bluuebunny/crossref_metadata_2025 huggingface dataset:
DILIC: An AI-Based Classifier to Search for Drug-Induced Liver Injury Literature
Authors: Rathee Sanjay , MacMahon Meabh , Liu Anika , Katritsis Nicholas M. , Youssef Gehad , Hwang Woochang , Wollman Lilly , Han Namshik
Published: June 2022

Drug-induced liver injury (DILI) is a class of adverse drug reactions (ADR) that causes problems in both clinical and research settings. It is the most frequent cause of acute liver failure in the majority of Western countries and is a major cause of attrition of novel drug candidates. Manual trawling of the literature is the main route of deriving information on DILI from research studies. This makes it an inefficient process prone to human error. Therefore, an automatized AI model capable of retrieving DILI-related articles from the huge ocean of literature could be invaluable for the drug discovery community. In this study, we built an artificial intelligence (AI) model combining the power of natural language processing (NLP) and machine learning (ML) to address this problem. This model uses NLP to filter out meaningless text (e.g., stop words) and uses customized functions to extract relevant keywords such as singleton, pair, and triplet. These keywords are processed by an apriori pattern mining algorithm to extract relevant patterns which are used to estimate initial weightings for a ML classifier. Along with pattern importance and frequency, an FDA-approved drug list mentioning DILI adds extra confidence in classification. The combined power of these methods builds a DILI classifier (DILIC), with 94.91% cross-validation and 94.14% external validation accuracy. To make DILIC as accessible as possible, including to researchers without coding experience, an R Shiny app capable of classifying single or multiple entries for DILI is developed to enhance ease of user experience and made available at https://researchmind.co.uk/diliclassifier/. Additionally, a GitHub link (https://github.com/sanjaysinghrathi/DILI-Classifier) for app source code and ISMB extended video talk (https://www.youtube.com/watch?v=j305yIVi_f8) are available as supplementary materials.
Tertiary Lymphatic Structures in Primary Hepatic Carcinoma: Controversy Cannot Overshadow Hope
Authors: Jia Weili , Zhang Tianchen , Yao Qianyun , Li Jianhui , Nie Ye , Lei Xinjun , Mao Zhenzhen , Wang Yanfang , Shi Wen , Song Wenjie
Published: June 2022

Tertiary lymphoid structures (TLSs) are organized aggregates of immune cells found in the tumor microenvironment. TLS can influence primary hepatic carcinoma (PHC) occurrence and have an active role in cancer. TLS can promote or inhibit the growth of PHC depending on their location, and although available findings are controversial, they suggest that TLS have a protective role in PHC tissues and a non-protective role in paracancerous tissues. In addition, the cellular composition of TLS can also influence the outcome of PHC. As an immunity marker, TLS can act as a marker of immunotherapy to predict its effect and help to identify patients who will respond well to immunotherapy. Modulation of TLS formation through the use of chemokines/cytokines, immunotherapy, or induction of high endothelial vein to interfere with tumor growth has been studied extensively in PHC and other cancers. In addition, new tools such as genetic interventions, cellular crosstalk, preoperative radiotherapy, and advances in materials science have been shown to influence the prognosis of malignant tumors by modulating TLS production. These can also be used to develop PHC treatment.
Immunological Changes of Basophil Hyperreactivity to Sweat in Patients With Well-Controlled Atopic Dermatitis
Authors: Numata Tomofumi , Takahagi Shunsuke , Ishii Kaori , Morioke Satoshi , Kan Takanobu , Mizuno Hayato , Yanase Yuhki , Kawaguchi Tomoko , Tanaka Akio , Hide Michihiro
Published: June 2022

Background

Sweat aggravates atopic dermatitis (AD). In patients with AD, type-I hypersensitivity to sweat may be shown by histamine release from patients’ basophils in response to the semi-purified sweat antigen (QR), and the presence of specific immunoglobulin E (IgE) binding to MGL_1304, the component of QR. However, there has been no information on the immunological changes of type-I hypersensitivity to the sweat antigen in patients with well-controlled AD using topical corticosteroids (TCSs) and/or biologics as treatments.

Method

Histamine-releasing tests using patients’ basophils and QR and the detection of serum IgE against MGL_1304 and mite allergen Der f 1 were performed in patients with AD who were well controlled by topical TCS with/without dupilumab for 53–96 weeks.

Results

In total, 14 patients were enrolled. Seven patients received TCS therapy alone (TCS group), and seven patients received TCS with dupilumab therapy (dupilumab group). In all participants, the level of specific IgE against MGL_1304 decreased after treatments, but histamine release from basophils in response to QR did not show a statistically significant reduction; rather, it increased. In the dupilumab group, all changes in histamine release induced by QR (increase), the IgE level against MGL_1304 (decrease), and that against Der f 1 (decrease) were statistically significant, whereas the TCS group showed no significant change in any of them.

Conclusion

The well-controlled condition for 53–96 weeks resulted in no reduction of the hyperreactivity of basophils against in patients with AD, even with the treatment with dupilumab. This study suggests persistent basophil hyperreactivity to sweat antigen over a year or longer.
The Strategy of Paratransgenesis for the Control of Malaria Transmission
Authors: Fofana Aminata , Yerbanga Rakiswendé Serge , Bilgo Etienne , Ouedraogo Georges Anicet , Gendrin Mathilde , Ouedraogo Jean-Bosco
Published: June 2022

Insect-borne diseases are responsible for important burdens on health worldwide particularly in Africa. Malaria alone causes close to half a million deaths every year, mostly in developing, tropical and subtropical countries, with 94% of the global deaths in 2019 occurring in the WHO African region. With several decades, vector control measures have been fundamental to fight against malaria. Considering the spread of resistance to insecticides in mosquitoes and to drugs in parasites, the need for novel strategies to inhibit the transmission of the disease is pressing. In recent years, several studies have focused on the interaction of malaria parasites, bacteria and their insect vectors. Their findings suggested that the microbiota of mosquitoes could be used to block Plasmodium transmission. A strategy, termed paratransgenesis, aims to interfere with the development of malaria parasites within their vectors through genetically-modified microbes, which produce antimalarial effectors inside the insect host. Here we review the progress of the paratransgenesis approach. We provide a historical perspective and then focus on the choice of microbial strains and on genetic engineering strategies. We finally describe the different steps from laboratory design to field implementation to fight against malaria.
Expected Limits on the Potential for Carbon Dioxide Removal From Artificial Upwelling
Authors: Koweek David A.
Published: June 2022

Artificial upwelling, the engineered upward pumping of deep ocean water, has long been proposed as a technique to fertilize the ocean and, more recently, remove atmospheric carbon dioxide. This study investigated the potential of artificial upwelling to contribute to carbon dioxide removal using a simple model with high-resolution (1° × 1°) gridded monthly climatologies of upper ocean and deep ocean physical and chemical properties. The potential for carbon dioxide removal was explored across a range of observationally-informed carbon-to-nitrogen-to-phosphorus ratios for microalgae and macroalgae communities, providing information on the sensitivity of the estimates to any assumed carbon-to-nutrient ratios. Simulated carbon dioxide removal across the tropical-to-subpolar ocean did not exceed 0.66 tons per square kilometer per year for microalgae, and did not exceed 0.85 tons per square kilometer per year for macroalgae. Using current technology, the estimated global aggregate potential for carbon dioxide removal using microalgae was less than 50 megatons (0.05 gigatons) of carbon dioxide annually and the estimated global aggregate potential for carbon dioxide removal using macroalgae was approximately 100 megatons (0.1 gigatons) of carbon dioxide annually. While controlled field trials are needed to validate or invalidate the findings of this study, this study suggests that artificial upwelling is unlikely to support annual carbon dioxide removal at, or close to, the rate of one gigaton of carbon dioxide annually.
Description and Spatial Modelling of Benthic Communities Distribution in the Canadian Arctic Archipelago
Authors: Dumais Philippe-Olivier , Grant Cindy , Bluhm Bodil A. , De Montety Laure , de Coeli Lisa Treau , Tremblay Jean-Éric , Archambault Philippe
Published: June 2022

In the Arctic, sea ice loss has already transformed the dominant sources and periodicity of primary production in some areas, raising concerns over climate change impacts on benthic communities. Considered to be excellent indicators of environmental changes, benthic invertebrates play important roles in nutrient cycling, sediment oxygenation and decomposition. However, this biological component of the Canadian Arctic Archipelago (CAA) is still somewhat poorly studied compared to other Arctic regions. To partly fill this need, this study aims to evaluate benthic community composition and its relationship to significant environmental drivers and to develop spatial predictive explanatory models of these communities to expand coverage between sampled stations across the Kitikmeot Sea region and Parry Channel. Results from previously collected samples suggest that biodiversity is higher in this region compared to the Beaufort and Baffin Seas, two adjacent regions to the West and East, respectively. This finding leads to the main hypothesis that (1) benthic communities are succeeding one another, forming an ecotone (transition area) between the Beaufort Sea and the Baffin Sea. Other hypotheses are that (2) Pacific Ocean water influence through the CAA can explain part of this gradient, and that (3) terrigenous inputs affect the distribution of species. Overall, results tend to confirm hypotheses. Generalized Linear Models (GLMs) (with R2 up to 0.80) clearly displayed a succession in community distribution from Queen-Maud Gulf (Southwest) to Lancaster Sound (Northeast). Such models can be useful in identifying potential biodiversity hotspots and as a baseline for marine spatial planning purposes. Further, Pacific origin water (traced with concentrations of nitrate relative to phosphate) and terrigenous inputs (traced with silicate concentrations) were related to species and community distribution. Given that these two inputs/factors are generally increasing in the Canadian Arctic, their influence on benthic communities may also be seen to increase in the upcoming years.
Association of COVID-19 Case-Fatality Rate With State Health Disparity in the United States
Authors: Lee Yu-Che , Chang Ko-Yun , Mirsaeidi Mehdi
Published: June 2022

Background

The disproportionate burden of COVID-19 pandemic has become a major concern in the United States (US), but the association between COVID-19 case-fatality rate (CFR) and factors influencing health outcomes at a state level has not been evaluated.

Methods

We calculated COVID-19 CFR for three different waves using COVID Data Tracker from the Centers for Disease Control and Prevention. America's Health Rankings assesses the factors that influence health outcomes to determine state's health rankings. The association between COVID-19 CFR and state health disparities was analyzed by linear regression.

Results

States with better rankings of Physical Environment were associated with lower CFR for the 1st wave (β = 0.06%, R2 = 0.170, P = 0.003). There was a paradoxical association between the 2nd wave CFR and Clinical Care (β = −0.04%, R2 = 0.112, P = 0.017) and Overall health rankings (β = −0.03%, R2 = 0.096, P = 0.029). For the 3rd wave, states with better rankings of Overall health factors (β = 0.01%, R2 = 0.179, P = 0.002), Social & Economic Factors (β = 0.01%, R2 = 0.176, P = 0.002), Behaviors (β = 0.01%, R2 = 0.204, P < 0.001), and Health Outcomes (β = 0.01%, R2 = 0.163, P = 0.004) were associated with lower CFR. COVID-19 vaccination coverage was also associated with state health rankings (at least one dose: β = −0.13%, R2 = 0.305, P < 0.001; fully vaccinated: β = −0.06%, R2 = 0.120, P = 0.014).

Conclusions

These findings suggested targeted public health interventions and mitigation strategies addressing health disparities are essential to improve inequitable outcomes of COVID-19 in the US.
Biochar and Manure Applications Differentially Altered the Class 1 Integrons, Antimicrobial Resistance, and Gene Cassettes Diversity in Paddy Soils
Authors: Ali Niyaz , Lin Yinfu , Jiang Ligeng , Ali Izhar , Ahmed Ishtiaq , Akhtar Kashif , He Bing , Wen Ronghui
Published: June 2022

Integrons are genetic components that are critically involved in bacterial evolution and antimicrobial resistance by assisting in the propagation and expression of gene cassettes. In recent decades, biochar has been introduced as a fertilizer to enhance physiochemical properties and crop yield of soil, while manure has been used as a fertilizer for centuries. The current study aimed to investigate the impact of biochar, manure, and a combination of biochar and manure on integrons, their gene cassettes, and relative antimicrobial resistance in paddy soil. Field experiments revealed class 1 (CL1) integrons were prevalent in all samples, with higher concentration and abundance in manure-treated plots than in biochar-treated ones. The gene cassette arrays in the paddy featured a broad pool of cassettes with a total of 35% novel gene cassettes. A majority of gene cassettes encoded resistance to aminoglycosides, heat shock protein, heavy metals, pilus secretory proteins, and twin-arginine translocases (Tat), TatA, TatB, and TatC. Both in combination and solo treatments, the diversity of gene cassettes was increased in the manure-enriched soil, however, biochar reduced the gene cassettes’ diversity and their cassettes array. Manure considerably enhanced CL1 integrons abundance and antimicrobial resistance, whereas biochar amendments significantly reduced integrons and antimicrobial resistance. The results highlighted the differential effects of biochar and manure on integrons and its gene cassette arrays, showing increased abundance of integrons and antibiotic resistance upon manure application and decrease of the same with biochar. The use of biochar alone or in combination with manure could be a beneficial alternative to mitigate the spread of antimicrobial resistance and bacterial evolution in the environment, specifically in paddy soils.
Biochemical and Structural Characterization of Thermostable GH159 Glycoside Hydrolases Exhibiting α-L-Arabinofuranosidase Activity
Authors: Baudrexl Melanie , Fida Tarik , Berk Berkay , Schwarz Wolfgang H. , Zverlov Vladimir V. , Groll Michael , Liebl Wolfgang
Published: June 2022

Functional, biochemical, and preliminary structural properties are reported for three glycoside hydrolases of the recently described glycoside hydrolase (GH) family 159. The genes were cloned from the genomic sequences of different Caldicellulosiruptor strains. This study extends the spectrum of functions of GH159 enzymes. The only activity previously reported for GH159 was hydrolytic activity on β-galactofuranosides. Activity screening using a set of para-nitrophenyl (pNP) glycosides suggested additional arabinosidase activity on substrates with arabinosyl residues, which has not been previously reported for members of GH159. Even though the thermophilic enzymes investigated—Cs_Gaf159A, Ch_Gaf159A, and Ck_Gaf159A—cleaved pNP-α-l-arabinofuranoside, they were only weakly active on arabinogalactan, and they did not cleave arabinose from arabinan, arabinoxylan, or gum arabic. However, the enzymes were able to hydrolyze the α-1,3-linkage in different arabinoxylan-derived oligosaccharides (AXOS) with arabinosylated xylose at the non-reducing end (A3X, A2,3XX), suggesting their role in the intracellular hydrolysis of oligosaccharides. Crystallization and structural analysis of the apo form of one of the Caldicellulosiruptor enzymes, Ch_Gaf159A, enabled the elucidation of the first 3D structure of a GH159 member. This work revealed a five-bladed β-propeller structure for GH159 enzymes. The 3D structure and its substrate-binding pocket also provides an explanation at the molecular level for the observed exo-activity of the enzyme. Furthermore, the structural data enabled the prediction of the catalytic amino acids. This was supported by the complete inactivation by mutation of residues D19, D142, and E190 of Ch_Gaf159A.
Association of Lesion Location and Fatigue Symptoms After Ischemic Stroke: A VLSM Study
Authors: Wang Jinjing , Gu Mengmeng , Xiao Lulu , Jiang Shiyi , Yin Dawei , He Ye , Wang Peng , Sun Wen , Liu Xinfeng
Published: June 2022

Background:

Poststroke fatigue (PSF) is a common symptom in stroke survivors, yet its anatomical mechanism is unclear. Our study was aimed to identify which brain lesions are related to the PSF in patients with acute stroke.

Method

Patients with first-ever acute ischemic stroke consecutively admitted from the first affiliated hospital of the University of Science and Technology of China (USTC) between January 2017 and June 2020. Fatigue was scored using the Fatigue Severity Scale. All the participants were assessed by 3.0 T brain MRI including diffusion-weighted imaging. The infarct lesions were delineated manually and transformed into a standard template. Voxel-based lesion-symptom mapping (VLSM) was applied to investigate the association between lesion location and the occurrence and severity of fatigue. The same analyses were carried out by flipping the left-sided lesions. Multivariate logistic regressions were applied to verify the associations.

Results

Of the 361 patients with acute stroke, 142 (39.3%) patients were diagnosed with fatigue in the acute phase and 116 (35.8%) at 6 months after the index stroke. VLSM analysis indicated clusters in the right thalamus which was significantly associated with the occurrence and severity of PSF at 6-month follow-up. In contrast, no significant cluster was found in the acute phase of stroke. The flipped analysis did not alter the results. Multivariate logistic regression verified that lesion load in the right thalamus (OR 2.67, 95% CI 1.46–4.88) was an independent predictor of 6-month PSF.

Conclusion

Our findings indicated that lesions in the right thalamus increased the risk of fatigue symptoms 6 months poststroke.
Somatotopic Mapping of the Fingers in the Somatosensory Cortex Using Functional Magnetic Resonance Imaging: A Review of Literature
Authors: Janko Daniel , Thoenes Kristina , Park Dahye , Willoughby W. R. , Horton Meredith , Bolding Mark
Published: June 2022

Multiple studies have demonstrated finger somatotopy in humans and other primates using a variety of brain mapping techniques including functional magnetic resonance imaging (fMRI). Here, we review the literature to better understand the reliability of fMRI for mapping the somatosensory cortex. We have chosen to focus on the hand and fingers as these areas have the largest representation and have been the subject of the largest number of somatotopic mapping experiments. Regardless of the methods used, individual finger somatosensory maps were found to be organized across Brodmann areas (BAs) 3b, 1, and 2 in lateral-to-medial and inferior-to-superior fashion moving from the thumb to the pinky. However, some consistent discrepancies are found that depend principally on the method used to stimulate the hand and fingers. Therefore, we suggest that a comparative analysis of different types of stimulation be performed to address the differences described in this review.
Clinical Features and Outcome of the Guillain–Barre Syndrome: A Single-Center 11-Year Experience
Authors: Ginanneschi Federica , Giannini Fabio , Sicurelli Francesco , Battisti Carla , Capoccitti Giorgio , Bartalini Sabina , Mignarri Andrea , Volpi Nila , Cioncoloni David , Franci Laura , De Stefano Nicola , Rossi Alessandro
Published: June 2022

Background

Clinical presentation, electrophysiological subtype, and outcome of the Guillain–Barre' Syndrome (GBS) may differ between patients from different geographical regions. This study aims to assess clinical–neurophysiological features of an adult, Italian GBS cohort over 11 years.

Methods

Retrospective (from 1 January 2011 to 31 December 2021) analysis was carried out on patients admitted to the Siena University Hospital who fulfilled the GBS diagnostic criteria. Demographic data, clinical characteristics, treatment, need of mechanical ventilation (MV), laboratory and electrophysiological tests, preceding infections/vaccination/other conditions, and comorbidities were collected for each patient.

Results

A total of 84 patients (51 men, median age of 61 years), were identified. GBS subtype was classified as acute inflammatory demyelinating polyneuropathy (AIDP) in the 66.6% of patients, acute motor/sensory axonal neuropathy (AMAN/AMSAN) in 20.2%, and the Miller Fisher syndrome in 5 (5.9%). Flu syndrome and gastrointestinal infection were the most common preceding conditions. In total, five (5.9%) subjects had concomitant cytomegalovirus (CMV) infection. Cranial nerve involvement occurred in 34.5% of subjects. Differences between the axonal and AIDP forms of GBS concerned the presence of anti-ganglioside antibodies. In total, seven (8.33%) patients required MV.

Discussion

The epidemiological and clinical characteristics of GBS in different countries are constantly evolving, especially in relation to environmental changes. This study provides updated clinical-epidemiological information in an Italian cohort.
miR-200a-3p- and miR-181-5p-Mediated HOXB5 Upregulation Promotes HCC Progression by Transcriptional Activation of EGFR
Authors: Li Weizhi , Li Yingchao , Li Peijie , Ma Fuquan , Liu Mengying , Kong Shuzhen , Xue Hui
Published: June 2022

Background

Hepatocellular carcinoma (HCC) remains a worldwide burden. However, the mechanisms behind the malignant biological behavior of HCC remain unclear. The homeobox (HOX) family could act as either promoters or suppressors in different kinds of malignancies. Our study discovered the role of HOXB5 in regulating HCC progression.

Methods

The HOXB5 expression was assessed by RT-PCR analysis in human HCC samples and cell lines. HOXB5 transcriptional regulation of the EGFR was verified by the luciferase reporter assay and chromatin immunoprecipitation experiment. The oncogenic role of HOXB5 in HCC progression was analyzed by CCK8, colony-forming, and transwell assays.

Results

Upregulation of HOXB5 was found in human HCC, and was strongly correlated with HCC tumor size, tumor-nodule metastasis, TNM stage, and relatively unfavorable OS and DFS. Ectopic expression of HOXB5 promoted the capacity of cell growth and clonogenicity, while the inhibition of HOXB5 decreased the proliferation and clonogenicity potential in vitro by CCK8 and colony-forming assays. In addition, HOXB5 also promoted cell migration by transwell experiment. Mechanism studies elucidated that HOXB5 triggers HCC progression via direct transcriptional activation of EGFR. The upregulation of HOXB5 is regulated by miR-200a-3p and miR-181-5p. Transfection of miR-200a-3p and miR-181-5p mimics blocked the cell proliferation and migration regulated by HOXB5, while overexpression of the 3′-UTR mutant HOXB5 abolished the suppressive effect of miR-200a-3p and miR-181-5p, but not the wild-type HOXB5.

Conclusion

HOXB5 is a promising prognostic factor in human HCC. Targeting miR-200a-3p and the miR-181-5p/HOXB5/EGFR signaling pathway may provide new options for the treatment strategies of HCC.
Biological Effectiveness of Ion Beam for In Vitro Cell Irradiations
Authors: Li Heng
Published: June 2022

Despite numerous ion beam irradiation of cell experiments performed over the past five decades, the relationship between the biological effectiveness of ion beams and the physical characteristics of the ion beam remains unclear. Using 1,118 sets of in vitro cell survival experiments with ion beam irradiation, compiled by the Particle Irradiation Data Ensemble (PIDE) project, the relationship between cell survival and the fluence and linear energy transfer (LET) of the ion beam was established. Unlike previous studies, the closed-form analytical function is independent of photon irradiation and takes a universal form across all ion and cell species. A new understanding of the biological effectiveness of ion beams is crucial for predicting tumor response and toxicities in ion beam radiation therapy, along with radiation protection for high-LET ion beams with low fluence.
p66Shc Deficiency in Chronic Lymphocytic Leukemia Promotes Chemokine Receptor Expression Through the ROS-Dependent Inhibition of NF-κB
Authors: Tatangelo Vanessa , Boncompagni Gioia , Capitani Nagaja , Lopresti Ludovica , Manganaro Noemi , Frezzato Federica , Visentin Andrea , Trentin Livio , Baldari Cosima T. , Patrussi Laura
Published: June 2022

The microenvironment of lymphoid organs is central to the pathogenesis of chronic lymphocytic leukemia (CLL). Within it, tumor cells find a favourable niche to escape immunosurveillance and acquire pro-survival signals. We have previously reported that a CLL-associated defect in the expression of the pro-apoptotic and pro-oxidant adaptor p66Shc leads to enhanced homing to and accumulation of leukemic cells in the lymphoid microenvironment. The p66Shc deficiency-related impairment in intracellular reactive oxygen species (ROS) production in CLL cells is causally associated to the enhanced expression of the chemokine receptors CCR2, CXCR3 and CCR7, that promote leukemic cell homing to both lymphoid and non-lymphoid organs, suggesting the implication of a ROS-modulated transcription factor(s). Here we show that the activity of the ROS-responsive p65 subunit of the transcription factor NF-κB was hampered in the CLL-derived cell line MEC-1 expressing a NF-κB-luciferase reporter following treatment with H2O2. Similar results were obtained when intracellular ROS were generated by expression of p66Shc, but not of a ROS-defective mutant, in MEC-1 cells. NF-κB activation was associated with increased expression of the chemokine receptors CCR2, CXCR3 and CCR7. Reconstitution of p66Shc in CLL cells normalized intracellular ROS and hampered NF-κB activation, which led to a decrease in the expression of these homing receptors. Our data provide direct evidence that the p66Shc-deficiency-related ROS depletion in CLL cells concurs to NF-κB hyperactivation and homing receptor overexpression, providing a mechanistic basis for the enhanced ability of these cells to accumulate in the pro-survival lymphoid niche.
B Cells in Tumor Microenvironment Associated With The Clinical Benefit to Programmed Cell Death Protein-1 Blockade Therapy in Patients With Advanced Esophageal Squamous Cell Carcinoma
Authors: Guo Jhe-Cyuan , Hsu Chia-Lang , Huang Yen-Lin , Lin Chia-Chi , Huang Ta-Chen , Wu I-Chen , Lin Chen-Yuan , Lien Ming-Yu , Kuo Hung-Yang , Cheng Ann-Lii , Hsu Chih-Hung
Published: June 2022

Background

B cells and B cell-related gene signatures in the tumor microenvironment (TME) are associated with the efficacy of anti-programmed cell death-1 (anti-PD-1) therapy in several cancer types, but not known for esophageal squamous cell carcinoma (ESCC).

Patients and Methods

Patients with advanced ESCC receiving anti-PD-1/PD-L1-based therapy were retrospectively included. A targeted RNA profiling of 770 immune-related genes from archival ESCC tissues was performed. Differential immune-related pathways and the levels of infiltrating immune cells were estimated through Gene Set Enrichment Analysis and CIBERSORT, respectively. CD19 and CD138 expression were evaluated through immunohistochemistry (IHC). The markers evaluated were correlated with clinical benefit (CB; defined as either objective response or stable disease for ≥6 months) and survival.

Results

A total of 64 patients were enrolled. The transcriptome analysis based on 25 patients revealed that B cell signature was significantly increased in patients with CB (P <.05) and correlated with a longer PFS (P = .032) and OS (P = .013). Multiple genes representative of B cells, B cell functions, and plasma cells were upregulated in patients with CB. On further analysis of B cell subtypes in patients with CB, increase of naïve B cells (P = .057) and plasma cells (P <.01) was found but not memory B cells (P = .27). The CD19 expression in tumor stroma, detected by IHC, was higher in patients with CB (P = .033).

Conclusion

B cells in the TME were associated with CB in patients with advanced ESCC receiving anti-PD-1/PD-L1-based therapy.
Whole-Genome DNA Methylation Sequencing Reveals Epigenetic Changes in Myelodysplastic Syndromes
Authors: Zhou Jing-dong , Xu Zi-jun , Jin Ye , Zhang Xin-long , Gu Yu , Ma Ji-chun , Wen Xiang-mei , Lin Jiang , Zhang Ting-juan , Qian Jun
Published: June 2022

Epigenetic dysregulation of cancer-associated genes has been identified to contribute to the pathogenesis of myelodysplastic syndromes (MDS). However, few studies have elucidated the whole-genome DNA methylation in the initiation pathogenesis of MDS. Reduced representation bisulfite sequencing was performed in five de novo MDS patients and four controls to investigate epigenetic alterations in MDS pathogenesis. The mean global methylation in five MDS patients showed no significant difference compared with the four controls. In depth, a total of 1,459 differentially methylated fragments, including 759 hypermethylated and 700 hypomethylated fragments, were identified between MDS patients and controls. Targeted bisulfite sequencing further identified that hypermethylation of DLEU7, FOXR1, LEP, and PANX2 were frequent events in an additional cohort of MDS patients. Subsequently, LEP hypermethylation was confirmed by real-time quantitative methylation-specific PCR in an expanded cohort of larger MDS patients. In clinics, LEP hypermethylation tended to be associated with lower bone marrow blasts and was significantly correlated with U2AF1 mutation. Survival analysis indicated that LEP hypermethylation was associated with a markedly longer survival time but was not an independent prognostic biomarker in MDS patients. Functional studies revealed pro-proliferative and anti-apoptotic effects of leptin in the MDS cell line SKM-1, and it was significantly associated with cell growth and death as well as the Toll-like receptor and NF-kappa B signaling pathways. Collectively, our findings demonstrated that whole-genome DNA methylation analysis identified novel epigenetic alterations such as DLEU7, FOXR1, LEP, and PANX2 methylations as frequent events in MDS. Moreover, LEP might play a role in MDS pathogenesis, and LEP hypermethylation was associated with longer survival but not as an independent prognostic biomarker in MDS.
Proteomic Analysis Identifies p62/SQSTM1 as a Critical Player in PARP Inhibitor Resistance
Authors: Uddin Mohammed Hafiz , Zhou Jun-Ying , Pimentel Julio , Patrick Steve M. , Kim Seongho , Shekhar Malathy P. , Wu Gen Sheng
Published: June 2022

Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) are currently being used for treating breast cancer patients with deleterious or suspected deleterious germline BRCA-mutated, HER2-negative locally advanced or metastatic diseases. Despite durable responses, almost all patients receiving PARPis ultimately develop resistance and succumb to their illness, but the mechanism of PARPi resistance is not fully understood. To better understand the mechanism of PARPi resistance, we established two olaparib-resistant SUM159 and MDA468 cells by chronically exposing olaparib-sensitive SUM159 and MDA468 cells to olaparib. Olaparib-resistant SUM159 and MDA468 cells displayed 5-fold and 7-fold more resistance over their corresponding counterparts. Despite defects in PARPi-induced DNA damage, these olaparib-resistant cells are sensitive to cisplatin-induced cell death. Using an unbiased proteomic approach, we identified 6 447 proteins, of which 107 proteins were differentially expressed between olaparib-sensitive and -resistant cells. Ingenuity pathway analysis (IPA) revealed a number of pathways that are significantly altered, including mTOR and ubiquitin pathways. Among these differentially expressed proteins, p62/SQSTM1 (thereafter p62), a scaffold protein, plays a critical role in binding to and delivering the ubiquitinated proteins to the autophagosome membrane for autophagic degradation, was significantly downregulated in olaparib-resistant cells. We found that autophagy inducers rapamycin and everolimus synergistically sensitize olaparib-resistant cells to olaparib. Moreover, p62 protein expression was correlated with better overall survival in estrogen receptor-negative breast cancer. Thus, these findings suggest that PARPi-sensitive TNBC cells hyperactivate autophagy as they develop acquired resistance and that pharmacological stimulation of excessive autophagy could lead to cell death and thus overcome PARPi resistance.
Emerging Perspectives of Bone Metastasis in Hepatocellular Carcinoma
Authors: Yuan Xiaofeng , Zhuang Ming , Zhu Xi , Cheng Dong , Liu Jie , Sun Donglin , Qiu Xubin , Lu Yunjie , Sartorius Kurt
Published: June 2022

Recent evidence suggests the global incidence and mortality of hepatocellular carcinoma (HCC) are increasing. Although the highest incidence of HCC remains entrenched in WHO regions with high levels of HBV-HCV infection, the etiology of this disease is rapidly changing to include other lifestyle risk factors. Extrahepatic metastasis is a frequent feature of advanced HCC and most commonly locates in the lungs and bone. Bone metastasis in HCC (HCC-BM) signals a more aggressive stage of disease and a poorer prognosis, simultaneously HCC-BM compromises the function and integrity of bone tissue. HCC induced osteolysis is a prominent feature of metastasis that complicates treatment needed for pathologic fractures, bone pain and other skeletal events like hypercalcemia and nerve compression. Early detection of bone metastases facilitates the treatment strategy for avoiding and relieving complications. Although recent therapeutic advances in HCC like targeting agents and immunotherapy have improved survival, the prognosis for patients with HCC-BM remains problematic. The identification of critical HCC-BM pathways in the bone microenvironment could provide important insights to guide future detection and therapy. This review presents an overview of the clinical development of bone metastases in HCC, identifying key clinical features and identifying potential molecular targets that can be deployed as diagnostic tools or therapeutic agents.
Cord Blood SARS-CoV-2 IgG Antibodies and Their Association With Maternal Immunity and Neonatal Outcomes
Authors: Helguera-Repetto Addy Cecilia , Villegas-Mota Isabel , Arredondo-Pulido Guadalupe Itzel , Cardona–Pérez Jorge Arturo , León-Juárez Moises , Rivera-Rueda Maria Antonieta , Arreola-Ramírez Gabriela , Mateu-Rogell Paloma , Acevedo-Gallegos Sandra , López-Navarrete Gloria Elena , Valdespino-Vázquez María Yolotzin , Martínez-Salazar Guadalupe , Rodríguez-Bosch Mario , Coronado-Zarco Irma Alejandra , Castillo-Gutiérrez María del Rosario , Cuevas-Jiménez Carlos Alberto , Moreno-Verduzco Elsa Romelia , Espino-y-Sosa Salvador , Cortés-Bonilla Manuel , Irles Claudine
Published: June 2022

Passive transplacental immunity is crucial for neonatal protection from infections. Data on the correlation between neonatal immunity to SARS-CoV-2 and protection from adverse outcomes is scarce. This work aimed to describe neonatal seropositivity in the context of maternal SARS-CoV-2 infection, seropositivity, and neonatal outcomes. This retrospective nested case-control study enrolled high-risk pregnant women with a SARS-CoV-2 RT-PCR positive test who gave birth at the Instituto Nacional de Perinatología in Mexico City and their term neonates. Anti-SARS-CoV-2 IgG antibodies in maternal and cord blood samples were detected using a chemiluminescent assay. In total, 63 mother-neonate dyads (mean gestational age 38.4 weeks) were included. Transplacental transfer of SARS-CoV-2 IgG occurred in 76% of neonates from seropositive mothers. A positive association between maternal IgG levels and Cycle threshold (Ct) values of RT-qPCR test for SARS-CoV-2 with neonatal IgG levels was observed. Regarding neonatal outcomes, most seropositive neonates did not require any mechanical ventilation, and none developed any respiratory morbidity (either in the COVID-19 positive or negative groups) compared to 7 seronegative neonates. Furthermore, the odds of neonatal respiratory morbidity exhibited a tendency to decrease when neonatal IgG levels increase. These results add further evidence suggesting passive IgG transfer importance.
Genetic Factors and Their Role in the Pathogenesis of Biliary Atresia
Authors: Wu Li-Na , Zhu Zhi-Jun , Sun Li-Ying
Published: June 2022

Biliary Atresia, a common basis for neonatal cholestasis and primary indication for Liver Transplantation, accounts for 60% of pediatric Liver Transplantations. While the pathogenesis of Biliary Atresia remains obscure, abnormalities within bile ducts and the liver, inflammation, fibrosis and cilia defects are thought to comprise the pathological basis for this condition. The findings of genetic variants in Biliary Atresia, such as Copy Number Variations and Single Nucleotide Polymorphism, are considered as essential factors in the development of this condition. In this review, we summarize and analyze these Biliary Atresia variants from a perspective of their pathological characteristics. In conclusion, such analyses may offer novel insights into the pathogenesis of Biliary Atresia and provide a foundation for future studies directed toward a better understanding and treatment of Biliary Atresia.
Treatment Strategy for Chronic Obstructive Parotitis Related to Diabetes: A Retrospective Analysis of 12 Cases
Authors: Wu Chuan-Bin , Xue Lei , Zhou Qing
Published: June 2022

Objectives: The aim of this study was to describe our experience in treating chronic obstructive parotitis (COP) related to diabetes.

Methods: Twelve patients with COP related to diabetes were selected for the study. A sialendoscope was introduced from the orifice to investigate the ductal wall and lumen. During the operation, chymotrypsin and gentamicin were injected. All patients were followed up for 6 months. Preoperative and postoperative visual analog scale (VAS) evaluations and salivary gland scintigraphy (SGS) examinations were applied to evaluate the therapeutic effect; differences were considered statistically significant at p < 0.05.

Results: A sialendoscope was successfully used under local anesthesia in all members of the cohort. As shown by the endoscope, mucus plugs were the most common feature. Some adhered tightly to the ductal wall. We also found ductal congestion in some cases. The postoperative VAS scores and SGS counts were both significantly lower than the preoperative values (p < 0.05).

Conclusion: Chymotrypsin administration during interventional sialendoscopy is significantly effective in the treatment of diabetes-related COP.
NEU1—A Unique Therapeutic Target for Alzheimer’s Disease
Authors: Khan Aiza , Sergi Consolato M.
Published: June 2022

Neuraminidase 1 (NEU1) is considered to be the most abundant and ubiquitous mammalian enzyme, with a broad tissue distribution. It plays a crucial role in a variety of cellular mechanisms. The deficiency of NEU1 has been implicated in various pathological manifestations of sialidosis and neurodegeneration. Thus, it is a novel therapeutic target for neurodegenerative changes in the Alzheimer’s brain. However, to manipulate NEU1 as a therapeutic target, it is imperative to understand that, although NEU1 is commonly known for its lysosomal catabolic function, it is also involved in other pathways. NEU1 is involved in immune response modulation, elastic fiber assembly modulation, insulin signaling, and cell proliferation. In recent years, our knowledge of NEU1 has continued to grow, yet, at the present moment, current data is still limited. In addition, the unique biochemical properties of NEU1 make it challenging to target it as an effective therapeutic option for sialidosis, which is a rare disease but has an enormous patient burden. However, the fact that NEU1 has been linked to the pathology of Alzheimer’s disease, which is rapidly growing worldwide, makes it more relevant to be studied and explored. In the present study, the authors have discussed various cellular mechanisms involving NEU1 and how they are relevant to sialidosis and Alzheimer’s disease.
Roles and Molecular Mechanisms of Physical Exercise in Sepsis Treatment
Authors: Wu You , Guo Xiaofeng , Peng Yuliang , Fang Zongping , Zhang Xijing
Published: June 2022

Physical exercise is a planned, purposeful action to keep a healthy lifestyle and improve physical fitness. Physical exercise has been widely used as a non-pharmacological approach to preventing and improving a wide range of diseases, including cardiovascular disease, cancer, metabolic disease, and neurodegenerative disease. However, the effects of physical exercise on sepsis have not been summarized until now. In this review, we discuss the effects of physical exercise on multiple organ functions and the short- and long-time outcomes of sepsis. Furthermore, the molecular mechanisms underlying the protective effects of physical exercise on sepsis are discussed. In conclusion, we consider that physical exercise may be a beneficial and non-pharmacological alternative for the treatment of sepsis.
Influence of Sex, BMI, and Skin Color on the Accuracy of Non-Invasive Cuffless Photoplethysmography-Based Blood Pressure Measurements
Authors: Nachman Dean , Eisenkraft Arik , Goldstein Nir , Ben-Ishay Arik , Fons Meir , Merin Roei , Gepner Yftach
Published: June 2022

Vital signs obtained by photoplethysmography-based devices might be influenced by subcutaneous fat and skin color. This observational comparison study aimed to test the accuracy of blood pressure (BP) measurements between a photoplethysmography-based device and cuff-based BP device in ambulatory individuals, coming for a routine BP checkup. Systolic BP (SBP) and diastolic BP (DBP) measurements were stratified based on sex, BMI (<25; 25 ≤BMI<30; 30 ≤kg/m2), and skin color (types 1–3 and 4–6 by the Fitzpatrick scale). A total of 1548 measurements were analyzed. Correlations of SBP and DBP between the devices among males/females were between 0.914–0.987 (p < 0.001), and Bland-Altman analysis showed a bias of less than 0.5 mmHg for both sexes. Correlations of SBP and DBP between the devices among BMI groups were between 0.931–0.991 (p < 0.001), and Bland-Altman analysis showed a bias of less than 1 mmHg for all. Correlations of SBP and DBP between the devices among the skin color groups were between 0.936–0.983 (p < 0.001), and Bland-Altman analysis showed a bias of less than 1 mmHg for all. This study shows similar and high agreements between BP measurements obtained using a PPG-based non-invasive cuffless BP device and a cuff-based BP device across sex, BMI, and skin color groups.
Using Multi-Task Learning-Based Framework to Detect ST-Segment and J-Point Deviation From Holter
Authors: Wu Shuang , Cao Qing , Chen Qiaoran , Jin Qi , Liu Zizhu , Zhuang Lingfang , Lin Jingsheng , Lv Gang , Zhang Ruiyan , Chen Kang
Published: June 2022

Artificial intelligence is increasingly being used on the clinical electrocardiogram workflows. Few electrocardiograms based on artificial intelligence algorithms have focused on detecting myocardial ischemia using long-term electrocardiogram data. A main reason for this is that interference signals generated from daily activities while wearing the Holter monitor lowered the ability of artificial intelligence to detect myocardial ischemia. In this study, an automatic system combining denoising and segmentation modules was developed to detect the deviation of the ST-segment and J point. We proposed a ECG Bidirectional Transformer network that applied in both denoising and segmentation tasks. The denoising model achieved RMSEde, SNRimp, and PRD values of 0.074, 10.006, and 16.327, respectively. The segmentation model achieved precision, sensitivity (recall), and F1-score of 96.00, 93.06, and 94.51%, respectively. The system’s ability to distinguish the depression and elevation of the ST-segment and J point was also verified by cardiologists as well. From our ECG dataset, 103 patients with ST-segment depression and 10 patients with ST-segment elevation were detected with positive predictive values of 80.6 and 60% respectively. Using Holter ECG and transformer-based deep neural networks, we can detect subtle ST-segment changes in noisy ECG signals. This system has the potential to improve the efficacy of daily medicine and to provide a broader population-level screening for asymptomatic myocardial ischemia.
Technostress Creators and Job Performance Among Frontliners: Theorizing the Moderating Role of Self-Efficacy
Authors: Saidy Jeannette , Garanti Zanete , Sadaka Richard
Published: June 2022

Technostress is evolving as an imperative area of academic research amid the “new normal” settings of working remotely. Research has investigated the relationships between technostress and job outcomes and proposed individual- and organizational-level approaches to manage it. However, insights into the influence of dynamic personality differences on this relationship are limited. This study ties the concept of self-efficacy to the transactional model of stress and coping, and investigates to what extent computer and social self-efficacy moderate the relationships between technostress creators and frontline employee’s job performance. Findings shift the focus from the negative aspects of technostress and outcomes to both positive and negative aspects. This study’s contributions and implications for theory and practice are discussed.
The Impact of the COVID-19 Pandemic on the Physical Fitness of Primary School Students in China Based on the Bronfenbrenner Ecological Theory
Authors: Li Hailing , Cheong Jadeera Phaik Geok
Published: June 2022

After the outbreak of the COVID-19 pandemic, nation lockdown became an effective way to isolate the spread of the virus. Schools were postponed, students had to stay at home and opportunities for physical activity amongst school children were severely affected. This research sought to determine the impact of the pandemic on the physical fitness of primary school students. In total, 1,235 students from grades one to five in a primary school in Beijing took part in this research. Using the Chinese National Student Physical Fitness Standard as a guide, the students were subjected to BMI, vital capacity, 50 m sprint, sit and reach, timed rope-skipping, timed sit-ups, and 50m × 8 shuttle run measurements. These tests were administered once before and once after the lockdown period. The results showed that the overall physical fitness of the participants was better after the lockdown [p= 0.000, r = −0.14, 95% CI (–0.219, –0.061)]. Specifically, vital capacity, sit and reach, timed rope-skipping and timed sit-ups had improved after the lockdown. Meanwhile, 50m × 8 shuttle run dropped slightly but not significantly whereas 50 m sprint dropped sharply after the lockdown. The proportion of overweight and obese students increased, but the difference before and after the lockdown was small. It appeared that during the pandemic, through the intervention of many comprehensive factors, home-based fitness was normalized and promoted the healthy development of students.