Miracle-dz/UniFAR-FTUs huggingface dataset:
Application of PCSK9 Inhibitors in Practice: Part 2 The Patient Experience

PCSK9i (protein convertase subtilisin/kexin type 9 inhibitors) are set to revolutionize the treatment of hypercholesterolemia in the management of atherosclerotic risk, but numerous reports have detailed unprecedented barriers to access for these drugs. To overcome these challenges, our group created a model to facilitate provision of this new therapy for patients who qualify according to Food and Drug Administration criteria. This report details the real-world follow-up experience of PCSK9i use in a large patient cohort structured to ensure rigor in data collection, analysis, and interpretation. The 271 patients approved and actively followed in our PCSK9i clinic between July 2015 and August 2018 represent a 97% approval rate from insurance, with 28% of prescriptions requiring at least one appeal. Over 50% of patients were statin intolerant. On average, there was a median lapse of 15 days between initial visit and insurance approval. PCSK9i therapy was affordable for most patients, with an average monthly out-of-pocket expense of $58.05 (median $0). Only 2.3% of patients were unable to initiate or continue therapy because of cost. Reductions from baseline in LDL (low-density lipoprotein) cholesterol and Lp(a) (lipoprotein [a])were comparable to published reports with median reductions of 60% and 23% at 1 year, respectively. PCSK9i therapy was well-tolerated overall, though 9% of patients reported adverse events, and 5% of patients discontinued due mostly to musculoskeletal and flu-like symptoms. Our practice model demonstrates that PCSK9i therapy can be accessed easily and affordably for the majority of eligible patients, resulting in dramatic improvement in lipid profile results. Moreover, our registry data suggest that results from the prospective clinical trials of PCSK9i on LDL and Lp(a) reduction and on tolerability are applicable to a real-world cohort.
Indole Inhibits ToxR Regulon Expression in Vibrio cholerae

Indole is a degradation product of tryptophan that functions as a signaling molecule in many bacteria. This includes Vibrio cholerae, where indole was shown to regulate biofilm and type VI secretion in nontoxigenic environmental isolates. ABSTRACT Indole is a degradation product of tryptophan that functions as a signaling molecule in many bacteria. This includes Vibrio cholerae, where indole was shown to regulate biofilm and type VI secretion in nontoxigenic environmental isolates. Indole is also produced by toxigenic V. cholerae strains in the human intestine, but its significance in the host is unknown. We investigated the effects of indole on toxigenic V. cholerae O1 El Tor during growth under virulence inducing conditions. The indole transcriptome was defined by RNA sequencing and showed widespread changes in the expression of genes involved in metabolism, biofilm production, and virulence factor production. In contrast, genes involved in type VI secretion were not affected by indole. We subsequently found that indole repressed genes involved in V. cholerae pathogenesis, including the ToxR virulence regulon. Consistent with this, indole inhibited cholera toxin and toxin-coregulated pilus production in a dose-dependent manner. The effects of indole on virulence factor production and biofilm were linked to ToxR and the ToxR-dependent regulator LeuO. The expression of leuO was increased by exogenous indole and linked to repression of the ToxR virulence regulon. This process was dependent on the ToxR periplasmic domain, suggesting that indole was a ToxR agonist. This conclusion was further supported by results showing that the ToxR periplasmic domain contributed to indole-mediated increased biofilm production. Collectively, our results suggest that indole may be a niche-specific cue that can function as a ToxR agonist to modulate virulence gene expression and biofilm production in V. cholerae.
Opposing Regulation of Cancer Properties via KRT19-Mediated Differential Modulation of Wnt/β-Catenin/Notch Signaling in Breast and Colon Cancers

Although Keratin 19 (KRT19) has been reported as a tumor cell marker and found to interact with other proteins that modulate cancer properties, its role in cancer prognosis remains to be fully elucidated. We found that KRT19 expression was increased in both colon and breast cancer, but that knockdown of KRT19 showed opposing effects on cancer properties. In colon cancer, KRT19 knockdown resulted in suppression of cancer via downregulation of Wnt/Notch signaling without altering NUMB transcription. In breast cancer, KRT19 knockdown led to an increase in cancer properties because of attenuated Wnt and enhanced Notch signaling. In colon cancer, KRT19 interacted with β-catenin but not with RAC1, allowing the LEF/TCF transcription factor to bind primarily to the LEF1 and TCF7 promoter regions, whereas in breast cancer, KRT19 interacted with the β-catenin/RAC1 complex and led to apparent upregulation of NUMB expression and NUMB-mediated suppression of Notch signaling. These results reveal a novel differential role of KRT19 in carcinogenesis, due to differential modulation of Wnt/β-catenin/Notch signaling crosstalk through various interactions of KRT19 with only β-catenin or with the β-catenin/RAC1 complex, which might have implications for clinical cancer research.
Inhibition of Breast Cancer Cell Invasion by Ras Suppressor-1 (RSU-1) Silencing Is Reversed by Growth Differentiation Factor-15 (GDF-15)

Extracellular matrix (ECM)-related adhesion proteins are important in metastasis. Ras suppressor-1 (RSU-1), a suppressor of Ras-transformation, is localized to cell–ECM adhesions where it interacts with the Particularly Interesting New Cysteine-Histidine rich protein (PINCH-1), being connected to Integrin Linked Kinase (ILK) and alpha-parvin (PARVA), a direct actin-binding protein. RSU-1 was also found upregulated in metastatic breast cancer (BC) samples and was recently demonstrated to have metastasis-promoting properties. In the present study, we transiently silenced RSU-1 in BC cells, MCF-7 and MDA-MB-231. We found that RSU-1 silencing leads to downregulation of Growth Differentiation Factor-15 (GDF-15), which has been associated with both actin cytoskeleton reorganization and metastasis. RSU-1 silencing also reduced the mRNA expression of PINCH-1 and cell division control protein-42 (Cdc42), while increasing that of ILK and Rac regardless of the presence of GDF-15. However, the downregulation of actin-modulating genes PARVA, RhoA, Rho associated kinase-1 (ROCK-1), and Fascin-1 following RSU-1 depletion was completely reversed by GDF-15 treatment in both cell lines. Moreover, complete rescue of the inhibitory effect of RSU-1 silencing on cell invasion was achieved by GDF-15 treatment, which also correlated with matrix metalloproteinase-2 expression. Finally, using a graph clustering approach, we corroborated our findings. This is the first study providing evidence of a functional association between RSU-1 and GDF-15 with regard to cancer cell invasion.
Biomaterial and stem cell‐based strategies for skeletal muscle regeneration

Adult skeletal muscle can regenerate effectively after mild physical or chemical insult. Muscle trauma or disease can overwhelm this innate capacity for regeneration and result in heightened inflammation and fibrotic tissue deposition resulting in loss of structure and function. Recent studies have focused on biomaterial and stem cell‐based therapies to promote skeletal muscle regeneration following injury and disease. Many stem cell populations besides satellite cells are implicated in muscle regeneration. These stem cells include but are not limited to mesenchymal stem cells, adipose‐derived stem cells, hematopoietic stem cells, pericytes, fibroadipogenic progenitors, side population cells, and CD133+ stem cells. However, several challenges associated with their isolation, availability, delivery, survival, engraftment, and differentiation have been reported in recent studies. While acellular scaffolds offer a relatively safe and potentially off‐the‐shelf solution to cell‐based therapies, they are often unable to stimulate host cell migration and activity to a level that would result in clinically meaningful regeneration of traumatized muscle. Combining stem cells and biomaterials may offer a viable therapeutic strategy that may overcome the limitations associated with these therapies when they are used in isolation. In this article, we review the stem cell populations that can stimulate muscle regeneration in vitro and in vivo. We also discuss the regenerative potential of combination therapies that utilize both stem cell and biomaterials for the treatment of skeletal muscle injury and disease. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1246–1262, 2019.
Morphology, Morphogenesis and Molecular Phylogeny of a New Obligate Halophile Ciliate, Schmidtiella ultrahalophila gen. nov., spec. nov. (Ciliophora, Hypotrichia) Isolated from a Volcanic Crater on Sal (Cape Verde Islands)

A new hypotrichous ciliate, Schmidtiella ultrahalophila gen. nov., spec. nov., was isolated from a solar saltern on the island of Sal, Cape Verde. The possession of only one short dorsal kinety clearly distinguishes S. ultrahalophila from other known hypotrichous genera and species. Further diagnostic characters include: a flexible and slender body, an average size of 85 × 15 μm in vivo; a bipartite adoral zone with two hypertrophied frontal adoral membranelles and nine to twelve ventral adoral membranelles; three frontal, one parabuccal, two frontoventral, two or three postoral ventral, and two or three frontoterminal cirri; and marginal cirral rows variable in number, usually one on each side. Ontogenetic data indicate the following: the frontal‐ventral cirri originate from six or five anlagen; the proter inherits the parental adoral zone; the frontal and ventral cirri originate from five or six anlagen; and the marginal cirral rows and the dorsal kinety tend to originate intrakinetally. Additional marginal rows are rarely derived from de novo anlagen. Based on its morphology, morphogenesis and its SSU rRNA phylogenetic placement, the new species should be assigned to the order Sporadotrichida Fauré‐Fremiet, 1961. Due to low taxon sampling, however, its exact position in this order remains enigmatic.
We Are What We Eat: A Stoichiometric and Ecometabolomic Study of Caterpillars Feeding on Two Pine Subspecies of Pinus sylvestris

Many studies have addressed several plant-insect interaction topics at nutritional, molecular, physiological, and evolutionary levels. However, it is still unknown how flexible the metabolism and the nutritional content of specialist insect herbivores feeding on different closely related plants can be. We performed elemental, stoichiometric, and metabolomics analyses on leaves of two coexisting Pinus sylvestris subspecies and on their main insect herbivore; the caterpillar of the processionary moth (Thaumetopoea pityocampa). Caterpillars feeding on different pine subspecies had distinct overall metabolome structure, accounting for over 10% of the total variability. Although plants and insects have very divergent metabolomes, caterpillars showed certain resemblance to their plant-host metabolome. In addition, few plant-related secondary metabolites were found accumulated in caterpillar tissues which could potentially be used for self-defense. Caterpillars feeding on N and P richer needles had lower N and P tissue concentration and higher C:N and C:P ratios, suggesting that nutrient transfer is not necessarily linear through trophic levels and other plant-metabolic factors could be interfering. This exploratory study showed that little chemical differences between plant food sources can impact the overall metabolome of specialist insect herbivores. Significant nutritional shifts in herbivore tissues could lead to larger changes of the trophic web structure.
A Phase II Trial of Lutikizumab, an Anti–Interleukin‐1α/β Dual Variable Domain Immunoglobulin, in Knee Osteoarthritis Patients With Synovitis

To assess the efficacy and safety of the anti–interleukin‐1α/β (anti–IL‐1α/β) dual variable domain immunoglobulin lutikizumab (ABT‐981) in patients with knee osteoarthritis (OA) and evidence of synovitis.
Cardiac adenylyl cyclase overexpression precipitates and aggravates age-related myocardial dysfunction.

Aims Increase of cardiac cAMP bioavailability and PKA activity through adenylyl-cyclase 8 (AC8) overexpression enhances contractile function in young transgenic mice (AC8TG). Ageing is associated with decline of cardiac contraction partly by the desensitization of β-adrenergic/cAMP signaling. Our objective was to evaluate cardiac cAMP signaling as age increases between 2 and 12 months and to explore whether increasing the bioavailability of cAMP by overexpression of AC8 could prevent cardiac dysfunction related to age. Methods and Results Cardiac cAMP pathway and contractile function were evaluated in AC8TG and their non-transgenic littermates (NTG) at 2-mo and 12-mo-old. AC8TG demonstrated increased AC8, PDE1, 3B and 4D expression at both ages, resulting in increased PDE and PKA activity, and increased phosphorylation of several PKA targets including SERCA2a cofactor phospholamban (PLN) and GSK3α/β, a main regulator of hypertrophic growth and aging. Confocal immunofluorescence revealed that the major phospho-PKA substrates were co-localized with Z-line in 2 mo-old NTG but with Z-line interspace in AC8TG, confirming the increase of PKA activity in the compartment of PLN/SERCA2a. In both 12-mo-old NTG and AC8TG, PLN and GSK3α/β phosphorylation was increased together with main localization of phospho-PKA substrates in Z-line interspaces. Hemodynamics demonstrated an increased contractile function in 2-mo and 12-mo-old AC8TG, but not in NTG. By contrast echocardiography and Tissue Doppler Imaging (TDI) performed in conscious mice unmasked myocardial dysfunction with a decrease of systolic strain rate in both old AC8TG and NTG. In AC8TG TDI showed a reduced strain rate even in 2-mo-old animals. Development of age-related cardiac dysfunction was accelerated in AC8TG, leading to HF and premature death. Histological analysis confirmed early cardiomyocyte hypertrophy and interstitial fibrosis in AC8TG as compared with NTG. Conclusions Our data demonstrated an early and accelerated cardiac remodeling in AC8TG mice, leading to the development of HF and reduced lifespan. Age-related reorganization of cAMP/PKA signaling can accelerate cardiac ageing, partly through GSK3α/β phosphorylation.
Survey of Deoxynivalenol Contamination in Agricultural Products in the Chinese Market Using An ELISA Kit

A total of 328 agricultural product samples highly suspected to be contaminated, from flour companies, feed companies, and livestock farms throughout China, were surveyed for deoxynivalenol (DON) contamination using a self-assembly enzyme-linked immunosorbent assay (ELISA) kit. An ELISA kit for DON was developed with a 4.9 ng mL-1 limit of detection (LOD) in working buffer and a 200 ng g-1 LOD in authentic samples. The DON contamination detection rate was 88.7%, concentrations ranged from 200.9 to 6480.6 ng g-1, and the highest DON contamination was found in distillers' dried grains with solubles with an average of 3204.5 ng g-1. Wheat bran and wheat were found to be the most commonly contaminated samples, and the corn meal samples had the lowest average DON level. This ELISA kit is a powerful alternative method for the rapid, sensitive, specific, accurate, and high-throughput determination of DON and can meet the maximum requirement levels. This survey suggests that DON contamination in the Chinese market is serious, and the contamination risk deserves attention. Essential preventive measures should be implemented to ensure food safety and human health.
Genetic variant in miR‐21 binding sites is associated with colorectal cancer risk

Single nucleotide polymorphisms (SNPs) within binding sites of microRNAs (miRNAs) could modify cancer susceptibility by changing the binding affinity of miRNAs on their target mRNA 3ʹ‐untranslated regions (UTRs). MicroRNA‐21 (miR‐21) is involved in the development of colorectal cancer. However, the relationship between SNPs within the binding sites of miR‐21 and colorectal cancer risk has not been widely investigated. A case‐control study including 1147 patients and 1203 controls was performed to evaluate the association of SNPs in miR‐21 binding sites and colorectal cancer risk. Dual‐luciferase reporter assays and functional assays were performed to evaluate the effects of miR‐21. The SNP rs6504593 C allele conferred an increased risk of colorectal cancer compared with the T allele in an additive model (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04‐1.36, P = 0.011). Dual‐luciferase reporter assays demonstrated that the rs6504593 T allele negatively post‐transcriptionally regulated IGF2BP1 by altering the binding affinity of miR‐21. Additionally, colorectal cancer cells transiently transfected with miR‐21 mimics promoted cell proliferation and suppressed apoptosis, whereas inhibition of miR‐21 decreased cell growth. These data suggest that the miR‐21 binding site SNP rs6504593 in the IGF2BP1 3ʹ‐UTR may alter IGF2BP1 expression and contribute to colorectal cancer risk.
Six-month clinical outcomes of non-surgical periodontal treatment with antibiotics on apoptosis markers in aggressive periodontitis.

OBJECTIVE Extrinsic and intrinsic pathways of apoptosis are involved in generalized aggressive periodontitis (GAgP). The aim of this study was to evaluate 6-month clinical outcomes relative to apoptosis of one-stage full-mouth disinfection (OSFMD) and systemic antibiotics (SA) in the treatment of GAgP. METHODS Twenty-six patients with GAgP were included in this prospective follow-up intervention study. Gingival crevicular fluid (GCF) was collected from patients at baseline and 3 and 6 months after periodontal therapy, which consisted of OSFMD and SA (amoxicillin and metronidazole, 500 mg each for 7 days). The levels of p53, caspase-3, TNF-α, TRAIL, IL-1β, and IL-10 in GCF were measured via ELISA. RESULTS Periodontal parameters were improved at 3 and 6 months compared to baseline (p < 0.05). p53 was decreased up to 6 months (p < 0.05). TRAIL, TNF-α, and IL-10 were similar at baseline and 3 and 6 months. Caspase-3 and IL-1β were decreased at 3 months (p < 0.05), but similar at 6 months compared to baseline (p > 0.05). CONCLUSION Although OSFMD plus SA improves clinical periodontal parameters up to 6 months, this treatment protocol differentially regulates the apoptosis markers caspase-3 at 3 months and p53 at 6 months without influencing TRAIL in GCF.
Gene polymorphism associated with TNF-α (G308A) IL-6 (C174G) and susceptibility to coronary atherosclerotic heart disease

Abstract To evaluate the association between gene polymorphisms of TNF-&agr; G308A, IL-6 C174G, and coronary atherosclerotic heart disease (CHD) risk. We used computers to collect related case-control studies. After screening, a meta-analysis was conducted to assess the strength of association by Stata 12.0 software. Thirty-five articles were included. Among them, 17 studies were related to TNF-&agr; (G308A) gene mutation and CHD, and 18 studies examined IL-6 (C174G) gene mutation. According to the results of subgroup analysis of ethnicity, it suggested that TNF-&agr; (G308A) polymorphism was not significantly associated with CHD risk under all models in Asians (P > .05). There were no connected of IL-6 C174G polymorphism with CHD risk under all models in Caucasians after subgroup analysis (P > .05). The present evidence shows that TNF-&agr; (G308A) have no connected with the risk of CHD in Asians; IL-6 (C174G) gene were not associated with the risk of CHD in Caucasians.
Successful Treatment of Acute Fulminant Eosinophilic Myocarditis in a Patient with Ulcerative Colitis Using Steroid Therapy and Percutaneous Cardiopulmonary Support

A 47-year-old man with ulcerative colitis was transferred to our hospital due to progressive dyspnea. Electrocardiography on admission showed ST elevation in leads II, III, aVF, and V5-V6. Coronary angiography revealed no remarkable coronary stenosis, and left ventriculography showed a depressed left ventricular ejection fraction (EF) of 23%. Although the patient received percutaneous cardiopulmonary support, his EF progressively decreased (7-15%), and both ventricular tachycardia (VT) and high-degree atrial-ventricular block occurred. An endomyocardial biopsy showed eosinophilic infiltration in the myocardium. Steroid therapy improved the patient's EF. However, his severe inferior wall hypokinesis and non-sustained VT remained after the abovementioned treatment.
Ten-Item Internet Gaming Disorder Test (IGDT-10): Measurement Invariance and Cross-Cultural Validation Across Seven Language-Based Samples

The Ten-Item Internet Gaming Disorder Test (IGDT-10) is a short screening instrument developed to assess Internet gaming disorder (IGD) as proposed in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM–5), adopting a concise, clear, and consistent item-wording. According to initial studies conducted in 2014, the instrument showed promising psychometric characteristics. The present study tested the psychometric properties, including language and gender invariance, in a large international sample of online gamers. In this study, data were collected from 7,193 participants comprising Hungarian (n = 3,924), Iranian (n = 791), English-speaking (n = 754), French-speaking (n = 421), Norwegian (n = 195), Czech (n = 496), and Peruvian (n = 612) online gamers via gaming-related websites and gaming-related social-networking-site groups. A unidimensional factor structure provided a good fit to the data in all language-based samples. In addition, results indicated both language and gender invariance on the level of scalar invariance. Criterion and construct validity of the IGDT-10 was supported by its strong association with the Problematic Online Gaming Questionnaire and moderate association with weekly gaming time, psychopathological symptoms, and impulsivity. The proportions of each sample that met the cut-off score on the IGDT-10 varied between 1.61% and 4.48% in the individual samples, except for the Peruvian sample (13.44%). The IGDT-10 shows robust psychometric properties and appears suitable for conducting cross-cultural and gender comparisons across seven languages.