Miracle-dz/UniFAR-FTUs huggingface dataset:
Everolimus Nanoformulation in Biological Nanoparticles Increases Drug Responsiveness in Resistant and Low-Responsive Breast Cancer Cell Lines

Everolimus (Eve) is an FDA approved drug that inhibits mammalian target of rapamycin (mTOR). It is employed in breast cancer treatment even if its responsiveness is controversial. In an attempt to increase Eve effectiveness, we have developed a novel Eve nanoformulation exploiting H-ferritin nanocages (HEve) to improve its subcellular delivery. We took advantage of the natural tumor targeting of H-Ferritin, which is mediated by the transferrin receptor-1 (TfR1). Breast cancer cells overexpressing TfR-1 were successfully recognized by H-Ferritin, displaying quick nanocage internalization. HEve has been tested and compared to Eve for in vitro efficacy in sensitive and resistant breast cancer cells. Nanoformulated Eve induced remarkable antiproliferative activity in vitro, making even resistant cell lines sensitive to Eve. Moreover, the antiproliferative activity of HEve is fully in accordance with cytotoxicity observed by cell death assay. Furthermore, the significant increase in anticancer efficacy displayed in HEve-treated samples is due to the improved drug accumulation, as demonstrated by UHPLC-MS/MS quantifications. Our findings suggest that optimizing Eve subcellular delivery, thanks to nanoformulation, determines its improved antitumor activity in a panel of Eve-sensitive or resistant breast cancer cell lines.
Head‐turning morphologies: Evolution of shape diversity in the mammalian atlas–axis complex

Mammals flex, extend, and rotate their spines as they perform behaviors critical for survival, such as foraging, consuming prey, locomoting, and interacting with conspecifics or predators. The atlas–axis complex is a mammalian innovation that allows precise head movements during these behaviors. Although morphological variation in other vertebral regions has been linked to ecological differences in mammals, less is known about morphological specialization in the cervical vertebrae, which are developmentally constrained in number but highly variable in size and shape. Here, we present the first phylogenetic comparative study of the atlas–axis complex across mammals. We used spherical harmonics to quantify 3D shape variation of the atlas and axis across a diverse sample of species, and performed phylogenetic analyses to investigate if vertebral shape is associated with body size, locomotion, and diet. We found that differences in atlas and axis shape are partly explained by phylogeny, and that mammalian subclades differ in morphological disparity. Atlas and axis shape diversity is associated with differences in body size and locomotion; large terrestrial mammals have craniocaudally elongated vertebrae, whereas smaller mammals and aquatic mammals have more compressed vertebrae. These results provide a foundation for investigating functional hypotheses underlying the evolution of neck morphologies across mammals.
Broad-Spectrum Antiviral Natural Products from the Marine-Derived Penicillium sp. IMB17-046

A new pyrazine derivative, trypilepyrazinol (1), a new α-pyrone polyketide, (+)-neocitreoviridin (2), and a new ergostane analogue, 3β-hydroxyergosta-8,14,24(28)-trien-7-one (3), were isolated and characterized along with five known compounds from the marine-derived fungus Penicillium sp. IMB17-046. The structures of these new compounds were determined using spectroscopic data analyses (HRESIMS, 1D- and 2D-NMR), X-ray crystallography analysis, and TDDFT ECD calculation. Compounds 1 and 3 exhibited broad-spectrum antiviral activities against different types of viruses, including human immunodeficiency virus (HIV), hepatitis C virus (HCV), and influenza A virus (IAV), with IC50 values ranging from 0.5 to 7.7 μM. Compounds 1 and 2 showed antibacterial activities against Helicobacter pylori, a causative pathogen of various gastric diseases, with minimum inhibitory concentration (MIC) values of 1–16 μg/mL.
REAL-WORLD EFFECTIVENESS AND SAFETY OF RANIBIZUMAB TREATMENT IN PATIENTS WITH AND WITHOUT POLYPOIDAL CHOROIDAL VASCULOPATHY

Supplemental Digital Content is Available in the Text. Twelve-month results from LUMINOUS support the use of ranibizumab as an effective first-line therapy for polypoidal choroidal vasculopathy. Higher baseline visual acuity and adequate injection frequency were associated with better visual acuity outcomes. No new safety signals were identified.
Drug Legalization and Decriminalization Beliefs Among Substance-using and Nonusing Individuals.

OBJECTIVES There has been advocacy for legalization of abusable substances, but systematic data on societal beliefs regarding such legalization are limited. People who use substances may have unique beliefs about legalization, and this study assessed whether they would be in favor of drug legalization/decriminalization. It was hypothesized that those who use particular drugs (especially marijuana) would support its legalization/decriminalization, but that this would not be the case across all classes (especially opioids and stimulants). METHODS A nationwide sample of 506 adults were surveyed online to assess demographic characteristics, substance misuse, and beliefs regarding drug legalization/decriminalization. Legalization/decriminalization beliefs for specific drugs were assessed on an 11-point scale (0, strongly disagree; 10, strongly agree). RESULTS For persons with opioid misuse (15.4%), when asked about their agreement with: "heroin should be legalized," the mean score was 4.6 (SEE = 0.4; neutral). For persons with stimulant misuse (12.1%), when asked about their agreement with: "cocaine should be legalized," the score was 4.2 (0.5). However, for persons with marijuana misuse (34.0%), when asked about their agreement with: "medical marijuana should be legalized" the score was 8.2 (0.3; indicating agreement), and for "recreational marijuana" the score was also 8.2 (0.3). CONCLUSIONS These results suggest that persons who used marijuana strongly support the legalization of both recreational and medical marijuana, whereas persons who primarily have opioid or stimulant misuse have less strongly held beliefs about legalization of substances within those respective categories. By including those who misuse drugs, these data assist in framing discussions of drug legalization and have the potential to inform drug policy considerations.
The Basics of Integra Dermal Regeneration Template and its Expanding Clinical Applications

Abstract First developed for coverage of burn wounds, Integra (Integra LifeSciences) is a synthetic acellular dermal regeneration template that provides a base for revascularization and neodermal formation. The use of Integra has slowly grown and has now become an important consideration along the reconstructive ladder. This article reviews the basic science of Integra and provides an overview of the many expanding applications based on anatomic location.
Effect of biotic and abiotic elicitors on production of betulin and betulinic acid in the hairy root culture of Betula pendula Roth

Abstract Betulin (B) and betulinic acid (BA) are two triterpenoids with a wide range of biological and medicinal activities in different organs of Betula pendula. This research aimed to increase the accumulation of B and BA in the hairy root culture of B. pendula by seven biotic and abiotic elicitors. Hairy root was induced in the stem’s inner bark of B. pendula using the C58C1 strain in the WPM (Woody Plant Medium). The effects of different concentrations of elicitors and different time of root harvest in hairy root culture of B. pendula showed that highest level of growth index (GI), B, and BA was acquired in treated hairy roots with chitosan (CTS), chlorocholine chloride (CCC) and chitosan nano-fiber (CTS NF). Highest GI of B. pendula hairy roots was 13 that was obtained in the roots treated with CTS 150 mg l−1 on the 8th day. The highest content of BA was 1.3 mg g−1 DW after treatment with 1 mg l−1CCC on the 4th and 6th days and 200 mg l−1CTS NF on the 10th day. The highest B content (0.94 mg g−1DW) was obtained in the treated hairy root by 2 mg l−1 CCC after 4 and 6 days.
Association between Peptic Ulcer Disease and Osteoporosis: The Population-Based Longitudinal Cohort Study in Korea

Objectives: The association between peptic ulcer disease (PUD) and osteoporosis remains unclear. We investigated the association between PUD and osteoporosis by classifying individuals based on gender in a prospective study on 10,030 adults in Korea at a 12-year follow-up examination. Design and setting: The baseline survey of the Ansung–Ansan cohort studies was conducted from May 2001 to February 2003, and 10,030 participants (5018 from the Ansung study and 5012 from the Ansan study) completed the examination. Primary outcome measures: The risk of developing osteoporosis was higher in both men and women in the PUD group than in the control group. Results: At the 12-year follow-up, osteoporosis had developed in 11.1% (21/189) and 29.9% (56/187) of men and women in the PUD group, respectively. Meanwhile, in the control group, 4.8% (70/1464) and 16.5% (271/1639) of men and women, respectively, were presented with osteoporosis. The incidence rates per 1000 person–years were 20.5% and 68.5% in men and women in the PUD group and 11.2% and 42.3% of men and women in the control group, respectively. The risk of developing osteoporosis was higher in both men and women in the PUD group than in the control group (men: hazard ratio [HR] = 1.72, 95% confidence interval [CI] = 1.02–2.92; women: HR = 1.62, 95% CI = 1.20–2.18). Conclusion: The risk of developing osteoporosis was significantly higher in both men and women in the PUD group than in the control group.
Impact of Electrocautery on Fatigue Life of Spinal Fusion Constructs—An In Vitro Biomechanical Study

Instrumentation failure in the context of spine surgery is attributed to cyclic loading leading to formation of fatigue cracks, which later propagate and result in rod fracture. A biomechanical analysis of the potential impact of electrocautery on the fatigue life of spinal implants has not been previously performed. The aim of this study was to assess the fatigue life of titanium (Ti) and cobalt-chrome (CoCr) rod-screw constructs after being treated with electrocautery. Twelve spinal constructs with CoCr and Ti rods were examined. Specimens were divided into four groups by rod material (Ti and CoCr) and application of monopolar electrocautery on the rods’ surface (control-group and electrocautery-group). Electrocautery was applied on each rod at three locations, then constructs were cyclically tested. Outcome measures were load-to-failure, total number of cycles-to-failure, and location of rod failure. Ti-rods treated with electrocautery demonstrated a significantly decreased fatigue life compared to non-treated Ti-rods. Intergroup comparison of cycles-to-failure revealed a significant mean decrease of almost 9 × 105 cycles (p = 0.03). No CoCr-rods failed in this experiment. Electrocautery application on the surface of Ti-rods significantly reduces their fatigue life. Surgeons should exercise caution when using electrocautery in the vicinity of Ti-rods to mitigate the risk of rod failure.
Exosomal long noncoding RNAs in aging and age‐related diseases

Molecules secreted by cells into the internal environment during aging, including those secreted in exosomes, have long been a matter of concern. Those cells that absorb exosomes, also known as recipient cells, exhibit certain phenotypic changes because of the regulatory role of functional molecules (including proteins and nucleic acids) released in exosomes. Involvement of noncoding RNAs (ncRNAs) in the regulation of aging has received increasing attention, and long ncRNAs (lncRNAs) have become one of the research hotspots in recent years. LncRNAs carried by exosomes play a role in intercellular communication between adjacent and distant cells. Moreover, exosomal lncRNAs promote the decline of organ functions and the development of age‐related diseases, including atherosclerosis, Type 2 diabetes, osteoporosis, osteoarthritis, rheumatoid arthritis, Parkinson's disease, multiple sclerosis, and cancer. Here, we review the regulatory roles of exosomal lncRNAs in aging and age‐related diseases.
Scope and nature of financial conflicts of interest between neurologists and industry

Objective To detail the scope and nature of financial conflicts of interest (COIs) between neurologists and the pharmaceutical and medical device industries (Industry) using the Centers for Medicare and Medicaid Services Open Payments (OP) database, with a focus on trends from 2013 to 2016. Methods Payments from Industry to US neurologists were categorized into research payments, general (nonresearch) payments, and value of ownership in Industry. We performed descriptive analyses to detail the scope and nature of these relationships and trends over time. Results At least 9,505 neurologists received at least one payment from Industry each year. From 2013 to 2016, 1.6 million payments totaled $354 million, of which 99.5% of payments and 85.6% of payment value were for general/nonresearch-related payments. Most neurologists (between 65% and 80%) received less than $1,000 per year, but over 200 neurologists each received more than $100,000 during some years. Several received over $1 million. General payments are increasing, research payments are steady, and neurologists' ownership and investments are decreasing. Conclusions Neurologists have extensive financial relationships with Industry, though this is driven by a well-paid minority. As a profession, we must work to establish firm rules to manage these potential COIs, ensuring that relationships with Industry yield synergistic advances while minimizing bias and maintaining public trust.
Histamine Is an Inducer of the Heat Shock Response in SOD1-G93A Models of ALS

(1) Background: Amyotrophic lateral sclerosis (ALS) is a multifactorial non-cell autonomous disease where activation of microglia and astrocytes largely contributes to motor neurons death. Heat shock proteins have been demonstrated to promote neuronal survival and exert a strong anti-inflammatory action in glia. Having previously shown that the pharmacological increase of the histamine content in the central nervous system (CNS) of SOD1-G93A mice decreases neuroinflammation, reduces motor neuron death, and increases mice life span, here we examined whether this effect could be mediated by an enhancement of the heat shock response. (2) Methods: Heat shock protein expression was analyzed in vitro and in vivo. Histamine was provided to primary microglia and NSC-34 motor neurons expressing the SOD1-G93A mutation. The brain permeable histamine precursor histidine was chronically administered to symptomatic SOD1-G93A mice. Spine density was measured by Golgi-staining in motor cortex of histidine-treated SOD1-G93A mice. (3) Results: We demonstrate that histamine activates the heat shock response in cultured SOD1-G93A microglia and motor neurons. In SOD1-G93A mice, histidine augments the protein content of GRP78 and Hsp70 in spinal cord and cortex, where the treatment also rescues type I motor neuron dendritic spine loss. (4) Conclusion: Besides the established histaminergic neuroprotective and anti-inflammatory effects, the induction of the heat shock response in the SOD1-G93A model by histamine confirms the importance of this pathway in the search for successful therapeutic solutions to treat ALS.
Central Nervous System Cryptococcal Infections in Non-HIV Infected Patients

Central nervous system (CNS) cryptococcosis in non-HIV infected patients affects solid organ transplant (SOT) recipients, patients with malignancy, rheumatic disorders, other immunosuppressive conditions and immunocompetent hosts. More recently described risks include the use of newer biologicals and recreational intravenous drug use. Disease is caused by Cryptococcus neoformans and Cryptococcus gattii species complex; C. gattii is endemic in several geographic regions and has caused outbreaks in North America. Major virulence determinants are the polysaccharide capsule, melanin and several ‘invasins’. Cryptococcal plb1, laccase and urease are essential for dissemination from lung to CNS and crossing the blood–brain barrier. Meningo-encephalitis is common but intracerebral infection or hydrocephalus also occur, and are relatively frequent in C. gattii infection. Complications include neurologic deficits, raised intracranial pressure (ICP) and disseminated disease. Diagnosis relies on culture, phenotypic identification methods, and cryptococcal antigen detection. Molecular methods can assist. Preferred induction antifungal therapy is a lipid amphotericin B formulation (amphotericin B deoxycholate may be used in non-transplant patients) plus 5-flucytosine for 2–6 weeks depending on host type followed by consolidation/maintenance therapy with fluconazole for 12 months or longer. Control of raised ICP is essential. Clinicians should be vigilant for immune reconstitution inflammatory syndrome.
Growing up with a disability following paralytic poliomyelitis: experiences from persons with late effects of polio

Abstract Purpose To describe the experiences of growing up after acute paralytic poliomyelitis and strategies used to adapt to the new situation. Methods Seven women and seven men (mean age 70 years, min–max 61–78 years) with late effects of polio, who had contracted paralytic polio in their childhood. Data were collected using semi-structured interviews, transcribed verbatim, and analyzed by systematic text condensation. Results Memories of contracting acute paralytic poliomyelitis involved being immobilized and sent away from home for surgical and physiotherapeutic treatment. Growing up in a social context that was often tough and unfriendly resulted in the development of strategies, such as optimistic thinking, trying to blend in, trusting one’s ability to manage, and to handle the preconceptions and expectations of others. At the onset of late effects of polio, some of these strategies were still functioning, whereas overachieving, disregarding pain, and weariness were not. Conclusion The challenges of growing up with a disability following paralytic polio led to the development of various psychological strategies for managing daily life. By understanding these experiences and strategies, knowledge may be gained in assisting rehabilitation professionals to better support persons with late effects of polio in adapting to the new situation. Implications for rehabilitation At the onset of late effects of polio, strategies developed earlier in life, such as overachieving, disregarding pain, and weariness, may not function anymore. Understanding the experiences of growing up with poliomyelitis can support rehabilitation professionals to provide targeted interventions for people with late effects of polio and enable them to develop new adaptive strategies. Developing new strategies, such as accepting increased symptoms, and augmenting self-esteem and self-efficacy, may improve daily functioning among people with late effects of polio.
Neutrophil Extracellular Traps in the Establishment and Progression of Renal Diseases

Uncontrolled inflammatory and immune responses are often involved in the development of acute and chronic forms of renal injury. Neutrophils are innate immune cells recruited early to sites of inflammation, where they produce pro-inflammatory cytokines and release mesh-like structures comprised of DNA and granular proteins known as neutrophil extracellular traps (NETs). NETs are potentially toxic, contribute to glomerular injury, activate autoimmune processes, induce vascular damage, and promote kidney fibrosis. Evidence from multiple studies suggests that an imbalance between production and clearance of NETs is detrimental for renal health. Hence strategies aimed at modulating NET-associated processes could have a therapeutic impact on a myriad of inflammatory diseases that target the kidney. Here, we summarize the role of NETs in the pathogenesis of renal diseases and their mechanisms of tissue damage.
A Systematic Review and Meta-analysis of Unguided Electronic and Mobile Health Technologies for Chronic Pain-Is It Time to Start Prescribing Electronic Health Applications?

OBJECTIVE Electronic (eHealth) and mobile (mHealth) technologies may be a useful adjunct to clinicians treating patients with chronic pain. The primary aim of this study was to investigate the effects of eHealth and mHealth interventions that do not require clinician contact or feedback on pain-related outcomes recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) guidelines in adults with chronic pain. METHODS We searched four databases and included English language randomized controlled trials of ambulatory adults with chronic pain from January, 1 2000, to January 31, 2018, with interventions that are independent of clinician contact or feedback. In the meta-analysis, outcomes were assessed at short- (three months or less), intermediate- (four to six months), and long-term (seven or more months) follow-up. RESULTS Seventeen randomized controlled trials (N = 2,496) were included in the meta-analysis. Both eHealth and mHealth interventions had a significant effect on pain intensity at short- and intermediate-term follow-up. Similarly, a significant but small effect was observed for depression at short- and intermediate-term follow-up and self-efficacy at short-term follow-up. Finally, a significant effect was observed for pain catastrophizing at short-term follow-up. CONCLUSIONS eHealth and mHealth interventions had significant effects on multiple short- and intermediate-term outcome measures recommended in the IMMPACT guidelines. Given widespread availability and low cost to patients, clinicians treating patients with chronic pain could consider using eHealth and mHealth interventions as part of a multidisciplinary pain treatment strategy.
Synergistic Effects of Melittin and Plasma Treatment: A Promising Approach for Cancer Therapy

Melittin (MEL), a small peptide component of bee venom, has been reported to exhibit anti-cancer effects in vitro and in vivo. However, its clinical applicability is disputed because of its non-specific cytotoxicity and haemolytic activity in high treatment doses. Plasma-treated phosphate buffered saline solution (PT-PBS), a solution rich in reactive oxygen and nitrogen species (RONS) can disrupt the cell membrane integrity and induce cancer cell death through oxidative stress-mediated pathways. Thus, PT-PBS could be used in combination with MEL to facilitate its access into cancer cells and to reduce the required therapeutic dose. The aim of our study is to determine the reduction of the effective dose of MEL required to eliminate cancer cells by its combination with PT-PBS. For this purpose, we have optimised the MEL threshold concentration and tested the combined treatment of MEL and PT-PBS on A375 melanoma and MCF7 breast cancer cells, using in vitro, in ovo and in silico approaches. We investigated the cytotoxic effect of MEL and PT-PBS alone and in combination to reveal their synergistic cytological effects. To support the in vitro and in ovo experiments, we showed by computer simulations that plasma-induced oxidation of the phospholipid bilayer leads to a decrease of the free energy barrier for translocation of MEL in comparison with the non-oxidized bilayer, which also suggests a synergistic effect of MEL with plasma induced oxidation. Overall, our findings suggest that MEL in combination with PT-PBS can be a promising combinational therapy to circumvent the non-specific toxicity of MEL, which may help for clinical applicability in the future.