Miracle-dz/UniFAR-FTUs huggingface dataset:
Selective Inhibition of Histone Deacetylases 1/2/6 in Combination with Gemcitabine: A Promising Combination for Pancreatic Cancer Therapy

Pancreatic ductal adenocarcinoma (PDAC) has a five-year survival rate of <10% due in part to a lack of effective therapies. Pan-histone deacetylase (HDAC) inhibitors have shown preclinical efficacy against PDAC but have failed in the clinic due to toxicity. Selective HDAC inhibitors may reduce toxicity while retaining therapeutic efficacy. However, their use requires identification of the specific HDACs that mediate the therapeutic effects of HDAC inhibitors in PDAC. We determined that the HDAC1/2/3 inhibitor Mocetinostat synergizes with the HDAC4/5/6 inhibitor LMK-235 in a panel of PDAC cell lines. Furthermore, while neither drug alone synergizes with gemcitabine, the combination of Mocetinostat, LMK-235, and gemcitabine showed strong synergy. Using small interfering (si)RNA-mediated knockdown, this synergy was attributed to inhibition of HDACs 1, 2, and 6. Pharmacological inhibition of HDACs 1 and 2 with Romidepsin and HDAC6 with ACY-1215 also potently synergized with gemcitabine in a panel of PDAC cell lines, and this drug combination potentiated the antitumor effects of gemcitabine against PDAC xenografts in vivo. Collectively, our data show that inhibition of multiple HDACs is required for therapeutic effects of HDAC inhibitors and support the development of novel strategies to inhibit HDACs 1, 2, and 6 for PDAC therapy.
Seasonal Abundance of Psyllid Species on Carrots and Potato Crops in Spain

Psyllids (Hemiptera: Psylloidea) can transmit the phloem restricted bacterium ‘Candidatus Liberibacter solanacearum’ (Lso). In Europe, Lso causes severe losses to carrot and represents a threat to the potato industry. A rising concern is Lso transmission from carrot to potato and within potato, and this has driven the need for monitoring populations of psyllid species which could serve as vectors on both crops. This would provide a fundamental understanding of the epidemiology of Lso. Different sampling methods were used to survey populations of psyllid species in commercial carrot and potato fields in central and eastern mainland Spain from 2015 to 2017. Two psyllid species, Bactericera trigonica and Bactericera nigricornis were found on carrot and potato crops. In carrot fields the most abundant species was B. trigonica (occurring from crop emergence to harvest); whereas in potato crops the most abundant psyllid species was B. nigricornis. Depending on field location, the maximum psyllid populations occurred between June and October. Since B. nigricornis was found on both carrot and potato and is the only psyllid species able to feed and reproduce on both these crops in Europe, there is the potential risk of Lso transmission from carrot to potato.
Colonic Dieulafoy lesion successfully treated by endoclips: a rare cause of lower gastrointestinal bleeding

Dieulafoy lesions account for 1%–2% of cases of acute gastrointestinal bleeding. Approximately 71% of Dieulafoy lesions are detected in the stomach, whereas only 2% are in the colon [1, 2]. We encountered a patient with a colonic Dieulafoy lesion that was successfully treated by endoclips. An 83-year-old man with cirrhosis related to hepatitis C virus presented to our hospital with a 4-day history of hematochezia. At admission, his hemoglobin level was 4.9 g/dL. Contrast-enhanced computed tomography revealed the presence of extravasation in the ascending colon (▶Fig. 1). Transcatheter arterial embolization (TAE) was performed instead of colonoscopy because the patient’s vital signs were unstable. Although hemostasis by TAE was successful (▶Fig. 2), he developed hematochezia 4 days after TAE. After bowel preparation with polyethylene glycol, urgent colonoscopy was performed. The presence of fresh blood and clotting was observed throughout the colon, and active bleeding was detected in the ascending colon (▶Fig. 3). No mucosal abnormality surrounding the lesion was noted (▶Fig. 4). The lesion was diagE-Videos
Physician Adherence to Treat-to-Target and Practice Guidelines in Rheumatoid Arthritis

Principles of treat-to-target (T2T) have been widely adopted in both multinational and regional guidelines for rheumatoid arthritis (RA). Several questionnaire studies among physicians and real-world data have suggested that an evidence–practice gap exists in RA management. Investigating physician adherence to T2T, which requires a process measure, is difficult. Different practice patterns among physicians are observed, while adherence to protocolized treatment declines over time. Rheumatologist awareness, agreement, and claims of adherence to T2T guidelines are not always consistent with medical records. Comorbidities, a difficult disease course, communication barriers, and individual preferences may hinder an intensive, proactive treatment stance. Interpreting deviations from protocolized treatment/T2T guidelines requires sufficient clinical context, though higher adherence seems to improve clinical outcomes. Nonmedical constraints in routine care may consist of barriers in healthcare structure and socioeconomic factors. Therefore, strategies to improve the institution of T2T should be tailored to local healthcare. Educational interventions to improve T2T adherence among physicians may show a moderate, although beneficial effect. Meanwhile, a proportion of patients with inadequately controlled RA exists, while management decisions may not be in accordance with T2T. Physicians tend to be aware of current guidelines, but their institution in routine practice seems challenging, which warrants attention and further study.
Resilience in Clinical Care: Getting a Grip on the Recovery Potential of Older Adults

Geriatricians are often confronted with unexpected health outcomes in older adults with complex multimorbidity. Aging researchers have recently called for a focus on physical resilience as a new approach to explaining such outcomes. Physical resilience, defined as the ability to resist functional decline or recover health following a stressor, is an emerging construct.
EV71 3C protease induces apoptosis by cleavage of hnRNP A1 to promote apaf-1 translation

Enterovirus 71 (EV71) induces apoptosis to promote viral particle release. Earlier work showed that EV71 utilizes its 3C protease to induce apoptosis in a caspase-3-dependent pathway, though the mechanism is unknown. However, work from Vagner, Holcik and colleagues showed that host protein heterogeneous ribonucleoprotein A1 (hnRNP A1) binds the IRES of cellular apoptotic peptidase activating factor 1 (apaf-1) mRNA to repress its translation. In this work, we show that apaf-1 expression is essential for EV71-induced apoptosis. EV71 infection or ectopic expression of 3C protease cleaves hnRNP A1, which abolishes its binding to the apaf-1 IRES. This allows IRES-dependent synthesis of apaf-1, activation of caspase-3, and apoptosis. Thus, we reveal a novel mechanism that EV71 utilizes for virus release via a 3C protease–hnRNP A1–apaf-1–caspase-3–apoptosis axis.
Passive Animal Surveillance to Identify Ticks in Wisconsin, 2011–2017

The introduction of new tick species poses a risk to human and animal health. Systematic active surveillance programs are expensive and uncommon. We evaluated a passive animal surveillance program as a monitoring tool to document the geographic distribution and host associations of ticks in Wisconsin. Passive surveillance partners included veterinary medical clinics, domestic animal shelters, and wildlife rehabilitation centers from 35 of the 72 Wisconsin counties. A total of 10,136 tick specimens were collected from 2325 animals from July 2011 to November 2017 and included Dermacentor variabilis Say (29.7% of all ticks), Ixodes texanus Banks (25.5%), Ixodes scapularis Say (19.5%), Haemaphysalis leporispalustris Packard (13.8%), Ixodes cookei Packard (4.4%), and Dermacentor albipictus Packard (1.7%). Less common species (<1% of collection) included Ixodes dentatus Marx, Ixodes sculptus Neumann, Ixodes marxi Banks, Amblyomma americanum Linnaeus, and Rhipicephalus sanguineus Latreille. Of the 2325 animals that were examined, most were domestic dogs (53%), eastern cottontail rabbits (16%), domestic cats (15%), and North American raccoons (11%). An additional 21 mammal and 11 bird species were examined at least once during the six years of the study. New county records are summarized for each species. Public health, academic, and veterinary and animal care partners formed a community of practice enabling effective statewide tick surveillance.
External Validation of the GREAT Score in Turkish Patients with Gravesʼ Hyperthyroidism Treated with the Titration Regimen Method of Antithyroid Drugs: A Multicenter Study

Abstract Recently, the Gravesʼ Recurrent Events After Therapy score (GREAT) was proposed as a useful tool to predict relapse before starting antithyroid drugs (ATD) in patients with Gravesʼ disease (GD). Therefore, we intended to assess the validity of the GREAT score in Turkish patients with GD, including patients who experienced a poorly controlled disease (multiple episodes of hyperthyroidism followed by euthyroidism or rarely hypothyroidism) during ATD dose titration. This is a retrospective multicenter study including 517 patients with the first episode of GD who were treated for at least 12 months. The patients were classified as relapse+poorly controlled disease (non-remission) and remission groups. During a median follow-up time of 35 months (12–144 months), 191 (37%) patients experienced a relapse, 136 (26.3%) a poorly controlled disease, and 190 (36.7%) remained in remission. Patients with non-remission disease tended to have significantly higher serum levels of TRAb, fT4, and fT3, and have larger goiter sizes on palpation at baseline, as compared with the remission group. Non-remission disease occurred in 12, 35, and, 53% of the patients falling into GREAT class I, II, and III, respectively (hazard ratio 2.56, 95% CI 2.02–3.51, p=0.012, and hazard ratio 3.54, 95% CI 2.12–5.91, p<0.001, for GREAT class II and III against class I, respectively). According to our study, the GREAT score is a useful tool to predict the risk of relapse as well as the occurrence of poorly controlled disease before starting treatment with ATDs.
Dietary Curcumin: Correlation between Bioavailability and Health Potential

The yellow pigment curcumin, extracted from turmeric, is a renowned polyphenol with a broad spectrum of health properties such as antioxidant, anti-inflammatory, anti-cancer, antidiabetic, hepatoprotective, anti-allergic, anti-dermatophyte, and neuroprotective. However, these properties are followed by a poor pharmacokinetic profile which compromises its therapeutic potential. The association of low absorption by the small intestine and the extensive reductive and conjugative metabolism in the liver dramatically weakens the oral bioavailability. Several strategies such as inhibition of curcumin metabolism with adjuvants as well as novel solid and liquid oral delivery systems have been tried to counteract curcumin poor absorption and rapid elimination from the body. Some of these drug deliveries can successfully enhance the solubility, extending the residence in plasma, improving the pharmacokinetic profile and the cellular uptake.
Outcome Measurements Used in Randomized Controlled Trials of Teledermatology: A Systematic Mapping Review.

Assessment of the effectiveness of teledermatology has been hampered by the variety of outcome measures used, limiting the possibility for meta-analysis. This systematic mapping review classified the outcome measurement instruments used in randomized controlled trials of teledermatology conducted between 2008 and 2018 using the Core Outcome Measures in Effectiveness Trials taxonomy. Sixteen articles describing 12 studies were identified. On average, each trial used 3.7 (range 2-7) outcome measurements, with a total of 55 different instruments employed. Most instruments mapped on the "skin and subcutaneous tissue outcomes" domain. The most frequently used instrument (Dermatology Life Quality Index) was used in only 3 studies. Over 60% of the instruments used did not cite any evidence of validation. This mapping review provides a list of outcome measurement instruments that can be used as a resource when designing teledermatology trials in the future and provides the foundation for the development of a core outcome set.
Virotherapy: Current Trends and Future Prospects for Treatment of Colon and Rectal Malignancies

Abstract Colorectal cancer (CRC) is one of the most common malignancies. In recent decades, early diagnosis and conventional therapies have resulted in a significant reduction in mortality. However, late stage metastatic disease still has very limited effective treatment options. There is a growing interest in using viruses to help target therapies to tumour sites. In recent years the evolution of immunotherapy has emphasised the importance of directing the immune system to eliminate tumour cells; we aim to give a state-of-the-art over-view of the diverse viruses that have been investigated as potential oncolytic agents for the treatment of CRC.
Developmental stages and gut microenvironments influence gut microbiota dynamics in the invasive beetle Popillia japonica Newman (Coleoptera: Scarabaeidae).

Popillia japonica Newman (Coleoptera: Scarabaeidae) is a highly polyphagous invasive beetle originating from Japan. This insect is highly resilient and able to rapidly adapt to new vegetation. Insect-associated microorganisms can play important roles in insect physiology, helping their hosts to adapt to changing conditions and potentially contributing to an insect's invasive potential. Such symbiotic bacteria can be part of a core microbiota that is stably transmitted throughout the host's life cycle or selectively recruited from the environment at each developmental stage. The aim of this study was to investigate the origin, stability and turnover of the bacterial communities associated with an invasive population of P. japonica from Italy. Our results demonstrate that soil microbes represent an important source of gut bacteria for P. japonica larvae, but as the insect develops, its gut microbiota richness and diversity decreased substantially, paralleled by changes in community composition. Notably, only 16.75% of the soil bacteria present in larvae are maintained until the adult stage. We further identified the micro-environments of different gut sections as an important factor shaping microbiota composition in this species, likely due to differences in pH, oxygen availability and redox potential. In addition, P. japonica also harbored a stable bacterial community across all developmental stages, consisting of taxa well-known for the degradation of plant material, namely the families Ruminococcacae, Christensenellaceae and Lachnospiraceae. Interestingly, the family Christensenallaceae had so far been observed exclusively in humans. However, the Christensenellaceae OTUs found in P. japonica belong to different taxonomic clades within this family. This article is protected by copyright. All rights reserved.
Circumnavigation on Multiple Circles Around a Nonstationary Target With Desired Angular Spacing

In this article, the objective for a group of nonholonomic agents is to achieve multicircular circumnavigation with any desired angular spacing around a nonstationary target. A cooperative protocol is proposed to achieve this objective and, additionally, generalizes the circumnavigation problem of unicycle vehicles around a target (moving and stationary). Due to the nonholonomic constraints, existing protocols cannot be extended directly to achieve this objective. Thus, the proposed algorithm is worked out from the desired geometry to achieve the objective. A fixed-time consensus estimator is designed under a cyclic digraph to arrive at the desired interagent angular separation in the target-centric frame. The target information and desired formation parameters are assumed to be known to only one agent partially. Due to uncertainty in the target’s motion, it is assumed that the target’s acceleration and angular velocity are unknown. Fixed-time estimators under a digraph address the lack of information. The tracking controller drives the agents to the desired position around the target, thus making the errors go to zero instead of any finite bounds. The controller guarantees the bounded control effort irrespective of the error magnitude. The numerical examples are presented to show the effectiveness of the algorithm.
Antioxidant Effect of Extracts from Native Chilean Plants on the Lipoperoxidation and Protein Oxidation of Bovine Muscle

The present study investigated the antioxidant potential and the ability to inhibit lipid and protein oxidation in bovine meat of four native Chilean species: canelo (Drimys winteri), nalca (Gunnera tinctoria), tiaca (Caldcluvia paniculata), and ulmo (Eucryphia cordifolia). Phenolic acids (gallic, chlorogenic, caffeic, and coumaric) and flavonoids (catechin, epicatechin, and rutin) were identified and quantified by HPLC-MS/MS. Drimys winteri extract exhibited the highest antioxidant capacity evaluated by oxygen radical absorption capacity-red pyrogallol method (ORAC-PGR) and ferric ion reducing antioxidant power (FRAP) assays. All extracts decreased lipid oxidation induced by 2,2’-azo-bis(2-amidinopropane) dihydrochloride (AAPH) derived peroxyl radicals by anywhere between 30% and 50% the. In addition, canelo and nalca extracts decreased spontaneous oxidation by around 57% and 37% in relation to the control group, being even more efficient than butylated hydroxyanisole (BHT) a synthetic antioxidant. Protein oxidation in the myofibrillar proteins was evaluated by the formation of protein carbonyls and loss of protein thiols. The canelo, ulmo, and nalca extracts decreased the formation of carbonyls by around 30%. Plant extracts and BHT did not show an antioxidant effect on protein thiol loss. However, tiaca and ulmo extracts exerted a pro-oxidant effect, favoring the oxidation of sulfhydryl groups. The oxidizing system induced structural changes in myofibrillar protein (SDS−PAGE). A protective effect on protein structure from the canelo extract can be observed during the incubation when compared to samples incubated with AAPH.
N6-methyladenosine-dependent primary microRNA-126 processing activated PI3K-AKT-mTOR pathway drove the development of pulmonary fibrosis induced by nanoscale carbon black particles in rats

Abstract The pulmonary fibrosis could be caused by long-term inhalation of carbon black (CB) particles. Studies on the mechanisms of pulmonary fibrosis induced by CB are required to develop the stratagem of prevention and treatment on fibrosis. The RNA-binding protein DiGeorge syndrome critical region gene 8 (DGCR8)-dependent pri-miRNAs processing is regulated by N6-methyladenosine (m6A) modification, which targets the downstream signal pathway. However, its role in pulmonary fibrosis has not been known clearly. In the present study, rats inhaled CB at dose of 0, 5 or 30 mg/m3 for 28 days, 6 h/day, respectively. The rats inhaled CB at dose of 0 or 30 mg/m3 for 14 days, 28 days and 90 days, respectively. In vitro experiments, the normal human bronchial epithelial cell line (16HBE) was treated with CB (0, 50, 100 and 200 μg/mL) for 24 h. In vitro and vivo study, the levels of fibrosis indicators including α-SMA, vimentin, collagen-I and hydroxyproline in CB treatment groups statistically increased in dose- or time- dependent manners compared with the control. After CB treatment, PI3K-AKT-mTOR pathway was activated and regulated by miRNA-126. We found that both of m6A modifications of pri-miRNA-126 and its binding with DGCR8 were decreased after CB treatment, which resulted in the reduction of mature miRNA-126 accompanied by accumulation of unprocessed pri-miRNA-126. This work demonstrated that m6A modification of pri-miRNA-126 and its binding with DGCR8 decreases blocked miRNA-126 maturation, and then activated the PI3K/AKT/mTOR pathway, which drove the fibro genesis in the lung after CB exposure.
Agent-Based Simulation for Investigating the Safety Concerns of Electric Vehicles in the US

When operated at low speeds, electric and hybrid vehicles have created pedestrian safety concerns in congested areas of various city centers because they have relatively silent engines compared to those of internal combustion engine vehicles (ICEVs), and there is no engine noise to warn pedestrians and cyclists of an oncoming electric or hybrid vehicle. However, driver behavior characteristics have also been considered in many studies, and the high-end prices of electric vehicles (EVs) indicate that EV drivers tend to have a higher prosperity index and are more likely to receive a better education, making them more alert while driving and more likely to obey traffic rules. In this paper, the positive and negative factors associated with EV adoption and the subsequent effects on pedestrian traffic safety are investigated using an agent-based modeling approach, in which a traffic micro-simulation of a real intersection is simulated in 3D using AnyLogic software. First, the interacting agents and dynamic parameters are defined in the agent-based model. Next, a 3D intersection environment is created to integrate the agent-based model into a visual simulation, where the simulation records the number of near-crashes occurring in certain pedestrian crossings throughout the virtual time duration of a year. A sensitivity analysis is also carried out with 9,000 subsequent simulations performed in a supercomputer to account for the variation in dynamic parameters (ambient sound level, vehicle sound level, and ambient illumination). According to the analyses, EVs pose a 25% overall higher risk to pedestrian traffic safety than ICEVs do. Although this safety risk is not as high as that observed in previous statistical reports, there is still a statistically significant difference between the near-crash risks of EVs and ICEVs, which necessitates certain solutions to EVs’ silent engines. The advantage of EVs in terms of stopping sight distance is not strong enough to compensate for their high near-crash risk due to their lower degree of 5 Agent-Based Simulation for Investigating the Safety Concerns of EVs in the US auditory detectability. Also, low levels of ambient illumination increase the number of pedestrians involved in near-crashes for both EVs and ICEVs. 1 The contents of this reports have been sent to publication. 6 Agent-Based Simulation for Investigating the Safety Concerns of EVs in the US
Morpho-Molecular Assessment Indicates New Prognostic Aspects and Personalized Therapeutic Options in Sinonasal Melanoma

Sinonasal melanoma is a rare subtype of melanoma and little is known about its molecular fingerprint. Systemic treatment options are limited, as targetable BRAF mutations are rare compared to cutaneous melanoma. Currently, metastatic sinonasal melanoma is being treated according to the guidelines of cutaneous melanoma. In this study, we investigated the molecular profile of 19 primary sinonasal melanomas, using a novel customized melanoma-specific next generation sequencing (NGS) panel (MelArray) of 190 genes. Results were correlated to histological and clinical features to further characterize this rare, aggressive type of melanoma and screen for prognostic markers and possible treatment options. Molecular profiles encompassed predominantly mutations in NRAS (25%), whereas KIT or BRAF p.V600 mutations were not detected. Tumor mutational burden was overall low. High level of copy number variations (CNVs) were associated with alterations in DNA-repair genes and shorter distant metastasis-free survival (p = 0.005). Monomorphic (vs. pleomorphic) morphology was found to be significantly associated with worse disease-specific survival (p < 0.001), however no correlation between morphology and molecular aberrations was found. A variety of alterations in different pathways were detected, justifying molecular testing and opening potential personalized treatment options in current study or compassionate use settings.