond between pollinarium and rostellum. This bond can be overcome by a potential pollinator, applying a load of at least 10.8 mN (O. otogaya) or 12.6 mN (O. wentworthianum), respectively, on the viscidium which at the same time disengages the pollinarium from its anchorage. The adhesive material produced by the viscidium creates sufficient adhesive contact between pollinarium and pollinator. Potential pollinators, such asCentrisspp. orTrigonaspp. bees, should be well able to exert such forces by pushing their head/forebody into the orchid flowers. Thus, whether a pollinator is able to detach the pollinarium depends on both how forcefully it can push and how strongly it can pull the orchid pollination apparatus.
Numeric Rating Scales Show Prolonged Post-exertional Symptoms After Orthostatic Testing of Adults With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Authors: van Campen C (Linda) M. C. , Rowe Peter C. , Verheugt Freek W. A. , Visser Frans C.
Published: January 2021

Introduction: Muscle pain, fatigue, and concentration problems are common among individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). These symptoms are commonly increased as part of the phenomenon of postexertional malaise (PEM). An increase in the severity of these symptoms is described following physical or mental exercise in ME/CFS patients. Another important symptom of ME/CFS is orthostatic intolerance, which can be detected by head-up tilt testing (HUT). The effect of HUT on PEM has not been studied extensively. For this purpose, we assessed numeric rating scales (NRS) for pain, fatigue, and concentration pre- and post-HUT. As pain is a core symptom in fibromyalgia (FM), we subgrouped ME/CFS patients by the presence or absence of FM.

Methods and Results: In eligible ME/CFS patients who underwent HUT, NRS of pain, fatigue, and concentration were obtained pre-HUT, immediately after HUT, at 24 and 48 h, and at 7 days posttest. We studied 174 ME/CFS patients with FM, 104 without FM, and 30 healthy controls (HC). Values for all symptoms were unchanged for HC pre- and post-HUT. Compared with pre-HUT, the three NRS post-HUT were significantly elevated in both ME/CFS patient groups even after 7 days. NRS pain was significantly higher at all time points measured in the ME/CFS patients with FM compared with those without FM. In ME/CFS patients, the maximum fatigue and concentration scores occurred directly post-HUT, whereas pain perception reached the maximum 24 h post-HUT.

Conclusion: NRS scores of pain, fatigue, and concentration were significantly increased even at 7 days post-HUT compared with pre-HUT in ME/CFS patients with and without FM, suggesting that orthostatic stress is an important determinant of PEM.
Functional Exhaustion of Type I and II Interferons Production in Severe COVID-19 Patients
Authors: Ruetsch Caroline , Brglez Vesna , Crémoni Marion , Zorzi Kévin , Fernandez Céline , Boyer-Suavet Sonia , Benzaken Sylvia , Demonchy Elisa , Risso Karine , Courjon Johan , Cua Eric , Ichai Carole , Dellamonica Jean , Passeron Thierry , Seitz-Polski Barbara
Published: January 2021

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged in Wuhan in December 2019 and has since spread across the world. Even though the majority of patients remain completely asymptomatic, some develop severe systemic complications. In this prospective study we compared the immunological profile of 101 COVID-19 patients with either mild, moderate or severe form of the disease according to the WHO classification, as well as of 50 healthy subjects, in order to identify functional immune factors independently associated with severe forms of COVID-19. Plasma cytokine levels, and cytokine levels upon in vitro non-specific stimulation of innate and adaptive immune cells, were measured at several time points during the course of the disease. As described previously, inflammatory cytokines IL1β, IL6, IL8, and TNFα associated with cytokine storm were significantly increased in the plasma of moderate and severe COVID-19 patients (p < 0.0001 for all cytokines). During follow-up, plasma IL6 levels decreased between the moment of admission to the hospital and at the last observation carried forward for patients with favorable outcome (p = 0.02148). After in vitro stimulation of immune cells from COVID-19 patients, reduced levels of both type I and type II interferons (IFNs) upon in vitro stimulation were correlated with increased disease severity [type I IFN (IFNα): p > 0.0001 mild vs. moderate and severe; type II IFN (IFNγ): p = 0.0002 mild vs. moderate and p < 0.0001 mild vs. severe] suggesting a functional exhaustion of IFNs production. Stimulated IFNα levels lower than 2.1 pg/ml and IFNγ levels lower than 15 IU/mL at admission to the hospital were associated with more complications during hospitalization (p = 0.0098 and p =0.0002, respectively). A low IFNγ level was also confirmed by multivariable analysis [p = 0.0349 OR = 0.98 (0.962; 0.999)] as an independent factor of complications. In vitro treatment with type IFNα restored type IFNγ secretion in COVID-19 patients while the secretion of pro-inflammatory cytokines IL6 and IL1β remained stable or decreased, respectively. These results (a) demonstrate a functional exhaustion of both innate and adaptive immune response in severe forms of COVID-19; (b) identify IFNα and IFNγ as new potential biomarkers of severity; and (c) highlight the importance of targeting IFNs when considering COVID-19 treatment in order to re-establish a normal balance between inflammatory and Th1 effector cytokines.
Humoral and Cellular Response of Frontline Health Care Workers Infected by SARS-CoV-2 in Nice, France: A Prospective Single-Center Cohort Study
Authors: Cremoni Marion , Ruetsch Caroline , Zorzi Kévin , Fernandez Céline , Boyer-Suavet Sonia , Benzaken Sylvia , Demonchy Elisa , Dellamonica Jean , Ichai Carole , Esnault Vincent , Brglez Vesna , Seitz-Polski Barbara
Published: January 2021

Frontline health care workers (HCWs) have been particularly exposed to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) since the start of the pandemic but the clinical features and immune responses of those infected with SARS-CoV-2 have not been well described. In a prospective single center cohort study, we enrolled 196 frontline HCWs exposed to the SARS-Cov-2 and 60 patients with moderate and severe forms of the coronavirus disease 2019 (COVID-19). Serological tests and cytokines assay were performed to analyze SARS-CoV-2-specific humoral and cellular immunity. Of the 196 HCWs tested, 15% had specific antibodies against SARS-CoV-2 and 45% of seropositive HCWs were strictly asymptomatic. However, in comparison to moderate and severe forms, HCWs with mild or asymptomatic forms of COVID-19 showed lower specific IgA and IgG peaks, consistent with their mild symptoms, and a robust immune cellular response, illustrated by a high production of type I and II interferons. Further studies are needed to evaluate whether this interferon functional immune assay, routinely applicable, can be useful in predicting the risk of severe forms of COVID-19.
Association of Viral Load in SARS-CoV-2 Patients With Age and Gender
Authors: Mahallawi Waleed H. , Alsamiri Ali Dakhilallah , Dabbour Alaa Faisal , Alsaeedi Hamdah , Al-Zalabani Abdulmohsen H.
Published: January 2021

Background: The coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is a global public health emergency. Age and sex are two important factors associated with risks and outcomes of various diseases. COVID-19 morbidity also seems to be affected by patient age and sex. It has been found that older age groups have more severe COVID-19 symptoms and higher fatality rates while children tend to have lower prevalence and milder symptoms than adults.

Methods: The study reviewed electronic medical records of COVID-19 patients from Madinah city, Saudi Arabia. The study included all cases who tested positive (n = 3,006) between March 20 and May 22, 2020. Data were obtained from the Health Electronic Surveillance Network (HESN) database.

Results: Approximately 80% of the study sample were males and half were in the 30–40-year-old age group. The Ct value of the whole sample ranged from 15.08 to 35, with a mean of 27.44 (SD: 5.23; 95% C.I. = 27.25–27.66). The means of Ct values varied between age groups from 27.05 to 27.82. Analysis of the mean differences between age groups using one-way ANOVA indicated no statistically significant difference among the groups (F6,2999 = 1.63; p-value = 0.135). A comparison of mean Ct values of males (n = 2,422) and females (n = 584) revealed that males had a statistically significant higher mean Ct value (27.61 ± 5.20) than females (26.72 ± 5.31). The difference between the means of the two groups was −0.89 (95% C.I. = −1.36 to −0.42; t-test −3.71; df = 3,004; p-value < 0.001).

Conclusion: The study found no statistically significant difference in viral loads between age groups. It showed that females had a higher SARS-CoV-2 viral load compared to males. The findings have implications for preventive strategies. Further studies are needed to correlate viral load with clinical symptoms and outcomes.
Immunologic “Cold” Squamous Cell Carcinomas of the Head and Neck Are Associated With an Unfavorable Prognosis
Authors: Ribbat-Idel Julika , Perner Sven , Kuppler Patrick , Klapper Luise , Krupar Rosemarie , Watermann Christian , Paulsen Finn-Ole , Offermann Anne , Bruchhage Karl-Ludwig , Wollenberg Barbara , Idel Christian
Published: January 2021

Background: Head and neck squamous cell carcinoma (HNSCC) represents a common cancer worldwide. Past therapeutic advances have not significantly improved HNSCC prognosis. Therefore, it is necessary to further stratify HNSCC, especially with recent advances in tumor immunology.

Methods: Tissue microarrays were assembled from tumor tissue samples and were complemented with comprehensive clinicopathological data of n = 419 patients. H&E whole slides from resection specimen (n = 289) were categorized according to their immune cell infiltrate as “hot,” “cold,” or “excluded.”

Results: Investigating tumor immune cell patterns, we found significant differences in survival rates. Immunologic “hot” and “excluded” HNSCCs are associated with better overall survival than “cold” HNSCC patients (p < 0.05). Interestingly, the percentage of all three patterns is nearly identical in p16 positive and negative HNSCCs.

Conclusions: Using a plain histological H&E approach to categorize HNSCC as being immunologic “hot,” “cold,” or “excluded” can offer a forecast of patients' prognosis and may thus aid as a potential prognostic tool in routine pathology reports. This “hot-cold-excluded” scheme needs to be applied to more HNSCC cohorts and possibly to other cancer types to determine prognostic meaning, e.g., regarding OS or DFS. Furthermore, our cohort reflects epidemiological data in the national, European, and international context. It may, therefore, be of use for future HNSCC characterization.
Cell Cycle, Filament Growth and Synchronized Cell Division in Multicellular Cable Bacteria
Authors: Geerlings Nicole M. J. , Geelhoed Jeanine S. , Vasquez-Cardenas Diana , Kienhuis Michiel V. M. , Hidalgo-Martinez Silvia , Boschker Henricus T. S. , Middelburg Jack J. , Meysman Filip J. R. , Polerecky Lubos
Published: January 2021

Cable bacteria are multicellular, Gram-negative filamentous bacteria that display a unique division of metabolic labor between cells. Cells in deeper sediment layers are oxidizing sulfide, while cells in the surface layers of the sediment are reducing oxygen. The electrical coupling of these two redox half reactions is ensured via long-distance electron transport through a network of conductive fibers that run in the shared cell envelope of the centimeter-long filament. Here we investigate how this unique electrogenic metabolism is linked to filament growth and cell division. Combining dual-label stable isotope probing (13C and 15N), nanoscale secondary ion mass spectrometry, fluorescence microscopy and genome analysis, we find that the cell cycle of cable bacteria cells is highly comparable to that of other, single-celled Gram-negative bacteria. However, the timing of cell growth and division appears to be tightly and uniquely controlled by long-distance electron transport, as cell division within an individual filament shows a remarkable synchronicity that extends over a millimeter length scale. To explain this, we propose the “oxygen pacemaker” model in which a filament only grows when performing long-distance transport, and the latter is only possible when a filament has access to oxygen so it can discharge electrons from its internal electrical network.
Functional Network Profiles in ARSACS Disclosed by Aptamer-Based Proteomic Technology
Authors: Morani Federica , Doccini Stefano , Chiorino Giovanna , Fattori Fabiana , Galatolo Daniele , Sciarrillo Elisa , Gemignani Federica , Züchner Stephan , Bertini Enrico Silvio , Santorelli Filippo Maria
Published: January 2021

Although the genetic basis of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) has been uncovered, our poor understanding of disease mechanisms requires new light on functional pathways and modifying factors to improve early diagnostic strategies and offer alternative treatment options in a rare condition with no cure. Investigation of the pathologic state combining disease models and quantitative omic approach might improve biomarkers discovery with possible implications in patients' diagnoses. In this study, we analyzed proteomics data obtained using the SomaLogic technology, comparing cell lysates from ARSACS patients and from a SACS KO SH-SY5Y neuroblastoma cell model. Single-stranded deoxyoligonucleotides, selected in vitro from large random libraries, bound and quantified molecular targets related to the neuroinflammation signaling pathway and to neuronal development. Changes in protein levels were further analyzed by bioinformatics and network approaches to identify biomarkers of ARSACS and functional pathways impaired in the disease. We identified novel significantly dysregulated biological processes related to neuroinflammation, synaptogenesis, and engulfment of cells in patients and in KO cells compared with controls. Among the differential expressed proteins found in this work, we identified several proteins encoded by genes already known to be mutated in other forms of neurodegeneration. This finding suggests that common dysfunctional networks could be therapeutic targets for future investigations.
The Error-Related Negativity Predicts Self-Control Failures in Daily Life
Authors: Overmeyer Rebecca , Berghäuser Julia , Dieterich Raoul , Wolff Max , Goschke Thomas , Endrass Tanja
Published: January 2021

Adaptive behavior critically depends on performance monitoring (PM), the ability to monitor action outcomes and the need to adapt behavior. PM-related brain activity has been linked to guiding decisions about whether action adaptation is warranted. The present study examined whether PM-related brain activity in a flanker task, as measured by electroencephalography (EEG), was associated with adaptive behavior in daily life. Specifically, we were interested in the employment of self-control, operationalized as self-control failures (SCFs), and measured using ecological momentary assessment. Analyses were conducted using an adaptive elastic net regression to predict SCFs from EEG in a sample of 131 participants. The model was fit using within-subject averaged response-locked EEG activity at each electrode and time point within an epoch surrounding the response. We found that higher amplitudes of the error-related negativity (ERN) were related to fewer SCFs. This suggests that lower error-related activity may relate to lower recruitment of interventive self-control in daily life. Altered cognitive control processes, like PM, have been proposed as underlying mechanisms for various mental disorders. Understanding how alterations in PM relate to regulatory control might therefore aid in delineating how these alterations contribute to different psychopathologies.
Case Report: Nutritional Examination of Weight Loss Treatment Using Kampo
Authors: Matsui Yutaka , Matsui Ikuko
Published: January 2021

Loss of appetite is a common symptom in patients with dementia, and if weight loss or difficulty eating occurs without subjective symptoms, the patient can easily become malnourished. There is also a close relationship between dementia and physical frailty, such as weight loss and muscle weakness, and thus early intervention to address frailty in patients with dementia is important. In this study, 3 patients with dementia who complained of loss of appetite and weight loss showed increases in body weight and muscle mass after taking Ninjin'yoeito. Ninjin'yoeito was found to be a potentially effective treatment option for physical frailty in patients with dementia.
Immune Cell Infiltration of the Primary Tumor Microenvironment Predicted the Treatment Outcome of Chemotherapy With or Without Bevacizumab in Metastatic Colorectal Cancer Patients
Authors: Wang Yixing , Dong Jun , Quan Qi , Liu Shousheng , Chen Xiuxing , Cai Xiuyu , Qiu Huijuan , Zhang Bei , Guo Guifang
Published: January 2021

Background

With the interest in cancer immunotherapy, it may be possible to combine immunotherapy with bevacizumab and chemotherapy. We evaluated whether tumor-infiltrating immune cells are associated with the efficacy of chemotherapy with or without bevacizumab for the treatment of metastatic colorectal cancer (mCRC).

Methods

This study enrolled mCRC patients on standard treatment with available detailed data and tumor tissue at Sun Yat-sen University Cancer Center between July 1, 2005, and October 1, 2017. CD3+ and CD8+ T cell densities examined by immunohistochemistry in both the tumor core (CT) and invasive margin (IM) were summed as the Immunoscore, and the CD8+/CD3+ T cell ratio was calculated. The predictive and prognostic efficacies of tumor-infiltrating immune cells for progression-free survival (PFS) and overall survival (OS) were analyzed with Kaplan-Meier and Cox analyses.

Results

The CD8+/CD3+ T cell ratio in the microenvironment was an independent prognostic factor for OS (28.12 mo vs. 16.56 mo, P = 0.017) among the 108 studied patients. In the chemotherapy only group, patients with a high Immunoscore had a high overall response rate (ORR, 40.0% vs. 60.0%, P = 0.022), those with a low CD8+/CD3+ T cell ratio in the microenvironment had a significantly longer PFS (8.64 mo vs. 6.01 mo, P = 0.017), and those with a high CD3+ T cell density in the CT had a longer OS (16.56 mo vs. 25.66 mo, P = 0.029). In the chemotherapy combined with bevacizumab group, patients with a higher CD8+ T cell density in the IM had a longer PFS (7.62 mo vs. 11.66 mo, P = 0.034) and OS (14.55 mo vs. 23.72 mo, P = 0.033).

Conclusion

Immune cells in primary tumors play an important role in predicting mCRC treatment efficacy. CD8 predicts the effect of bevacizumab plus chemotherapy, while CD3 and CD8/CD3 predict chemotherapy efficacy.
Water and Collagen Content Are High in Pancreatic Cancer: Implications for Quantitative Metabolic Imaging
Authors: Penet Marie-France , Kakkad Samata , Wildes Flonné , Bhujwalla Zaver M.
Published: January 2021

In magnetic resonance metabolic imaging, signal from the water content is frequently used for normalization to derive quantitative or semi-quantitative values of metabolites in vivo or ex vivo tumors and tissues. Ex vivo high-resolution metabolic characterization of tumors with magnetic resonance spectroscopy (MRS) provides valuable information that can be used to drive the development of noninvasive MRS biomarkers and to identify metabolic therapeutic targets. Variability in the water content between tumor and normal tissue can result in over or underestimation of metabolite concentrations when assuming a constant water content. Assuming a constant water content can lead to masking of differences between malignant and normal tissues both in vivo and ex vivo. There is a critical need to develop biomarkers to detect pancreatic cancer and to develop novel treatments. Our purpose here was to determine the differences in water content between pancreatic tumors and normal pancreatic tissue as well as other organs to accurately quantify metabolic differences when using the water signal for normalization. Our data identify the importance of factoring the differences in water content between tumors and organs. High-resolution proton spectra of tumors and pancreatic tissue extracts normalized to the water signal, assuming similar water content, did not reflect the significantly increased total choline observed in tumors in vivo without factoring the differences in water content. We identified significant differences in the collagen 1 content between Panc1 and BxPC3 pancreatic tumors and the pancreas that can contribute to the differences in water content that were observed.
Harnessing the Immune System Against Multiple Myeloma: Challenges and Opportunities
Authors: Yamamoto Leona , Amodio Nicola , Gulla Annamaria , Anderson Kenneth Carl
Published: January 2021

Multiple myeloma (MM) is an incurable malignancy of plasma cells that grow within a permissive bone marrow microenvironment (BMM). The bone marrow milieu supports the malignant transformation both by promoting uncontrolled proliferation and resistance to cell death in MM cells, and by hampering the immune response against the tumor clone. Hence, it is expected that restoring host anti-MM immunity may provide therapeutic benefit for MM patients. Already several immunotherapeutic approaches have shown promising results in the clinical setting. In this review, we outline recent findings demonstrating the potential advantages of targeting the immunosuppressive bone marrow niche to restore effective anti-MM immunity. We discuss different approaches aiming to boost the effector function of T cells and/or exploit innate or adaptive immunity, and highlight novel therapeutic opportunities to increase the immunogenicity of the MM clone. We also discuss the main challenges that hamper the efficacy of immune-based approaches, including intrinsic resistance of MM cells to activated immune-effectors, as well as the protective role of the immune-suppressive and inflammatory bone marrow milieu. Targeting mechanisms to convert the immunologically “cold” to “hot” MM BMM may induce durable immune responses, which in turn may result in long-lasting clinical benefit, even in patient subgroups with high-risk features and poor survival.
Consecutive Hypoalbuminemia Predicts Inferior Outcome in Patients With Diffuse Large B-Cell Lymphoma
Authors: Wei Xiaolei , Zheng Jingxia , Zhang Zewen , Liu Qiongzhi , Zhan Minglang , Huang Weimin , Chen Junjie , Wei Qi , Wei Yongqiang , Feng Ru
Published: January 2021

The prognostic value of albumin changes between diagnosis and end-of-treatment (EoT) in diffuse large B-cell lymphoma (DLBCL) remains unknown. We retrospectively analyzed 574 de novo DLBCL patients treated with R-CHOP from our and two other centers. All patients were divided into a training cohort (n = 278) and validation cohort (n = 296) depending on the source of the patients. Overall survival (OS) and progression-free survival (PFS) were analyzed by the method of Kaplan–Meier and Cox proportional hazard regression model. In the training cohort, 163 (58.6%) patients had low serum albumin at diagnosis, and 80 of them were present with consecutive hypoalbuminemia at EoT. Patients with consecutive hypoalbuminemia showed inferior OS and PFS (p = 0.010 and p = 0.079, respectively). Similar survival differences were also observed in the independent validation cohort (p = 0.006 and p = 0.030, respectively). Multivariable analysis revealed that consecutive hypoalbuminemia was an independent prognostic factor OS [relative risk (RR), 2.249; 95% confidence interval (CI), 1.441–3.509, p < 0.001] and PFS (RR, 2.001; 95% CI, 1.443–2.773, p < 0.001) in all DLBCL patients independent of IPI. In conclusion, consecutive hypoalbuminemia is a simple and effective adverse prognostic factor in patients with DLBCL, which reminds us to pay more attention to patients with low serum albumin at EoT during follow-up.
The E-Twenty-Six Family in Hepatocellular Carcinoma: Moving into the Spotlight
Authors: Zhang Tongyue , Liu Danfei , Wang Yijun , Sun Mengyu , Xia Limin
Published: January 2021

Hepatocellular carcinoma (HCC) is a major cause of morbidity and mortality worldwide. Although therapeutic strategies have recently advanced, tumor metastasis and drug resistance continue to pose challenges in the treatment of HCC. Therefore, new molecular targets are needed to develop novel therapeutic strategies for this cancer. E-twenty-six (ETS) transcription family has been implicated in human malignancies pathogenesis and progression, including leukemia, Ewing sarcoma, gastrointestinal stromal tumors. Recently, increasing studies have expanded its great potential as functional players in other cancers, including HCC. This review focuses primarily on the key functions and molecular mechanisms of ETS factors in HCC. Elucidating these molecular details may provide novel potential therapeutic strategies for cancers.
Pueraria tuberosa: A Review on Traditional Uses, Pharmacology, and Phytochemistry
Authors: Bharti Ram , Chopra Bhupinder Singh , Raut Sachin , Khatri Neeraj
Published: January 2021

Puerariatuberosa (Roxb. ex Willd.) DC. (Fabaceae), also known as Indian Kudzu (vidari kand), is a perennial herb distributed throughout India and other Asian countries. Traditionally, tuber and leaves of this plant have extensively been reported for nutritional and medicinal properties in Ayurveda as well as in Chinese traditional practices. The objective of the present review is to compile and update the published data on traditional uses, pharmacological potential, and phytochemistry of compounds isolated from the plant Pueraria tuberosa. P. tuberosa extracts and its purified compounds possess multiple activities such as anticancer, anticonvulsant, antidiabetic, antifertility, anti-inflammatory, antioxidant, anti-stress, antiulcerogenic, cardioprotective, hypolipidemic, hepatoprotective, immunomodulatory, nephroprotective, nootropic, neuroprotective, and wound healing. Tuber and leaf extracts of P. tuberosa contain several bioactive constituents such as puerarin, daidzein, genistein, quercetin, irisolidone, biochanin A, biochanin B, isoorientin, and mangiferin, which possess an extensive range of pharmacological activities. The extensive range of pharmacological properties of P. tuberosa provides opportunities for further investigation and presents a new approach for the treatment of ailments. Many phytochemicals have been identified and characterized from P. tuberosa; however, some of them are still unexplored, and there is no supporting data for their activities and exact mechanisms of action. Therefore, further investigations are warranted to unravel the mechanisms of action of individual constituents of this plant.
Nasal Delivery of Hesperidin/Chitosan Nanoparticles Suppresses Cytokine Storm Syndrome in a Mouse Model of Acute Lung Injury
Authors: Jin Hua , Zhao Zuguo , Lan Qian , Zhou Haotong , Mai Zesen , Wang Yuan , Ding Xiaowen , Zhang Wenting , Pi Jiang , Evans Colin E. , Liu Xinguang
Published: January 2021

The cytokine storm or cytokine storm syndrome (CSS) is associated with high mortality in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), for example following sepsis or infectious diseases including COVID-19. However, there are no effective treatments for CSS-associated ALI or ALI/ARDS. Thus, there remains an urgent need to develop effective drugs and therapeutic strategies against CSS and ALI/ARDS. Nasal and inhaled drug delivery methods represent a promising strategy in the treatment of inflammatory lung disease as a result of their ability to improve drug delivery to lungs. Improving the nasal mucosa absorption of poorly water-soluble drugs with poor mucosa bioavailability to a therapeutically effective level is another promising strategy in the fight against ALI/ARDS. Here, chitosan nanoparticles loaded with hesperidin (HPD/NPs) were developed for nasal delivery of the anti-inflammatory HPD compound to inflammatory lungs. In vitro and in vivo, HPD/NPs exhibited enhanced cellular uptake in the inflammatory microenvironment compared with free HPD. In a mouse model of inflammatory lung disease, the HPD/NPs markedly inhibited lung injury as evidenced by reduced inflammatory cytokine levels and suppressed vascular permeability compared with free HPD. Collectively, our study demonstrates that nasal delivery of HPD/NPs suppresses CSS and ALI/ARDS in a murine model of inflammatory lung disease, and that nanoparticle-based treatment strategies with anti-inflammatory effects could be used to reduce CSS and ALI in patients with inflammatory lung injury.