Miracle-dz/UniFAR-FTUs huggingface dataset:
Clinical Potential and Current Progress of Dental Pulp Stem Cells for Various Systemic Diseases in Regenerative Medicine: A Concise Review

Dental pulp stem cells (DPSCs) are mesenchymal stem cells (MSCs) that have multipotent differentiation and a self-renewal ability. They have been useful not only for dental diseases, but also for systemic diseases. Extensive studies have suggested that DPSCs are effective for various diseases, such as spinal cord injuries, Parkinson’s disease, Alzheimer’s disease, cerebral ischemia, myocardial infarction, muscular dystrophy, diabetes, liver diseases, eye diseases, immune diseases, and oral diseases. DPSCs have the potential for use in a cell-therapeutic paradigm shift to treat these diseases. It has also been reported that DPSCs have higher regenerative potential than the bone marrow-derived mesenchymal stem cells known as representative MSCs. Therefore, DPSCs have recently gathered much attention. In this review, the therapeutic potential of DPSCs, the latest progress in the pre-clinical study for treatment of these various systemic diseases, and the clinical applications of DPSCs in regenerative medicine, are all summarized. Although challenges, including mechanisms of the effects and establishment of cell processing and transplantation methods for clinical use, still remain, DPSCs could be promising stem cells sources for various clinical applications, because of their easy isolation by a noninvasive procedure without ethical concerns.
Improving breast cancer risk prediction by using demographic risk factors, abnormality features on mammograms and genetic variants

The predictive capability of combining demographic risk factors, germline genetic variants, and mammogram abnormality features for breast cancer risk prediction is poorly understood. We evaluated the predictive performance of combinations of demographic risk factors, high risk single nucleotide polymorphisms (SNPs), and mammography features for women recommended for breast biopsy in a retrospective case-control study (n = 768) with four logistic regression models. The AUC of the baseline demographic features model was 0.580. Both genetic variants and mammography abnormality features augmented the performance of the baseline model: demographics + SNP (AUC =0.668), demographics + mammography (AUC =0.702). Finally, we found that the demographics + SNP + mammography model (AUC = 0.753) had the greatest predictive power, with a significant performance improvement over the other models. The combination of demographic risk factors, genetic variants and imaging features improves breast cancer risk prediction over prior methods utilizing only a subset of these features.
Pharmacological Restoration of Visual Function in a Zebrafish Model of von-Hippel Lindau Disease

Von Hippel-Lindau (VHL) syndrome is rare, autosomal dominant disorder, characterized by hypervascularised tumour formation in multiple organ systems. Vision loss associated with retinal capillary hemangioblastomas remains one of the earliest complications of VHL disease. The mortality of Vhl-/- mice in utero restricted modelling of VHL disease in this mammalian model. Zebrafish harbouring a recessive germline mutation in the vhl gene represent a viable, alterative vertebrate model to investigate associated ocular loss-of-function phenotypes. Previous studies reported neovascularization of the brain, eye and trunk together with odema in the vhl-/- zebrafish eye. In this study, we demonstrate vhl-/- zebrafish almost entirely lack visual function. Furthermore, hyaloid vasculature networks in the vhl-/- eye are improperly formed and this phenotype is concomitant with development of an ectopic intraretinal vasculature. Sunitinib, a multi tyrosine kinase inhibitor, market authorised for cancer, reversed the ocular behavioural and morphological phenotypes observed in vhl-/- zebrafish. We conclude that the zebrafish vhl gene contributes to the endogenous molecular barrier that prevents development of intraretinal vasculature and that sunitinib can improve visual function and hyaloid vessel patterning while reducing abnormally formed ectopic intraretinal and choroidal vessels in vhl-/- zebrafish.
The High-throughput sequencing of Sillago japonica mitochondrial genome reveals the phylogenetic position within the genus Sillago

Abstract The complete mitogenome of Sillago japonica was determined through high-throughput DNA sequencing technology. The circular mtDNA molecule was 16 645 bp in size and encoded 13 protein-coding genes, 2 rRNAs, 22 tRNAs and 2 non-coding regions, with the gene arrangement and content identical to other typical vertebrate mitogenomes. The identity analysis revealed that the mitogenome sequence of S. japonica shared a relatively high sequence identity to S. asiatica (81.5%) compared with S. aeolus (77.5%), S. indica (77.1%), and S. sihama (76.3%). The neighbor-joining tree of complete mitogenome sequence showed that S. japonica firstly clustered together with S. asiatica, then grouped with S. indica and S. sihama, and finally gathered with S. aeolus. Taken together, the results absolutely supported the evolutionary position of S. japonica and provided new insights into phylogenetic relationships of Sillago.
Impact of USP8 Gene Mutations on Protein Deregulation in Cushing Disease.

CONTEXT Cushing disease (CD) is a rare disorder with severe sequels and incompletely understood pathogenesis. The underlying corticotroph adenomas harbor frequently somatic mutations in the ubiquitin-specific peptidase 8 (USP8) gene. These mutations render USP8 hyperactive and prevent client proteins from degradation. OBJECTIVE To investigate the impact of USP8 mutations on proteins deregulated in CD. DESIGN One hundred eight pituitary adenomas (75 corticotroph [58 USP8 wild type (WT) and 17 USP8 mutated], 14 somatotroph, and 19 nonfunctioning) were investigated by immunohistochemistry. All evaluated proteins [USP8, arginine vasopressin receptor 1b and 2, corticotropin-releasing hormone receptor, cAMP response element-binding protein (CREB), p27/kip1, cyclin E, heat shock protein 90 (HSP90), orphan nuclear receptor 4, epidermal growth factor receptor, histone deacetylase 2, glucocorticoid receptor, cyclin-dependent kinase 5 and Abelson murine leukemia viral oncogene homolog 1 enzyme substrate 1] were known to be deregulated in CD. Furthermore, AtT20 cells were transfected with USP8 to investigate the expression of possible downstream proteins by immunoblot. RESULTS Whereas most of the investigated proteins were not differentially expressed, the cell-cycle inhibitor p27 was significantly reduced in USP8 mutated corticotroph adenoma (H-score 2.0 ± 1.0 vs 1.1 ± 1.1 in WT adenomas; P = 0.004). In contrast, the chaperone HSP90 was expressed higher (0.5 ± 0.4 vs 0.2 ± 0.4; P = 0.29), and the phosphorylation of the transcription factor CREB was increased in USP8 mutated adenomas (1.30.5 ± 0.40.9 vs 0.70.5 ± 0.40.7; P = 0.014). Accordingly, AtT20 cells transfected with the USP8 P720R mutant had higher phosphorylated CREB (pCREB) levels than WT transfected cells (1.3 ± 0.14 vs 1 ± 0.23; P = 0.13). CONCLUSIONS We could demonstrate that USP8 mutations are associated with deregulation of p27/kip1, HSP90, and pCREB. These findings suggest that these proteins are direct or indirect clients of USP8 and could therefore be potential targets for therapeutic approaches in patients with CD.
Qualitative research as evidence: expanding the paradigm for evidence-based healthcare

Writing in the BMJ , David Sackett and John Wennberg pointed out over 20 years ago we need to stop ‘squabbling over the best methods’ and focus on the research question, since it is the nature of the question that determines the best research design to answer it.1 Yet, the majority of evidence hierarchies and ‘levels’2 still do not include qualitative methodologies, and Evidence-based Health Care (EBHC) still largely focuses on the positivist perspective of generating and applying knowledge in healthcare practice.3 Despite its lack of prominence in EBHC, qualitative research in healthcare has increasingly been conducted and published since Sackett and Wennberg’s editorial, and the publication of qualitative evidence syntheses have doubled in the past decade.4 The argument for qualitative research within EBHC has been made for over 20 years,5 including a series of educational articles in the BMJ 6–9 and all of which have citations in the 1000s. NB: the journal has since reversed their position on qualitative research to one where qualitative research seems no longer a priority for the journal to the dismay of prominent proponents.10 To understand why qualitative research has yet to achieve the same status as other forms of evidence within the evidence-based healthcare movement, we need to consider wider contextual factors surrounding research and the underlying epistemological differences between the quantitative and qualitative paradigms. Qualitative research can be of exploratory and/or explanatory nature. It seeks to answer …
High‐throughput screening of excipients with a biological effect: a kinetic study on the effects of surfactants on efflux‐mediated transport

In this study, we develop and apply a high‐throughput screening protocol to investigate the activity of non‐ionic surfactants, with a broad range of hydrophilic–lipophilic balance values, against ABCB1‐mediated efflux transport and ABCC2‐mediated efflux transport.
An overview of microbiome based strategies on anti‐obesity

With the significant global obesity epidemic and emerging strong scientific evidence that connected gut microbiota to obesity, intervening obesity by targeting gut microbiota has become a trendy strategy. Particularly the application of probiotics has become remarkably popular because of their expected association with gut microbiota modulation. Although there are many literatures on the effects of probiotics in obese animal models, most of them reported the effects of probiotic bacteria on metabolic indications with limited information on anti‐obesity itself. Besides, some probiotics have been shown to reduce certain metabolic symptoms but they failed to achieve weight loss. This report reviewed the current literatures on the anti‐obesity effects of next‐generation probiotics in various animal obesity models and discussed the beneficial potential of fecal microbiota transplantation in treating obesity in humans. The purpose of this article is to help guide further research improve the probiotic bacteria experiments in more precise animal obesity models by standardizing the anti‐obesogenesis, obesity control, and treatment assays and hopefully the evidence‐based investigations on harnessing gut microbiota through next‐generation probiotics or fecal microbiota transplantation will develop new interventions to promote and achieve anti‐obesity.
VKORC1 and Novel CYP2C9 Variation Predict Warfarin Response in Alaska Native and American Indian People

Alaska Native and American Indian (AN/AI) people have unique pharmacogene variation that may affect warfarin disposition and therapeutic response. We performed targeted genotyping for cytochrome P450 (CYP)2C9, vitamin K epoxide oxidase reductase complex subunit 1 (VKORC1), CYP4F2, CYP4F11, and gamma‐glutamyl carboxylase (GGCX) variants in AN/AI people receiving warfarin. The primary outcome was stable warfarin dose, defined as one dose, and associated international normalized ratio within the target range, at least 6 months after starting therapy, with two matching doses at least 2 weeks apart. Genotype–phenotype relationships were assessed by multivariate regression analysis, adjusted for self‐reported heritage, age, gender, and concurrent statin use. VKORC1 genotype explained 34% of dose variability, with VKORC1 −1639G>A and 1173C>T associated with a 1.7 mg/day (P = 1.4e‐05) dose reduction. Additionally, CYP2C9 N218I was suggestively significant (P = 0.077), with heterozygotes requiring 1.1 mg/day less than reference individuals. Self‐reported heritage was significantly associated with dose, largely driven by differences in the diagnostic VKORC1 allele frequencies among AN/AI people.
Communicating Risk Regarding Food Consumption: The Case of Processed Meat

The present research combines real data and parameters found in recent literature that were used to design realistic scenarios demonstrating the potential effects (benefits and costs) of the World Health Organization (WHO)’s risk communication regarding the consumption of processed meat, which was proven to be associated with an increased risk of colorectal cancer (CRC) in an International Agency for Research on Cancer (IARC)/WHO report. The impact of the risk communication of processed meat consumption was simulated using Monte Carlo microsimulation models. The results showed that a 1% reduction in the number of high-level processed meat consumers may lead to a yearly decrease in CRC cases of 406.43 (IC 95%: −243.94, 1056.81), while the more extreme scenario of a 15% reduction may lead to 2086.62 fewer cases (IC 95%: 1426.66, 2746.57). On the other hand, if demand contraction in the processed meat sector resulted in a 0.1% loss in employment, one could expect 27.23 all-cause mortalities attributable to job loss (IC 95%: 16.55, 37.80). This simulation study demonstrates that caution should be taken when implementing public awareness campaigns, particularly when the prevention message is not straightforward.
Effects of basal insulin glargine and omega‐3 on lower limb arterial disease outcome in patients with dysglycaemia: An analysis of the Outcome Reduction with an Initial Glargine INtervention (ORIGIN) trial

The impact of insulin or omega‐3 supplements on the incidence and progression of peripheral artery disease (PAD) in patients with dysglycaemia has not been well studied. The Outcome Reduction with an Initial Glargine INtervention (ORIGIN) trial randomized participants with dysglycaemia and cardiovascular risk factors to titrated insulin glargine vs standard care, and to either 1 g of omega‐3 per day or placebo. We assessed incident PAD, defined as the composite of either asymptomatic or symptomatic PAD according to the randomized interventions in the 11 119 ORIGIN participants whose baseline ankle‐brachial index (ABI) was >0.9 (no PAD), and PAD progression in the 971 ORIGIN participants whose baseline ABI was ≤0.9. Hazard ratios (HR) were adjusted for confounders. During a 6.2‐year follow‐up period, allocation to insulin glargine vs standard care had a neutral effect on the composite of PAD incidence (HR, 0.99; 95% CI, 0.86‐1.15) and progression (HR, 0.88; 95% CI, 0.63‐1.22). Similar findings were noted for allocation to omega‐3 vs placebo for PAD incidence (HR, 1.02; 95% CI, 0.89‐1.18) and progression (HR, 0.93; 95% CI, 0.67‐1.28). In this large study, neither insulin glargine nor omega‐3 affected the incidence or progression of PAD.
Novel Ca2+‐independent carbohydrate recognition of the C‐type lectins, SPL‐1 and SPL‐2, from the bivalve Saxidomus purpuratus

Novel Ca2+‐independent C‐type lectins, SPL‐1 and SPL‐2, were purified from the bivalve Saxidomus purpuratus. They are composed of dimers with either identical (SPL‐2 composed of two B‐chains) or distinct (SPL‐1 composed of A‐ and B‐chains) polypeptide chains, and show affinity for N‐acetylglucosamine (GlcNAc)‐ and N‐acetylgalactosamine (GalNAc)‐containing carbohydrates, but not for glucose or galactose. A database search for sequence similarity suggested that they belong to the C‐type lectin family. X‐ray crystallographic analysis revealed definite structural similarities between their subunits and the carbohydrate‐recognition domain (CRD) of the C‐type lectin family. Nevertheless, these lectins (especially SPL‐2) showed Ca2+‐independent binding affinity for GlcNAc and GalNAc. The crystal structure of SPL‐2/GalNAc complex revealed that bound GalNAc was mainly recognized via its acetamido group through stacking interactions with Tyr and His residues and hydrogen bonds with Asp and Asn residues, while widely known carbohydrate‐recognition motifs among the C‐type CRD (the QPD [Gln‐Pro‐Asp] and EPN [Glu‐Pro‐Asn] sequences) are not involved in the binding of the carbohydrate. Carbohydrate‐binding specificities of individual A‐ and B‐chains were examined by glycan array analysis using recombinant lectins produced from Escherichia coli cells, where both subunits preferably bound oligosaccharides having terminal GlcNAc or GalNAc with α‐glycosidic linkages with slightly different specificities.
Inhibition of Nucleotide Synthesis Targets Brain Tumor Stem Cells in a Subset of Glioblastoma

Inhibition of both the de novo (DNP) and salvage (NSP) pathways of nucleoside synthesis has been demonstrated to impair leukemia cells. We endeavored to determine whether this approach would be efficacious in glioblastoma. To diminish nucleoside biosynthesis, we utilized compound DI-39, which selectively targets NSP, in combination with thymidine (dT), which selectively targets DNP. We employed in vitro and ex vivo models to determine the effects of pretreatment with dT + DI-39 on brain tumor stem cells (BTSC). Here, we demonstrate that this combinatorial therapy elicits a differential response across a spectrum of human patient–derived glioblastoma cultures. As determined by apoptotic markers, most cultures were relatively resistant to treatment, although a subset was highly sensitive. Sensitivity was unrelated to S-phase delay and to DNA damage induced by treatment. Bioinformatics analysis indicated that response across cultures was associated with the transcription factor PAX3 (associated with resistance) and with canonical pathways, including the nucleotide excision repair pathway, PTEN (associated with resistance), PI3K/AKT (associated with sensitivity), and ErbB2-ErbB3. Our in vitro assays demonstrated that, in sensitive cultures, clonal sphere formation was reduced upon removal from pretreatment. In contrast, in a resistant culture, clonal sphere formation was slightly increased upon removal from pretreatment. Moreover, in an intracranial xenograft model, pretreatment of a sensitive culture caused significantly smaller and fewer tumors. In a resistant culture, tumors were equivalent irrespective of pretreatment. These results indicate that, in the subset of sensitive glioblastoma, BTSCs are targeted by inhibition of pyrimidine synthesis. Mol Cancer Ther; 15(6); 1271–8. ©2016 AACR.
Progress in the genomics and genome-wide study of sake yeast

ABSTRACT Completion of the whole genome sequence of a laboratory yeast strain Saccharomyces cerevisiae in 1996 ushered in the development of genome-wide experimental tools and accelerated subsequent genetic study of S. cerevisiae. The study of sake yeast also shared the benefit of such tools as DNA microarrays, gene disruption-mutant collections, and others. Moreover, whole genome analysis of representative sake yeast strain Kyokai no. 7 was performed in the late 2000s, and enabled comparative genomics between sake yeast and laboratory yeast, resulting in some notable finding for of sake yeast genetics. Development of next-generation DNA sequencing and bioinformatics also drastically changed the field of the genetics, including for sake yeast. Genomics and the genome-wide study of sake yeast have progressed under these circumstances during the last two decades, and are summarized in this article. Abbreviations: AFLP: amplified fragment length polymorphism; CGH: comparative genomic hybridization; CNV: copy number variation; DMS: dimethyl succinate; DSW: deep sea water; LOH: loss of heterozygosity; NGS: next generation sequencer; QTL: quantitative trait loci; QTN: quantitative trait nucleotide; SAM: S-adenosyl methionine; SNV: single nucleotide variation Graphical abstract Improvement of genetic infrastructures has supported the recent development of genomics and genome-wide studies of sake yeast.
Limited Field of View of Head-Mounted Displays Is Not the Cause of Distance Underestimation in Virtual Environments

Observers binocularly viewed a target placed in a large open field under two viewing conditions: unrestricted field of view and reduced field of view, as effected using a simulated head-mounted display. Observers indicated the perceived distance of the target, which ranged from 2 to 15 m, using both verbal report and blind walking. For neither response was there a reliable effect of limiting the field of view on the perception of distance. This result indicates that the significant underperception of distance observed in several studies on distance perception in virtual environments is not caused by the limited field of view of the head-mounted display.
Strategies for controlling egress of therapeutic cells from hydrogel microcapsules

Endothelial progenitor cells and human mesenchymal stem cells (hMSCs) have shown great regenerative potential to repair damaged tissue; however, their injection in vivo results in low retention and poor cell survival. Early clinical research has focussed on cell encapsulation to improve viability and integration of delivered cells. However, this strategy has been limited by the inability to reproduce large volumes of standardized microcapsules and the lack of information on cell‐specific egress and timed release from hydrogel microcapsules. Here, we address both of these limitations. First, we use a droplet microfluidic platform to generate monodisperse agarose microcapsules, and second we encapsulate and characterize egress of therapeutically relevant cells (human umbilical vein endothelial cells, endothelial progenitor cells, and hMSCs). With increased temporal resolution, we demonstrate distinct differences in egress between cell types. Importantly, therapeutic cells (hMSCs) egress quickly, in <6 hr following encapsulation. Further, we examined potential escape mechanisms and showed that proliferation can be exploited by cells for microcapsule translocation. We also systematically characterized the egress of fibroblasts (as model cells) following alterations to the microcapsules. Specifically, we show that microcapsule size and hydrogel density impact cell egress efficiency. Overall, our results demonstrate the need for characterization of cell‐specific egress and tuning of the cocoon microenvironment prior to delivery, for timely release and successful engraftment.
Predictors of pneumonitis-free survival following lung stereotactic body radiation therapy.

Background Radiation pneumonitis is a common toxicity following lung stereotactic body radiation therapy (SBRT). We explored whether motion management technique, in conjunction with patient and treatment characteristics, is a predictor of radiation pneumonitis-free survival (PNFS). Methods A single institution multi-center lung SBRT database was retrospectively reviewed. PNFS was defined as time to earliest onset of radiation pneumonitis or last clinical follow-up. Patients were simulated using a 4-dimensional approach, and those with 1 cm or greater tumor motion were selected for respiratory-gated treatment. Real-time Position Management and phase-based gating were employed. Univariate and multivariable Cox proportional hazard models were fit for relevant covariates to determine the impact of free-breathing versus respiratory-gated treatment on PNFS. Results The initial treatment courses of 208 patients were included, with a median follow-up length of 23 months. The median age at treatment was 71 years. About 91.8% of patient had early stage (T1-2) non-small cell lung cancer and were treated with common regimens including 10 Gy ×5, 12 Gy ×4 and 18 Gy ×3; 26.4% underwent respiratory-gated SBRT. The overall rate of grade 3 or higher radiation pneumonitis was 10.1%. PNFS was not significantly different between patients treated with respiratory-gated versus free-breathing SBRT (HR =0.88; P=0.707); tumor location and fractionation were predictors of PNFS in the multivariate setting. Conclusions The method of motion management does not appear to impact PNFS when the tolerance for tumor displacement is 1 cm or less for free-breathing treatment planning and delivery. This approach may be appropriate when selecting patients for respiratory gating.