Miracle-dz/UniFAR-FTUs huggingface dataset:
Two Hits for Bone Regeneration in Aged Patients: Vertebral Bone Marrow Clot as a Biological Scaffold and Powerful Source of Mesenchymal Stem Cells

Recently, the use of a new formulation of bone marrow aspirate (BMA), the BMA clot, has been described. This product entails a naturally formed clot from the harvested bone marrow, which retains all the BMA components preserved in a matrix biologically molded by the clot. Even though its beneficial effects were demonstrated by some studies, the impact of aging and aging-associated processes on biological properties and the effect of BMA cell-based therapy are currently unknown. The purpose of our study was to compare selected parameters and properties of clotted BMA and BMA-derived mesenchymal stem cells (MSCs) from younger (<45 years) and older (>65 years) female donors. Clotted BMA growth factors (GFs) expression, MSCs morphology and viability, doubling time, surface marker expression, clonogenic potential, three-lineage differentiation, senescence-associated factors, and Klotho synthesis from younger and older donors were analyzed. Results indicated that donor age does not affect tissue-specific BMA clot regenerative properties such as GFs expression and MSCs morphology, viability, doubling time, surface antigens expression, colony-forming units, osteogenic and adipogenic differentiation, and Klotho and senescence-associated gene expression. Only few differences, i.e., increased platelet-derived growth factor-AB (PDGF-AB) synthesis and MSCs Aggrecan (ACAN) expression, were detected in younger donors in comparison with older ones. However, these differences do not interfere with all the other BMA clot biological properties. These results demonstrated that BMA clot can be applied easily, without any sample processing and avoiding potential contamination risks as well as losing cell viability, proliferation, and differentiation ability, for autologous transplantation in aged patients. The vertebral BMA clot showed two successful hits since it works as a biological scaffold and as a powerful source of mesenchymal stem cells, thus representing a novel and advanced therapeutic alternative for the treatment of orthopedic injuries.
Lung Adenocarcinoma Cells Promote Self-Migration and Self-Invasion by Activating Neutrophils to Upregulate Notch3 Expression of Cancer Cells

Background: Invasion and migration of cancer cells play a key role in lung cancer progression and metastasis. Tumor-associated neutrophils (TANs) are related to poor prognosis in many types of cancer. However, the role of TANs in lung cancer is controversial. In this study, we investigated the effect of TANs on the invasion and migration of lung adenocarcinoma. Methods: Immunohistochemistry was performed to detect the density of infiltrating TANs and the expression of Notch3 in 100 lung adenocarcinoma tissues. Flow cytometry was used to observe the viability of neutrophils, which were isolated from healthy peripheral blood and then exposed to the supernatant of cultured lung adenocarcinoma cell lines. After treating with tumor-associated neutrophils culture supernatant, NeuCS (supernatant of cultured neutrophils), tumor cells culture supernatant, Medium (serum-free medium), respectively, the migration and invasion of the lung cancer cells before and after transfected by si-Notch3 were detected by transwell assay and wound healing assay. Kaplan-Meier plotter (http://kmplot.com/analysis/index.php? p) was used to analyze the prognostic role of the density of TANs on lung adenocarcinoma and TIMER ((http://cistrome.dfci.harvard.edu/TIMER/) was used to detect the expression of Notch3 on lung adenocarcinoma. Results: The infiltration of TANs was observed in the parenchyma and stroma of the lung adenocarcinoma, the density of TANs was positively related to the TNM stage and negatively related to the differentiation and prognosis. Notch3 expression of cancer cells was negatively related to the tumor differentiation and prognosis. Compared to quiescent neutrophils, the viability of TCCS-activated neutrophils was enhanced. Both migration and invasion of A549 and PC9 cells were significantly promoted by TANs, while after knocking down Notch3, the migration and invasion of the cancer cells were not affected by TANs. Bioinformatics analysis showed that the density of TANs and the expression of Notch3 were related to the poor prognosis. Conclusion: The results indicated that lung adenocarcinoma cells promote self-invasion and self-migration by activating neutrophils to upregulate the Notch3 expression of cancer cells. The density of infiltrating TANs may be a novel marker for the poor prognosis of lung adenocarcinoma. Targeting TANs might be a potential therapeutic strategy for lung cancer treatment.
Cancer-Specific Survival Outcome in Early-Stage Young Breast Cancer: Evidence From the SEER Database Analysis

Background Young women with breast cancer are determined to present poorer survival compare with elderly patients. Therefore, identifying the clinical prognostic factors in young women with early-stage (T1-2N0-1M0) breast cancer is pivotal for surgeons to make better postoperative management. Methods The clinicopathological characteristics of female patients with early-stage breast cancer from the Surveillance, Epidemiology, and End Results program between Jan 2010 and Dec 2015 were retrospectively reviewed and analyzed. Univariate and multivariate Cox regression analyses were used to determine the potential risk factors of cancer-specific survival in young women with early-stage breast cancer. The nomogram was constructed and further evaluated by an internal validation cohort. The Kaplan-Meier survival curves were used to estimate cancer-specific survival probability and the cumulative incidence. Results Six variables including race, tumor location, grade, regional lymph node status, tumor subtype, and size were identified to be significantly associated with the prognosis of young women with early-stage breast cancer during the postoperative follow-up. A nomogram for predicting the 3-, 5- year cancer-specific survival probability in this subpopulation group was established with a favorable concordance index of 0.783, supported by an internal validation cohort with the AUC of 0.722 and 0.696 in 3-, 5- year cancer-specific survival probability, respectively. Conclusions The first predictive nomogram containing favorable discrimination is successfully established and validated for predicting the 3-, 5- year cancer-specific survival probability in young women with early-stage breast cancer during the postoperative follow-up. This model would help clinicians to make accurate treatment decisions in different clinical risk population.
Neuron to Oligodendrocyte Precursor Cell Synapses: Protagonists in Oligodendrocyte Development and Myelination, and Targets for Therapeutics

The development of neuronal circuitry required for cognition, complex motor behaviors, and sensory integration requires myelination. The role of glial cells such as astrocytes and microglia in shaping synapses and circuits have been covered in other reviews in this journal and elsewhere. This review summarizes the role of another glial cell type, oligodendrocytes, in shaping synapse formation, neuronal circuit development, and myelination in both normal development and in demyelinating disease. Oligodendrocytes ensheath and insulate neuronal axons with myelin, and this facilitates fast conduction of electrical nerve impulses via saltatory conduction. Oligodendrocytes also proliferate during postnatal development, and defects in their maturation have been linked to abnormal myelination. Myelination also regulates the timing of activity in neural circuits and is important for maintaining the health of axons and providing nutritional support. Recent studies have shown that dysfunction in oligodendrocyte development and in myelination can contribute to defects in neuronal synapse formation and circuit development. We discuss glutamatergic and GABAergic receptors and voltage gated ion channel expression and function in oligodendrocyte development and myelination. We explain the role of excitatory and inhibitory neurotransmission on oligodendrocyte proliferation, migration, differentiation, and myelination. We then focus on how our understanding of the synaptic connectivity between neurons and OPCs can inform future therapeutics in demyelinating disease, and discuss gaps in the literature that would inform new therapies for remyelination.
Protective Effects of Appropriate Amount of Nuts Intake on Childhood Blood Pressure Level: A Cross-Sectional Study

Objective Increased blood pressure (BP) is a major risk factor for cardiovascular disease (CVD) in adults. Regular consumption of nuts may improve some BP in adults whereas evidence in children is relatively lacking. This study aimed to determine the efficacy of nuts intake on BP in children. Methods Stratified cluster sampling was performed to include a total of 15,268 primary school children aged 6–12 years in urban and rural areas in Southwest China. The daily nuts intake dosage was collected by questionnaires, and generalized linear model (GLM) and logistic regression were used to analyze the relationship between nuts intake and BP. Results For the total subjects, 11,130 (72.9%) participants consumed <35 g/day of nuts, 1,145 (7.5%) participants consumed 35 g/day ≤ nut <50 g/day of nuts, 2,053 (13.4%) participants consumed 50~100 g/day of nuts, and 940 (6.2%) participants consumed over 100 g/day of nut. For sex subgroup, 1,074 (13.53%) boys and 979 (13.35%) girls consumed 50~100 g/day of nuts. Compared with the 50~100 g/day of nuts intake group, systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) were significantly different in <35 g/day, 35g/day ≤ nut <50 g/day, and >100 g/day nuts intake groups (all p < 0.001). The logistic regression showed that compared with the 50~100 g/day group, the other three groups are more likely associated with childhood hypertension (all p < 0.001). Therefore, a U-shaped relationship between nuts intake and BP level was identified. Conclusions The finding suggests that intake of 50~100 g/day nuts is the recommended dose of nuts intake to control childhood hypertension, as well as for cardioprotection purposes.
Hantavirus Induced Kidney Disease

Hantavirus induced hemorrhagic fever with renal syndrome (HFRS) is an emerging viral zoonosis affecting up to 200,000 humans annually worldwide. This review article is focused on recent advances in the mechanism, epidemiology, diagnosis, and treatment of hantavirus induced HFRS. The importance of interactions between viral and host factors in the design of therapeutic strategies is discussed. Hantavirus induced HFRS is characterized by thrombocytopenia and proteinuria of varying severities. The mechanism of kidney injury appears immunopathological with characteristic deterioration of endothelial cell function and compromised barrier functions of the vasculature. Although multidisciplinary research efforts have provided insights about the loss of cellular contact in the endothelium leading to increased permeability, the details of the molecular mechanisms remain poorly understood. The epidemiology of hantavirus induced renal failure is associated with viral species and the geographical location of the natural host of the virus. The development of vaccine and antiviral therapeutics is necessary to avoid potentially severe outbreaks of this zoonotic illness in the future. The recent groundbreaking approach to the SARS-CoV-2 mRNA vaccine has revolutionized the general field of vaccinology and has provided new directions for the use of this promising platform for widespread vaccine development, including the development of hantavirus mRNA vaccine. The combinational therapies specifically targeted to inhibit hantavirus replication and vascular permeability in infected patients will likely improve the disease outcome.
Comparison of Systemic Treatments for Metastatic Castration-Resistant Prostate Cancer After Docetaxel Failure: A Systematic Review and Network Meta-analysis

Background: Lacking head-to-head trial, the optimal treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) after docetaxel failure is unclear. This study is to compare the efficacy and safety of systemic treatments in patients who progressed after docetaxel to aid clinical decision-making. Methods: Databases including MEDLINE, EMBASE, and the Cochrane Library were searched from inception to June 15th, 2021. The outcomes of interest include overall survival (OS), biochemical progression-free survival (bPFS), and serious adverse events (SAEs). The Cochrane risk of bias tools were used to assess study quality. Indirect comparisons of competing treatments were performed via Bayesian network meta-analysis. Results: Five trials with 3,862 patients comparing four treatments (abiraterone, enzalutamide, cabazitaxel, and radium-223) were identified. All the four treatments were associated with improved OS and bPFS relative to best supportive care. Among them, enzalutamide (hazard ratio [HR] = 0.58, 95% credible interval [Crl]: 0.49–0.69) had the highest probability of ranking first in terms of OS, followed by cabazitaxel (HR = 0.70, 95% Crl: 0.59–0.83), radium-223 (HR = 0.71, 95% Crl: 0.56–0.90) and abiraterone (HR = 0.73, 95% Crl: 0.63–0.84). Similarly, enzalutamide (HR = 0.25, 95% Crl: 0.20–0.31) showed the greatest improvement of bPFS, followed by abiraterone (HR = 0.60, 95% Crl: 0.51–0.71) and cabazitaxel (HR = 0.75, 95% Crl: 0.63–0.89). In terms of safety, treatments ranked from the safest to the least safe were radium-223 (OR = 0.58, 95% Crl: 0.20–1.68), enzalutamide (OR = 0.80, 95% Crl: 0.28–2.29), abiraterone (OR = 0.94, 95% Crl: 0.39–2.27) and cabazitaxel (OR = 2.50, 95% Crl: 0.84–7.44). Conclusion: For patients with mCRPC who progressed after docetaxel, enzalutamide may offer the most significant survival benefits and satisfying safety. Cabazitaxel is effective in post-docetaxel settings but associated with a high risk of SAEs. Although network meta-analysis provides indirect comparisons and ranking probabilities, the results should be treated with caution as it cannot replace randomized direct comparison. Systematic Review Registration: https://www.crd. york.ac. uk/prospero/display_record. php? ID=CRD42020223040, identifier CRD42020223040.
Associations Between Diabetic Retinopathy and Parkinson's Disease: Results From the Catalonian Primary Care Cohort Study

The purpose of this study was to assess the risk of occurrence of Parkinson's disease (PD) among subjects with type 2 diabetes and diabetic retinopathy (DR) in our large primary health care database from Catalonia (Spain). A retrospective cohort study with pseudo-anonymized routinely collected health data from SIDIAP was conducted from 2008 to 2016. We calculated the number of events, time to event, cumulative incidence, and incidence rates of PD for subjects with and without DR and for different stages of DR. The proportional hazards regression analysis was done to assess the probability of occurrence between DR and PD. In total, 26,453 type 2 diabetic subjects with DR were identified in the database, and 216,250 subjects without DR at inclusion. During the follow-up period, 1,748 PD events occurred. PD incidence rate and cumulative incidence were higher among subjects with DR (16.95 per 10,000 person-years and 0.83%, respectively). In the unadjusted analysis, subjects with DR were at 1.25 times higher risk (hazard ratio: 1.22, 95% confidence interval: 1.06; 1.41) of developing PD during the study period. However, we did not find any statistically significant HR for DR in any models after adjusting for different risk factors (age, sex, duration of diabetes, smoking, body mass index, glycosylated hemoglobin, comorbidities). In conclusion, in our primary health care population database, DR was not associated with an increased risk of PD after adjusting for different risk factors. In our retrospective cohort study, age, male sex, and diabetes duration were independent risk factors for developing PD.
Multidimensional Deep Learning Reduces False-Positives in the Automated Detection of Cerebral Aneurysms on Time-Of-Flight Magnetic Resonance Angiography: A Multi-Center Study

Current deep learning-based cerebral aneurysm detection demonstrates high sensitivity, but produces numerous false-positives (FPs), which hampers clinical application of automated detection systems for time-of-flight magnetic resonance angiography. To reduce FPs while maintaining high sensitivity, we developed a multidimensional convolutional neural network (MD-CNN) designed to unite planar and stereoscopic information about aneurysms. This retrospective study enrolled time-of-flight magnetic resonance angiography images of cerebral aneurysms from three institutions from June 2006 to April 2019. In the internal test, 80% of the entire data set was used for model training and 20% for the test, while for the external tests, data from different pairs of the three institutions were used for training and the remaining one for testing. Images containing aneurysms > 15 mm and images without aneurysms were excluded. Three deep learning models [planar information-only (2D-CNN), stereoscopic information-only (3D-CNN), and multidimensional information (MD-CNN)] were trained to classify whether the voxels contained aneurysms, and they were evaluated on each test. The performance of each model was assessed using free-response operating characteristic curves. In total, 732 aneurysms (5.9 ± 2.5 mm) of 559 cases (327, 120, and 112 from institutes A, B, and C; 469 and 263 for 1.5T and 3.0T MRI) were included in this study. In the internal test, the highest sensitivities were 80.4, 87.4, and 82.5%, and the FPs were 6.1, 7.1, and 5.0 FPs/case at a fixed sensitivity of 80% for the 2D-CNN, 3D-CNN, and MD-CNN, respectively. In the external test, the highest sensitivities were 82.1, 86.5, and 89.1%, and 5.9, 7.4, and 4.2 FPs/cases for them, respectively. MD-CNN was a new approach to maintain sensitivity and reduce the FPs simultaneously.
Experimental Periodontitis Deteriorated Atherosclerosis Associated With Trimethylamine N-Oxide Metabolism in Mice

Background Periodontitis is considered a risk factor for atherosclerosis, but the mechanism is not clear. It was reported that oral administration of Porphyromonas gingivalis altered the gut microbiota in mice. Gut dysbiosis and the intestinal metabolite trimethylamine N-oxide (TMAO) were verified to be associated with atherosclerosis. Therefore, the possible TMAO-related mechanism between periodontitis and atherosclerosis needs to be explored. Methods Experimental periodontitis was established by oral administration of P. gingivalis for 2 months in ApoE−/− mice. Mouse hemi-mandibles were scanned using Micro-CT. Quantification of TMAO was performed using liquid chromatography–tandem mass spectrometry. Mouse feces were collected and the bacterial DNA was extracted, then the gut microbiota was analyzed using 16S rRNA genes. Atherosclerotic lesion areas were quantified. Livers, small intestines, and large intestines were analyzed for gene expression. Results Aggravated atherosclerosis plaques were found in experimental periodontitis mice. Plasma TMAO, a pathogenic factor of atherosclerosis, was initially found to be increased in periodontitis mice. Changes in the composition and abundance of the intestinal microflora of periodontitis mice were found. Flavin monooxygenase 3 (FMO3), the catalyzing enzyme of TMAO in the liver, was significantly increased, accompanied by an increase of IL-6 in liver, the abnormal intestinal integrity and enhanced plasma LPS. The IL-6 and LPS were verified to be able to increase FMO3 in HepG2 cells. Conclusion Our research discovered that experimental periodontitis in ApoE−/− mice induced gut dysbiosis and an increase in TMAO. These results suggest a possible mechanism by which periodontitis may accelerate atherosclerosis by influencing the intestinal microbes and the metabolism, which were triggered by inflammation of the liver and intestine.
Relationship Between Peripheral Refraction in Different Retinal Regions and Myopia Development of Young Chinese People

Objective To observe the associations between regional peripheral refraction and myopia development in young Chinese people. Methods Two hundred and forty-one young adult subjects (21 emmetropes, 88 low myopes, 94 moderate myopes, and 38 high myopes) aged 18–28 years were included, and only the right eyes were tested. Eye biometrics were measured before pupil dilation using the Lenstar. Relative peripheral refractive errors (RPRE) were measured after pupil dilation using multispectral refractive topography (MRT), at nine retinal eccentricities: 0–5, 5–10, 10–15, 15–20, 20–25, 25–30, 30–35, 35–40, and 40–45 degrees. Results In this study, RPRE increased with eccentricity, and it shows a growing trend with the increase of the degree of myopia among emmetropia, low myopia and moderate myopia groups, and RPRE varied with myopia severity at eccentricities between 20 and 35 degrees only. In addition, axial length (AL) and RPRE were positively correlated between 20 and 45 degrees, and AL was an independent risk factor for RPRE between 20 and 35 degrees. Conclusion These findings indicate that the eccentricities between 20 and 35 degrees RPRE may be closely related to refractive development and eye growth in young Chinese people.
Common Variable Immunodeficiency Disorders as a Model for Assessing COVID-19 Vaccine Responses in Immunocompromised Patients

1 Department of Clinical Immunology, Auckland Hospital, Auckland, New Zealand, 2 Department of Virology and Immunology, Auckland Hospital, Auckland, New Zealand, 3 Department of Molecular Medicine and Pathology, School of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand, 4 Department of Respiratory Medicine, Wellington Hospital, Wellington, New Zealand, 5 School of Biological Sciences, University of Auckland, Auckland, New Zealand, 6 Maurice Wilkins Centre, School of Biological Sciences, University of Auckland, Auckland, New Zealand, 7 Auckland Cancer Society Research Centre, School of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand, 8 Allergy and Clinical Immunology Laboratory, Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC, Australia