bluuebunny/crossref_metadata_2025 huggingface dataset:
Screening and Identification of Key Microenvironment-Related Genes in Non-functioning Pituitary Adenoma
Authors: Guo Jing , Fang Qiuyue , Liu Yulou , Xie Weiyan , Li Chuzhong , Zhang Yazhuo
Published: April 2021

Purpose

Non-functioning pituitary adenoma (NFPA) is a very common type of intracranial tumor, which can be locally invasive and can have a high recurrence rate. The tumor microenvironment (TME) shows a high correlation with tumor pathogenesis and prognosis. The current study aimed to identify microenvironment-related genes in NFPAs and assess their prognostic value.

Methods

73 NFPA tumor samples were collected from Beijing Tiantan Hospital and transcriptional expression profiles were obtained through microarray analysis. The immune and stromal scores of each sample were calculated through the ESTIMATE algorithm, and the patients were divided into high and low immune/stromal score groups. Intersection differentially expressed genes (DEGs) were then obtained to construct a protein–protein interaction (PPI) network. Potential functions and pathways of intersection DEGs were then analyzed through Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes. The prognostic value of these genes was evaluated. The quantitative real-time polymerase chain reaction in another set of NFPA samples was used to confirm the credibility of the bioinformatics analysis.

Results

The immune/stromal scores were significantly correlated with cavernous sinus (CS) invasion. The Kaplan–Meier curve indicated that the high immune score group was significantly related to poor recurrence-free survival. We identified 497 intersection DEGs based on the high vs. low immune/stromal score groups. Function enrichment analyses of 497 DEGs and hub genes from the PPI network showed that these genes are mainly involved in the immune/inflammatory response, T cell activation, and the phosphatidylinositol 3 kinase-protein kinase B signaling pathway. Among the intersection DEGs, 88 genes were further verified as significantly expressed between the CS invasive group and the non-invasive group, and five genes were highly associated with NFPA prognosis.

Conclusion

We screened out a series of critical genes associated with the TME in NFPAs. These genes may play a fundamental role in the development and prognosis of NFPA and may yield new therapeutic targets.
Very Long-Chain Acyl-CoA Dehydrogenase Deficiency: High Incidence of Detected Patients With Expanded Newborn Screening Program
Authors: Remec Ziga I. , Groselj Urh , Drole Torkar Ana , Zerjav Tansek Mojca , Cuk Vanja , Perko Dasa , Ulaga Blanka , Lipovec Neza , Debeljak Marusa , Kovac Jernej , Battelino Tadej , Repic Lampret Barbka
Published: April 2021

Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a rare autosomal recessive disorder of fatty acid metabolism with a variable presentation. The aim of this study was to describe five patients with VLCADD diagnosed through the pilot study and expanded newborn screening (NBS) program that started in 2018 in Slovenia. Four patients were diagnosed through the expanded NBS program with tandem mass spectrometry; one patient was previously diagnosed in a pilot study preceding the NBS implementation. Confirmatory testing consisted of acylcarnitines analysis in dried blood spots, organic acids profiling in urine, genetic analysis of ACADVL gene, and enzyme activity determination in lymphocytes or fibroblasts. Four newborns with specific elevation of acylcarnitines diagnostic for VLCADD and disease-specific acylcarnitines ratios (C14:1, C14, C14:2, C14:1/C2, C14:1/C16) were confirmed with genetic testing: all were compound heterozygotes, two of them had one previously unreported ACDVL gene variant each (NM_000018.3) c.1538C > G; (NP_000009) p.(Ala513Gly) and c.661A > G; p.(Ser221Gly), respectively. In addition, one patient diagnosed in the pilot study also had a specific elevation of acylcarnitines. Subsequent ACDVL genetic analysis confirmed compound heterozygosity. In agreement with the diagnosis, enzyme activity was reduced in five patients tested. In seven other newborns with positive screening results, only single allele variants were found in the ACDVL gene, so the diagnosis was not confirmed. Among these, two variants were novel, c.416T > C and c.1046C > A, respectively (p.Leu139Pro and p.Ala349Glu). In the first 2 years of the expanded NBS program in Slovenia altogether 30,000 newborns were screened. We diagnosed four cases of VLCADD. The estimated VLCADD incidence was 1:7,500 which was much higher than that of the medium-chain acyl-CoA dehydrogenase deficiency (MCADD) cases in the same period. Our study also provided one of the first descriptions of ACADVL variants in Central-Southeastern Europe and reported on 4 novel variants.
Bioinformatics-Based Analysis of the lncRNA-miRNA-mRNA Network and TF Regulatory Network to Explore the Regulation Mechanism in Spinal Cord Ischemia/Reperfusion Injury
Authors: Wang Dan , Wang Limei , Han Jie , Zhang Zaili , Fang Bo , Chen Fengshou
Published: April 2021

Background

Spinal cord ischemia/reperfusion injury (SCII) is a catastrophic complication involved with cardiovascular, spine, and thoracic surgeries and can lead to paraplegia. Nevertheless, the molecular mechanism of SCII remain ill-defined.

Methods

Expression profiling (GSE138966) data were obtained from GEO database. Then, differentially expressed (DE) lncRNAs and DEmRNAs were screened out withp< 0.05, and | fold change| > 1.5. Aberrant miRNAs expression in SCII was obtained from PubMed. Functional enrichment analysis of overlapping DEmRNAs between predicted mRNAs in miRDB database and DEmRNAs obtained from GSE138966 was performed using cluster Profiler R package. The lncRNA-miRNA-mRNA competitive endogenous RNA (ceRNA) network was established in light of ceRNA theory. The key lncRNAs in the ceRNA network were identified by topological analysis. Subsequently, key lncRNAs related ceRNA-pathway network and transcription factors (TFs)-mRNAs network were constructed. Simultaneously, the expression levels of hub genes were measured via qRT-PCR.

Results

The results in this study indicated that 76 miRNAs, 1373 lncRNAs, and 4813 mRNAs were differentially expressed in SCII. A SCII-related ceRNA network was constructed with 154 ncRNAs, 139 mRNAs, and 51 miRNAs. According topological analysis, six lncRNAs (NONRATT019236.2, NONRATT009530.2, NONRATT026999.2, TCONS_00032391, NONRATT023112.2, and NONRATT021956.2) were selected to establish the ceRNA-pathway network, and then two candidate hub lncRNAs (NONRATT009530.2 and NONRATT026999.2) were identified. Subsequently, two lncRNA-miRNA-mRNA regulatory axes were identified. NONRATT026999.2 and NONRATT009530.2 might involve SCII via miR-20b-5p/Map3k8 axis based on the complex ceRNA network. SP1 and Hnf4a acting as important TFs might regulate Map3k8. Furthermore, qRT-PCR results showed that the NONRATT009530.2, NONRATT026999.2, Map3k8, Hfn4a, and SP1 were significantly upregulated in SCII of rats, while the miR-20b-5p was downregulated.

Conclusion

Our results offer a new insight to understand the ceRNA regulation mechanism in SCII and identify highlighted lncRNA-miRNA-mRNA axes and two key TFs as potential targets for prevention and treatment of SCII.
Programmed Death-Ligand 1 Expression Potentiates the Immune Modulatory Function Of Myeloid-Derived Suppressor Cells in Systemic Lupus Erythematosus
Authors: Park Min-Jung , Baek Jin-Ah , Choi Jeong Won , Jang Se Gwang , Kim Da-Som , Park Sung-Hwan , Cho Mi-La , Kwok Seung-Ki
Published: April 2021

Multiple studies have explored the potential role of programmed death-ligand 1 (PD-L1) as a mediator of Myeloid-derived suppressor cells (MDSCs) effects in various cancers. However, the role PD-L1 expression in MDSCs on autoimmune disease is still largely unknown.This study was undertaken to whether MDSC expressing PD-L1 have more potent immunoregulatory activity and control autoimmunity more effectively in two murine models of lupus (MRL/lpr mice and Roquinsan/san mice). The populations of MDSC were increased in peripheral blood of lupus patients. The mRNA levels of immunosuppressive molecules were profoundly decreased in MDSCs from lupus patients and mice. Co-culture with splenocytes showed that PD-L1 expressing MDSCs from control mice expand both Treg cells and regulatory B cells more potently. Infusion of PD-L1 expressing MDSCs reduced autoantibody levels and degree of proteinuria and improved renal pathology of two animal models of lupus. Moreover, PD-L1 expressing MDSCs therapy can suppress double negative (CD4-CD8-CD3+) T cells, the major pathogenic immune cells and follicular helper T cells in MRL/lpr mice, and podocyte damage. Our results indicate PD-L1 expressing MDSCs have more potent immunoregualtory activity and ameliorate autoimmunity more profoundly. These findings suggest PD-L1 expressing MDSCs be a promising therapeutic strategy targeting systemic autoimmune diseases.
Identification, Validation, and Utilization of Immune Cells in Pancreatic Ductal Adenocarcinoma Based on Marker Genes
Authors: de Koning Willem , Latifi Diba , Li Yunlei , van Eijck Casper H. J. , Stubbs Andrew P. , Mustafa Dana A. M.
Published: April 2021

The immune response affects tumor biological behavior and progression. The specific immune characteristics of pancreatic ductal adenocarcinoma (PDAC) can determine the metastatic abilities of cancerous cells and the survival of patients. Therefore, it is important to characterize the specific immune landscape in PDAC tissue samples, and the effect of various types of therapy on that immune composition. Previously, a set of marker genes was identified to assess the immune cell composition in different types of cancer tissue samples. However, gene expression and subtypes of immune cells may vary across different types of cancers. The aim of this study was to provide a method to identify immune cells specifically in PDAC tissue samples. The method is based on defining a specific set of marker genes expressed by various immune cells in PDAC samples. A total of 90 marker genes were selected and tested for immune cell type-specific definition in PDAC; including 43 previously used, and 47 newly selected marker genes. The immune cell-type specificity was checked mathematically by calculating the “pairwise similarity” for all candidate genes using the PDAC RNA-sequenced dataset available at The Cancer Genome Atlas. A set of 55 marker genes that identify 22 different immune cell types for PDAC was created. To validate the method and the set of marker genes, an independent mRNA expression dataset of 24 samples of PDAC patients who received various types of (neo)adjuvant treatments was used. The results showed that by applying our method we were able to identify PDAC specific marker genes to characterize immune cell infiltration in tissue samples. The method we described enabled identifying different subtypes of immune cells that were affected by various types of therapy in PDAC patients. In addition, our method can be easily adapted and applied to identify the specific immune landscape in various types of tissue samples.
Excessive Unbalanced Meat Consumption in the First Year of Life Increases Asthma Risk in the PASTURE and LUKAS2 Birth Cohorts
Authors: Hose Alexander J. , Pagani Giulia , Karvonen Anne M. , Kirjavainen Pirkka V. , Roduit Caroline , Genuneit Jon , Schmaußer-Hechfellner Elisabeth , Depner Martin , Frei Remo , Lauener Roger , Riedler Josef , Schaub Bianca , Fuchs Oliver , von Mutius Erika , Divaret-Chauveau Amandine , Pekkanen Juha , Ege Markus J.
Published: April 2021

A higher diversity of food items introduced in the first year of life has been inversely related to subsequent development of asthma. In the current analysis, we applied latent class analysis (LCA) to systematically assess feeding patterns and to relate them to asthma risk at school age. PASTURE (N=1133) and LUKAS2 (N=228) are prospective birth cohort studies designed to evaluate protective and risk factors for atopic diseases, including dietary patterns. Feeding practices were reported by parents in monthly diaries between the 4thand 12thmonth of life. For 17 common food items parents indicated frequency of feeding during the last 4 weeks in 4 categories. The resulting 153 ordinal variables were entered in a LCA. The intestinal microbiome was assessed at the age of 12 months by 16S rRNA sequencing. Data on feeding practice with at least one reported time point was available in 1042 of the 1133 recruited children. Best LCA model fit was achieved by the 4-class solution. One class showed an elevated risk of asthma at age 6 as compared to the other classes (adjusted odds ratio (aOR): 8.47, 95% CI 2.52–28.56, p = 0.001) and was characterized by daily meat consumption and rare consumption of milk and yoghurt. A refined LCA restricted to meat, milk, and yoghurt confirmed the asthma risk effect of a particular class in PASTURE and independently in LUKAS2, which we thus termed unbalanced meat consumption (UMC). The effect of UMC was particularly strong for non-atopic asthma and asthma irrespectively of early bronchitis (aOR: 17.0, 95% CI 5.2–56.1, p < 0.001). UMC fostered growth of iron scavenging bacteria such as Acinetobacter (aOR: 1.28, 95% CI 1.00-1.63, p = 0.048), which was also related to asthma (aOR: 1.55, 95% CI 1.18-2.03, p = 0.001). When reconstructing bacterial metabolic pathways from 16S rRNA sequencing data, biosynthesis of siderophore group nonribosomal peptides emerged as top hit (aOR: 1.58, 95% CI 1.13-2.19, p = 0.007). By a data-driven approach we found a pattern of overly meat consumption at the expense of other protein sources to confer risk of asthma. Microbiome analysis of fecal samples pointed towards overgrowth of iron-dependent bacteria and bacterial iron metabolism as a potential explanation.
Construction and Validation of an Immune Infiltration-Related Gene Signature for the Prediction of Prognosis and Therapeutic Response in Breast Cancer
Authors: Peng Yang , Yu Haochen , Jin Yudi , Qu Fanli , Ren Haoyu , Tang Zhenrong , Zhang Yingzi , Qu Chi , Zong Beige , Liu Shengchun
Published: April 2021

Breast cancer patients show significant heterogeneity in overall survival. Current assessment models are insufficient to accurately predict patient prognosis, and models for predicting treatment response are lacking. We evaluated the relationship between various immune cells and breast cancer and confirmed the association between immune infiltration and breast cancer progression. Different bioinformatics and statistical approaches were combined to construct a robust immune infiltration-related gene signature for predicting patient prognosis and responses to immunotherapy and chemotherapy. Our research found that a higher immune infiltration-related risk score (IRS) indicates that the patient has a worse prognosis and is not very sensitive to immunotherapy. In addition, a new nomogram was constructed based on the gene signature and clinicopathological features to improve the risk stratification and quantify the risk assessment of individual patients. Our study might contribute to the optimization of the risk stratification for survival and the personalized management of breast cancer.
Refining Estimates of Greenhouse Gas Emissions From Salt Marsh “Blue Carbon” Erosion and Decomposition
Authors: McTigue Nathan D. , Walker Quentin A. , Currin Carolyn A.
Published: April 2021

Coastal wetlands have sediments that contain organic matter preserved against decomposition for timespans that can range up to millennia. This “blue carbon” in wetland sediments has been proposed as a sink for atmospheric carbon dioxide and a potential source of greenhouse gases if coastal habitats are lost. A missing gap in the role of coastal habitats in the global carbon cycle is elucidating the fate of wetland sediment carbon following disturbance events, such as erosion, that can liberate organic matter to an oxygenated environment where decomposition can more readily occur. Here, we track the fate of previously stored salt marsh sediment by measuring the production of carbon dioxide (CO2) and methane (CH4) during an oxygenated incubation. Sediments from two depth horizons (5–10 cm and 20–25 cm) were incubated at two temperatures (20 and 30°C) for 161 days. Q10 of the decomposition process over the entire course of the experiment was 2.0 ± 0.1 and 2.2 ± 0.2 for shallow and deep horizons, respectively. Activation energy for the decomposition reaction (49.7 kJ ⋅ mol–1 and 58.8 kJ ⋅ mol–1 for shallow and deep sediment horizons, respectively) was used to calculate temperature-specific decomposition rates that could be applied to environmental data. Using high-frequency water temperature data, this strategy was applied to coastal states in the conterminous United States (CONUS) where we estimated annual in situ decomposition of eroded salt marsh organic matter as 7–24% loss per year. We estimate 62.90 ± 2.81 Gg C ⋅ yr–1 is emitted from eroded salt marsh sediment decomposition in the CONUS.
Prevalence of Birt-Hogg-Dubé Syndrome Determined Through Epidemiological Data on Spontaneous Pneumothorax and Bayes Theorem
Authors: Muller Marie-Eve , Daccord Cécile , Taffé Patrick , Lazor Romain
Published: April 2021

Background: Birt-Hogg-Dubé syndrome (BHD) is a rare inherited disorder characterized by cutaneous fibrofolliculomas, multiple pulmonary cysts, recurrent spontaneous pneumothorax (SP), and renal tumors. More than 40 years after its description, the prevalence of BHD in the general population remains unknown. This study aimed at determining the prevalence of BHD by applying the Bayes theorem of conditional probability to epidemiological data on SP.

Methods: We performed a meta-analysis of published data on: (1) the probability of having BHD among patients with apparent primary SP (4 studies), (2) the incidence rate of primary SP in the general population (9 studies), and (3) the probability of experiencing a SP in BHD (16 studies). Results were corrected for SP relapses, stratified by gender and year of study publication (before and after 2000), and computed with the Bayes equation.

Results: The probability of having BHD among patients with apparent primary SP was 0.09 (95% confidence interval: 0.07, 0.11) or 9%. It was 0.20 (0.14, 0.27) in women and 0.05 (0.04, 0.07) in men. The incidence rate of primary SP in the general population was 8.69 (6.58, 11.46) per 100,000 person-years (p-y). It was 3.44 (2.36, 4.99) per 100,000 p-y in women and 13.96 (10.72, 18.18) per 100,000 p-y in men, and was about 2 times higher in studies published after 2000 than in those published before 2000. The probability of experiencing at least one SP among patients with BHD was 0.43 (0.31, 0.54) or 43%, without gender difference. By combining these data in the Bayes equation, we found a prevalence of BHD in the general population of 1.86 (1.16, 3.00) per million, with values of 1.86 (1.02, 3.39) per million in men, and 1.88 (0.97, 3.63) per million in women.

Conclusion: The prevalence of BHD in the general population is about 2 cases per million, without difference between genders.
Case Report: CD8+ T-Lymphocyte Deficit: A Prerequisite for Pasteurella spp. Infection?
Authors: Denes Eric , Fiorenza Fabrice , Armendariz Mateo , Martin Christian
Published: April 2021

Background: Immunity against Pasteurella spp. is not well-known for humans.

Methods: We've tested T CD8+ lymphocytes in a patient with a chronic prosthetic joint infection due to Pasteurella spp. to search for a deficit which could have favored her infection. As this deficit was found, we've searched for such a deficit in other patients with Pasteurella spp. Infections, either acute or subacute.

Results: Eight patients were tested and all had a persistent T CD8+ lymphocytes deficit. This is striking as these cells are involved in the response to this type of infection in animal models.

Conclusion: The authors suggest that a deficit in CD8+ T lymphocytes can be one of the causes for the onset of infections with P. multocida.
Features Associated With Quality of Life Impairment in Hidradenitis Suppurativa Patients
Authors: Schneider-Burrus Sylke , Tsaousi Athanasia , Barbus Sebastian , Huss-Marp Johannes , Witte Katrin , Wolk Kerstin , Fritz Björn , Sabat Robert
Published: April 2021

Background: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with an adverse impact on patients' quality of life (QoL).

Objectives: To quantify QoL impairment in patients in Germany suffering from HS and to identify the parameters associated with QoL impairment.

Methods: A non-interventional, cross-sectional, mono-centric study with 500 HS patients. QoL data (measured using the Dermatology Life Quality Index; DLQI) and demographic, anamnestic, clinical, and blood parameters were collected. All patients were examined by dermatologists that documented the skin alterations. QoL data from 462 HS patients were available and evaluated.

Results: The mean (± standard deviation) DLQI score of HS patients was 13.18 ± 7.99. Approximately 40% and 20% of HS patients declared very large and extremely large QoL impairment, respectively. The degree of QoL disturbance correlated with the severity of skin alterations, blood leucocyte count and, in particular, with anogenital localization and the presence of nodules and fistulas. Furthermore, QoL impairment was associated with specific comorbidities, such as adiposity and back pain, but not with HS family history. QoL impairment was not influenced by whether or not the patients had undergone resection surgery or antibiotic treatment but was more severe in HS patients that had undergone abscess lancing compared to patients without such treatment in the past.

Limitations: It was a mono-centric study and most data were obtained from self-administered patient questionnaires. The association of QoL with type of treatment was analyzed for abscess lancing, resection surgery, and antibiotic treatment. Further therapeutic modalities recommended in the guidelines were not investigated.

Conclusion: A profound impairment in QoL was present in patients with HS, and this was higher than that observed in other studied dermatoses. The degree of impairment correlated with the extent of cutaneous and some extra-cutaneous alterations. Surgical and conventional medicamentous therapies of HS were not associated with long-lasting reduction of QoL impairment. Our data support the implementation of patient-reported outcome measures for the assessment of therapy responses.
Cleavage of TANK-Binding Kinase 1 by HIV-1 Protease Triggers Viral Innate Immune Evasion
Authors: Jeremiah Sundararaj Stanleyraj , Miyakawa Kei , Matsunaga Satoko , Nishi Mayuko , Kudoh Ayumi , Takaoka Akinori , Sawasaki Tatsuya , Ryo Akihide
Published: April 2021

Type-I interferons (IFN-I) are the innate immune system’s principal defense against viral infections. Human immunodeficiency virus-1 (HIV-1) has evolved several ways to suppress or evade the host’s innate immunity in order to survive and replicate to sustain infection. Suppression of IFN-I is one among the multiple escape strategies used by HIV-1 to prevent its clearance. HIV-1 protease which helps in viral maturation has also been observed to cleave host cellular protein kinases. In this study we performed a comprehensive screening of a human kinase library using AlphaScreen assay and identified that TANK binding kinase-1 (TBK1) was cleaved by HIV-1 protease (PR). We demonstrate that PR cleaved TBK1 fails to phosphorylate IFN regulatory factor 3 (IRF3), thereby reducing the IFN-I promoter activity and further reveal that the PR mediated suppression of IFN-I could be counteracted by protease inhibitors (PI) in vitro. We have also revealed that mutations of HIV-1 PR that confer drug resistance to PIs reduce the enzyme’s ability to cleave TBK1. The findings of this study unearth a direct link between HIV-1 PR activity and evasion of innate immunity by the virus, the possible physiological relevance of which warrants to be determined.
The Effects of CSF Neurogranin and APOE ε4 on Cognition and Neuropathology in Mild Cognitive Impairment and Alzheimer’s Disease
Authors: Fan Yulan , Gao Ying , Therriault Joseph , Luo Jing , Ba Maowen , Zhang Hua ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: April 2021

Cerebrospinal fluid (CSF) measurements of neurogranin (Ng) have emerged as a promising biomarker for cognitive decline in mild cognitive impairment (MCI) and Alzheimer’s disease (AD). The apolipoprotein E ε4 (APOE ε4) allele is by far the most consistent genetic risk factor for AD. However, it is not known whether the pathophysiological roles of Ng in MCI or AD are related to APOEε4. We stratified 250 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database into cognitively normal (CN) ε4 negative (CN ε4−), CN ε4 positive (CN ε4+), MCI ε4 negative (MCI ε4−), MCI ε4 positive (MCI ε4+), AD ε4 negative (AD ε4−), and AD ε4 positive (AD ε4+). CSF Ng levels were significantly increased in APOE ε4 carriers compared to APOE ε4 non-carriers with MCI. In addition, CSF Ng identified MCI ε4+ versus CN ε4−, but not MCI ε4− versus CN ε4−. Similarly, CSF Ng negatively correlated with Mini-Mental State Examination (MMSE) scores at baseline in the MCI ε4+ group. Our findings support the use of CSF Ng as a biomarker of synaptic pathology for AD. We propose that the roles of CSF Ng in the pathophysiology of MCI may be related to APOE ε4.
Engineering Method for Tailoring Electrical Characteristics in TiN/TiOx/HfOx/Au Bi-Layer Oxide Memristive Devices
Authors: Park Seongae , Klett Stefan , Ivanov Tzvetan , Knauer Andrea , Doell Joachim , Ziegler Martin
Published: April 2021

Memristive devices have led to an increased interest in neuromorphic systems. However, different device requirements are needed for the multitude of computation schemes used there. While linear and time-independent conductance modulation is required for machine learning, non-linear and time-dependent properties are necessary for neurobiologically realistic learning schemes. In this context, an adaptation of the resistance switching characteristic is necessary with regard to the desired application. Recently, bi-layer oxide memristive systems have proven to be a suitable device structure for this purpose, as they combine the possibility of a tailored memristive characteristic with low power consumption and uniformity of the device performance. However, this requires technological solutions that allow for precise adjustment of layer thicknesses, defect densities in the oxide layers, and suitable area sizes of the active part of the devices. For this purpose, we have investigated the bi-layer oxide system TiN/TiOx/HfOx/Au with respect to tailored I-V non-linearity, the number of resistance states, electroforming, and operating voltages. Therefore, a 4-inch full device wafer process was used. This process allows a systematic investigation, i.e., the variation of physical device parameters across the wafer as well as a statistical evaluation of the electrical properties with regard to the variability from device to device and from cycle to cycle. For the investigation, the thickness of the HfOx layer was varied between 2 and 8 nm, and the size of the active area of devices was changed between 100 and 2,500 µm2. Furthermore, the influence of the HfOx deposition condition was investigated, which influences the conduction mechanisms from a volume-based, filamentary to an interface-based resistive switching mechanism. Our experimental results are supported by numerical simulations that show the contribution of the HfOx film in the bi-layer memristive system and guide the development of a targeting device.
The Function of Paraventricular Thalamic Circuitry in Adaptive Control of Feeding Behavior
Authors: Petrovich Gorica D.
Published: April 2021

The paraventricular nucleus of the thalamus (PVT) is a complex area that is uniquely embedded across the core feeding, reward, arousal, and stress circuits. The PVT role in the control of feeding behavior is discussed here within a framework of adaptive behavioral guidance based on the body’s energy state and competing drives. The survival of an organism depends on bodily energy resources and promotion of feeding over other behaviors is adaptive except when in danger or sated. The PVT is structurally set up to respond to homeostatic and hedonic needs to feed, and to integrate those signals with physiological and environmental stress, as well as anticipatory needs and other cognitive inputs. It can regulate both food foraging (seeking) and consumption and may balance their expression. The PVT is proposed to accomplish these functions through a network of connections with the brainstem, hypothalamic, striatal, and cortical areas. The connectivity of the PVT further indicates that it could broadcast the information about energy use/gain and behavioral choice to impact cognitive processes—learning, memory, and decision-making—through connections with the medial and lateral prefrontal cortical areas, the hippocampal formation, and the amygdala. The PVT is structurally complex and recent evidence for specific PVT pathways in different aspects of feeding behavior will be discussed.
Severe Form of ßIV-Spectrin Deficiency With Mitochondrial Dysfunction and Cardiomyopathy—A Case Report
Authors: Belkheir Aziza Miriam , Reunert Janine , Elpers Christiane , van den Heuvel Lambert , Rodenburg Richard , Seelhöfer Anja , Rust Stephan , Jeibmann Astrid , Frosch Michael , Marquardt Thorsten
Published: April 2021

ßIV-spectrin is a protein of the spectrin family which is involved in the organization of the cytoskeleton structure and is found in high quantity in the axon initial segment and the nodes of Ranvier. Together with ankyrin G, ßIV-spectrin is responsible for the clustering of KCNQ2/3-potassium channels and NaV-sodium channels. Loss or reduction of ßIV-spectrin causes a destabilization of the cytoskeleton and an impairment in the generation of the action potential, which leads to neuronal degeneration. Furthermore, ßIV-spectrin has been described to play an important role in the maintenance of the neuronal polarity and of the diffusion barrier. ßIV-spectrin is also located in the heart where it takes an important part in the structural organization of ion channels and has also been described to participate in cell signaling pathways through binding of transcription factors. We describe two patients with a severe form of ßIV-spectrin deficiency. Whole-exome sequencing revealed the homozygous stop mutation c.6016C>T (p.R2006*) in the SPTBN4 gene. The phenotype of these patients is characterized by profound psychomotor developmental arrest, respiratory insufficiency and deafness. Additionally one of the patients presents with cardiomyopathy, optical nerve atrophy, and mitochondrial dysfunction. This is the first report of a severe form of ßIV-spectrin deficiency with hypertrophic cardiomyopathy and mitochondrial dysfunction.
Phonological Variations Are Compensated at the Lexical Level: Evidence From Auditory Neural Activity
Authors: Zora Hatice , Riad Tomas , Ylinen Sari , Csépe Valéria
Published: April 2021

Dealing with phonological variations is important for speech processing. This article addresses whether phonological variations introduced by assimilatory processes are compensated for at the pre-lexical or lexical level, and whether the nature of variation and the phonological context influence this process. To this end, Swedish nasal regressive place assimilation was investigated using the mismatch negativity (MMN) component. In nasal regressive assimilation, the coronal nasal assimilates to the place of articulation of a following segment, most clearly with a velar or labial place of articulation, as inutan mej“without me” > [ʉːtam mɛjː]. In a passive auditory oddball paradigm, 15 Swedish speakers were presented with Swedish phrases with attested and unattested phonological variations and contexts for nasal assimilation. Attested variations – a coronal-to-labial change as inutan“without” > [ʉːtam] – were contrasted with unattested variations – a labial-to-coronal change as inutom“except” >∗[ʉːtɔn] – in appropriate and inappropriate contexts created bymej“me” [mɛjː] anddej“you” [dɛjː]. Given that the MMN amplitude depends on the degree of variation between two stimuli, the MMN responses were expected to indicate to what extent the distance between variants was tolerated by the perceptual system. Since the MMN response reflects not only low-level acoustic processing but also higher-level linguistic processes, the results were predicted to indicate whether listeners process assimilation at the pre-lexical and lexical levels. The results indicated no significant interactions across variations, suggesting that variations in phonological forms do not incur any cost in lexical retrieval; hence such variation is compensated for at the lexical level. However, since the MMN response reached significance only for a labial-to-coronal change in a labial context and for a coronal-to-labial change in a coronal context, the compensation might have been influenced by the nature of variation and the phonological context. It is therefore concluded that while assimilation is compensated for at the lexical level, there is also some influence from pre-lexical processing. The present results reveal not only signal-based perception of phonological units, but also higher-level lexical processing, and are thus able to reconcile the bottom-up and top-down models of speech processing.
Tumor Volume Predicts High-Risk Patients and Guides Initial Chemoradiotherapy for Early Cervical Cancer
Authors: Zhang Jingjing , Cao Dongyan , Yang Jiaxin , Shen Keng , He Yonglan , Xue Huadan
Published: April 2021

We evaluated the relationship between the minimum tumor-free margin, tumor volume, and adverse pathological risk factors in early cervical cancer and explored the predictive value of these parameters for different types of risk patients to guide individualized therapeutic strategies. Patients who received the initial treatment of radical operation of cervical cancer and their postoperative pathological reports in our hospital from July 1, 2017, to June 30, 2019, were reviewed. Their minimum tumor-free margin and tumor volume were measured on preoperative magnetic resonance imaging. Student’s t-test and the receiver operating characteristic curve analysis were used for data analysis. A total of 240 patients were included. Adverse pathological risk factors were as follows: deep cervical infiltration, 95 (39.6%) cases; lymph vascular space invasion, 91 (37.9%); lymph node metastasis, 20 (8.3%); parametrial infiltration, 8 (3.3%); tumor diameter ≥4 cm, 7 (2.9%); and positive surgical margin, 1 (0.4%). According to the adverse pathological factors, there were 20 (8.3%) high-risk patients, 50 (20.8%) medium-risk patients, and 170 (70.8%) low-risk patients. The ranges of the minimum tumor-free margin and tumor volume were 0.01–13.5 mm and 105–27,990 mm3, respectively. The minimum tumor-free margin with lymph node metastasis was significantly smaller than that without (P <0.05). The tumor volume with parametrial infiltration, deep cervical infiltration, or lymph vascular space invasion was significantly greater than that without (P < 0.05). The tumor volume was significantly different among low-, medium-, and high-risk patients (P <0.05). Tumor volume was of predictive value for high-risk patients (P < 0.05). With 3,505 mm3 as the cutoff value, the sensitivity and specificity for the prediction of high-risk patients were 88.9% and 84.8%, respectively. Tumor volume can be used as a great predictor of high-risk patients (cutoff value, 3,505 mm3), which could be an indication of initial chemoradiotherapy for early cervical cancer.
Allicin and Digestive System Cancers: From Chemical Structure to Its Therapeutic Opportunities
Authors: Sarvizadeh Mahshad , Hasanpour Omid , Naderi Ghale-Noie Zari , Mollazadeh Samaneh , Rezaei Mohammad , Pourghadamyari Hossein , Masoud Khooy Mohammadjaber , Aschner Michael , Khan Haroon , Rezaei Nima , Shojaie Layla , Mirzaei Hamed
Published: April 2021

Digestive system cancer tumors are one of the major causes of cancer-related fatalities; the vast majority of them are colorectal or gastric malignancies. Epidemiological evidence confirmed that allium-containing food, such as garlic, reduces the risk of developing malignancies. Among all compounds in garlic, allicin has been most researched, as it contains sulfur and produces many second degradation compounds, such as sulfur dioxide, diallyl sulfide (DAS), diallyl trisulfide (DATS), and diallyl disulfide (DADS) in the presence of enzymatic reactions in gastric juice. These substances have shown anti-inflammatory, antidiabetic, antihypertensive, antifungal, antiviral, antibacterial, and anticancer efficacy, including gastrointestinal (GI) cancers, leukemia, and skin cancers. Herein, we summarize the therapeutic potential of allicin in the treatment of GI cancers.
An Immune Model to Predict Prognosis of Breast Cancer Patients Receiving Neoadjuvant Chemotherapy Based on Support Vector Machine
Authors: Wang Mozhi , Pang Zhiyuan , Wang Yusong , Cui Mingke , Yao Litong , Li Shuang , Wang Mengshen , Zheng Yanfu , Sun Xiangyu , Dong Haoran , Zhang Qiang , Xu Yingying
Published: April 2021

Tumor microenvironment has been increasingly proved to be crucial during the development of breast cancer. The theory about the conversion of cold and hot tumor attracted the attention to the influences of traditional therapeutic strategies on immune system. Various genetic models have been constructed, although the relation between immune system and local microenvironment still remains unclear. In this study, we tested and collected the immune index of 262 breast cancer patients before and after neoadjuvant chemotherapy. Five indexes were selected and analyzed to form the prediction model, including the ratio values between after and before neoadjuvant chemotherapy of CD4+/CD8+ T cell ratio; lymphosum of T, B, and natural killer (NK) cells; CD3+CD8+ cytotoxic T cell percent; CD16+CD56+ NK cell absolute value; and CD3+CD4+ helper T cell percent. Interestingly, these characters are both the ratio value of immune status after neoadjuvant chemotherapy to the baseline. Then the prediction model was constructed by support vector machine (accuracy rate = 75.71%, area under curve = 0.793). Beyond the prognostic effect and prediction significance, the study instead emphasized the importance of immune status in traditional systemic therapies. The result provided new evidence that the dynamic change of immune status during neoadjuvant chemotherapy should be paid more attention.
Inferring Cell Subtypes and LncRNA Function by a Cell-Specific CeRNA Network in Breast Cancer
Authors: Chen Xin , Xu Jing , Zeng Feng , Yang Chao , Sun Weijun , Yu Tao , Zhang Haokun , Li Yan
Published: April 2021

Single-cell RNA sequencing is a powerful tool to explore the heterogeneity of breast cancer. The identification of the cell subtype that responds to estrogen has profound significance in breast cancer research and treatment. The transcriptional regulation of estrogen is an intricate network involving crosstalk between protein-coding and non-coding RNAs, which is still largely unknown, particularly at the single cell level. Therefore, we proposed a novel strategy to specify cell subtypes based on a cell-specific ceRNA network (CCN). The CCN was constructed by integrating a cell-specific RNA-RNA co-expression network (RCN) with an existing ceRNA network. The cell-specific RCN was built based on single cell expression profiles with predefined reference cells. Heterogeneous cell subtypes were inferred by enriching RNAs in CCN to the estrogen response hallmark. Edge biomarkers were identified in the early estrogen response subtype. Topological analysis revealed that NEAT1 was a hub lncRNA for the early response subtype, and its ceRNAs could predict patient survival. Another hub lncRNA, DLEU2, could potentially be involved in GPCR signaling, based on CCN. The CCN method that we proposed here facilitates the inference of cell subtypes from a network perspective and explores the function of hub lncRNAs, which are promising targets for RNA-based therapeutics.
Innovative Approaches in the Battle Against Cancer Recurrence: Novel Strategies to Combat Dormant Disseminated Tumor Cells
Authors: Sauer Scott , Reed Damon R. , Ihnat Michael , Hurst Robert E. , Warshawsky David , Barkan Dalit
Published: April 2021

Cancer recurrence remains a great fear for many cancer survivors following their initial, apparently successful, therapy. Despite significant improvement in the overall survival of many types of cancer, metastasis accounts for ~90% of all cancer mortality. There is a growing understanding that future therapeutic practices must accommodate this unmet medical need in preventing metastatic recurrence. Accumulating evidence supports dormant disseminated tumor cells (DTCs) as a source of cancer recurrence and recognizes the need for novel strategies to target these tumor cells. This review presents strategies to target dormant quiescent DTCs that reside at secondary sites. These strategies aim to prevent recurrence by maintaining dormant DTCs at bay, or eradicating them. Various approaches are presented, including: reinforcing the niche where dormant DTCs reside in order to keep dormant DTCs at bay; promoting cell intrinsic mechanisms to induce dormancy; preventing the engagement of dormant DTCs with their supportive niche in order to prevent their reactivation; targeting cell-intrinsic mechanisms mediating long-term survival of dormant DTCs; sensitizing dormant DTCs to chemotherapy treatments; and, inhibiting the immune evasion of dormant DTCs, leading to their demise. Various therapeutic approaches, some of which utilize drugs that are already approved, or have been tested in clinical trials and may be considered for repurposing, will be discussed. In addition, clinical evidence for the presence of dormant DTCs will be reviewed, along with potential prognostic biomarkers to enable the identification and stratification of patients who are at high risk of recurrence, and who could benefit from novel dormant DTCs targeting therapies. Finally, we will address the shortcomings of current trial designs for determining activity against dormant DTCs and provide novel approaches.
Comparison of Perioperative Outcomes Between Precise and Routine Segmentectomy for Patients With Early-Stage Lung Cancer Presenting as Ground-Glass Opacities: A Propensity Score-Matched Study
Authors: Wu Xianning , Li Tian , Zhang Chuankai , Wu Gao , Xiong Ran , Xu Meiqing , Su Dan , Xie Mingran
Published: April 2021

Introduction

Segmentectomy is widely used for early-stage lung cancer presenting as single or multiple ground-glass opacities (GGOs). Precise segmentectomy is the recommended procedure in China. However, clinically, most routine segmentectomies are performed using only high-resolution computed tomography (CT). The aim of this study was to evaluate the effect of two segmentectomy approaches for GGOs in the lung.

Methods

From January 2020 to September 2020, 55 precise segmentectomies performed with real-time guidance using 3D reconstruction and 343 routine segmentectomies for patients with single or multiple GGOs were performed as uniportal procedures. To reduce bias related to outcomes, preoperative clinical factors were used for propensity score matching (1:1); 55 precision and 55 routine segmentectomies were selected and further analyzed. Perioperative outcomes, namely operation time, blood loss, resection margins, number of removed lymph nodes, postoperative pulmonary function (1 month after surgery), length of postoperative stay, and postoperative complications were compared between the two groups.

Results

Patients constituted 43 men and 67 women, with an age range of 25–68 years (median: 53 years). No significant differences were seen between the groups regarding blood loss, complications, histological type, and postoperative pulmonary function, and there were no 30-day postoperative deaths in either group. The median operation time for the Precision group (74 min) was longer than in the Routine group (55 min) (p <0.01), and the number of removed lymph nodes in the Precision group (5 ± 1.1) was higher than in the Routine group (3 ± 0.8) (p <0.01). Chest tube duration days and postoperative stay days were similar in both groups; however, the rate of air leakage on postoperative day 1 was higher in the Precision group (p = 0.020). All patients in the Precision group had adequate resection margins. Four patients (7.3%) undergoing complex segmentectomy in the Routine group had inadequate resection margins and required resection of additional lung tissue.

Conclusion

Routine segmentectomy can significantly shorten the operation time and might prevent postoperative air leakage in uniportal segmentectomy for lung GGOs. However, precision segmentectomy may be more precise for complex cases, ensuring adequate resection margins and lymph node dissection.
On the Corner of Models and Cure: Gene Editing in Cystic Fibrosis
Authors: Ensinck Marjolein , Mottais Angélique , Detry Claire , Leal Teresinha , Carlon Marianne S.
Published: April 2021

Cystic fibrosis (CF) is a severe genetic disease for which curative treatment is still lacking. Next generation biotechnologies and more efficient cell-based and in vivo disease models are accelerating the development of novel therapies for CF. Gene editing tools, like CRISPR-based systems, can be used to make targeted modifications in the genome, allowing to correct mutations directly in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. Alternatively, with these tools more relevant disease models can be generated, which in turn will be invaluable to evaluate novel gene editing-based therapies for CF. This critical review offers a comprehensive description of currently available tools for genome editing, and the cell and animal models which are available to evaluate them. Next, we will give an extensive overview of proof-of-concept applications of gene editing in the field of CF. Finally, we will touch upon the challenges that need to be addressed before these proof-of-concept studies can be translated towards a therapy for people with CF.
Shexiang Baoxin Pill, a Proprietary Multi-Constituent Chinese Medicine, Prevents Locomotor and Cognitive Impairment Caused by Brain Ischemia and Reperfusion Injury in Rats: A Potential Therapy for Neuropsychiatric Sequelae of Stroke
Authors: Qin Zong-Shi , Zheng Yu , Zhou Xi-Dan , Shi Dong-Dong , Cheng Dan , Shek Chun Shum , Zhan Chang-Sen , Zhang Zhang-Jin
Published: April 2021

Ischemic stroke is a common type of cerebrovascular event and also the leading cause of disability. Post-stroke cognitive impairment occurs frequently in stroke survivors. Shexiang Baoxin Pill (SBP) is a proprietary Chinese medicine, initially used to treat cardiovascular diseases. Herein, we aim to explore the effects of SBP on oxygen glucose deprivation and reoxygenation (OGD/R) in neuronal cells (CATH.a) and cerebral ischemia/reperfusion injury induced post-stroke cognitive impairment in middle cerebral artery occlusion (MCAO) rat model. MCAO rats received two doses of oral SBP treatment (28 or 56 mg/kg) after 1 h of operation and once daily for 2 weeks continuously. Behavioral tests, immunoblotting, and immunofluorescence were examined after 14 days. Current data suggest that SBP enhanced cell viability and downregulated apoptosis via activating the PI3K/Akt signaling pathway in CATH. a cells. Furthermore, 14 days of SBP treatment promoted the recovery of learning and locomotor function in the MCAO rats. SBP up-regulated the expression of p-Akt, p-GSK3β, as well as the expression of NMDAR1, PSD-95, and AMPAR. Also, SBP down-regulated the expression of p-CaMKII. These results indicated that long-term SBP treatment might be a potential option for cognitive impairment induced by the ischemic stroke.