Miracle-dz/UniFAR-FTUs huggingface dataset:
Carfilzomib in Combination with Bortezomib Enhances Apoptotic Cell Death in B16-F1 Melanoma Cells

Simple Summary The incidence rate of metastatic melanoma has been rapidly increasing worldwide and its 5-year survival rate is very low. Due to partial responses, various side effects, and resistance to any known cancer therapeutics, more potent and safer therapeutics are needed to increase the survival rate of patients with melanoma. Since proteasome inhibitors, such as bortezomib and carfilzomib, have been suggested as treatments for various cancers, we investigated their potential for the treatment of melanoma by studying their molecular mechanisms of action in B16-F1 melanoma cells. In this study, we found that both bortezomib and carfilzomib lead to apoptosis via ER stress as well as ROS accumulation and MMP loss in melanoma cells. Bortezomib and carfilzomib synergistically reduced B16-F1 tumor growth in vitro and in a C57BL/6 xenograft mouse model. Therefore, a combination therapy with carfilzomib and bortezomib at submaximal concentrations may reduce their side effects and be beneficial for melanoma treatment. Abstract Proteasome inhibitors, such as bortezomib (BZ) and carfilzomib (CFZ), have been suggested as treatments for various cancers. To utilize BZ and/or CFZ as effective therapeutics for treating melanoma, we studied their molecular mechanisms using B16-F1 melanoma cells. Flow cytometry of Annexin V-fluorescein isothiocyanate-labeled cells indicated apoptosis induction by treatment with BZ and CFZ. Apoptosis was evidenced by the activation of various caspases, including caspase 3, 8, 9, and 12. Treatment with BZ and CFZ induced endoplasmic reticulum (ER) stress, as indicated by an increase in eIF2α phosphorylation and the expression of ER stress-associated proteins, including GRP78, ATF6α, ATF4, XBP1, and CCAAT/enhancer-binding protein homologous protein. The effects of CFZ on ER stress and apoptosis were lower than that of BZ. Nevertheless, CFZ and BZ synergistically induced ER stress and apoptosis in B16-F1 cells. Furthermore, the combinational pharmacological interactions of BZ and CFZ against the growth of B16-F1 melanoma cells were assessed by calculating the combination index and dose-reduction index with the CompuSyn software. We found that the combination of CFZ and BZ at submaximal concentrations could obtain dose reduction by exerting synergistic inhibitory effects on cell growth. Moreover, this drug combination reduced tumor growth in C57BL/6 syngeneic mice. Taken together, these results suggest that CFZ in combination with BZ may be a beneficial and potential strategy for melanoma treatment.
Toxocara cati and Other Parasitic Enteropathogens: More Commonly Found in Owned Cats with Gastrointestinal Signs Than in Clinically Healthy Ones

Intestinal parasites are involved in the health and wellbeing of cats and some of them, due to their zoonotic potential, represent a problem for public health. This study aimed to assess the prevalence of parasitic infections in cats with gastrointestinal signs. Fecal samples collected from 137 cats were analyzed by the flotation method using a sodium chloride saturated solution. The overall prevalence of intestinal parasites was 50.4%. Intestinal parasites were significantly (p < 0.0001) more common in cats with digestive clinical signs (66.7%) than in clinically healthy ones (19.2%). Toxocara cati (40.2%) was the most frequently identified intestinal parasite, followed by Cystoisospora spp. (10.2%), hookworms (3.7%), Taeniidae (2.2%), Giardia duodenalis (2.2%), and Toxoplasma gondii (0.7%). Toxocara cati (53.3%, p < 0.0001) and Cystoisospora spp. (15.6%, p < 0.001) were significantly more frequently diagnosed in cats with clinical signs. A lack of deworming in the last three months (OR: 15.9), outdoor access (OR: 13.8), the presence of digestive symptoms (OR: 5.4), and young age (OR: 4.2) were identified as risk factors for T. cati infection by logistic regression analysis. Regardless of age, gastrointestinal signs like vomiting, diarrhea, and inappetence were positively associated with T. cati.
Enhancement of Curcumin Anti-Inflammatory Effect via Formulation into Myrrh Oil-Based Nanoemulgel

Background: Curcumin (Cur) possesses a variety of beneficial pharmacological properties including antioxidant, antimicrobial, anti-cancer and anti-inflammatory activities. Nevertheless, the low aqueous solubility and subsequent poor bioavailability greatly limits its effectiveness. Besides, the role of myrrh oil as an essential oil in treating inflammatory disorders has been recently demonstrated. The objective of the current investigation is to enhance Cur efficacy via developing Cur nanoemulgel, which helps to improve its solubility and permeability, for transdermal delivery. Methods: The formulated preparations (Cur gel, emulgel and nanoemulgel) were evaluated for their physical appearance, spreadability, viscosity, particle size, in vitro release and ex vivo drug permeation studies. The in vivo anti-inflammatory activity was estimated using the carrageenan-induced rat hind paw edema method. Results: The formulated Cur-loaded preparations exhibited good physical characteristics that were in the acceptable range of transdermal preparations. The release of Cur from gel, emulgel and nanoemulgel after 12 h was 72.17 ± 3.76, 51.93 ± 3.81 and 62.0 ± 3.9%, respectively. Skin permeation of Cur was significantly (p < 0.05) improved when formulated into nanoemulgel since it showed the best steady state transdermal flux (SSTF) value (108.6 ± 3.8 µg/cm2·h) with the highest enhancement ratio (ER) (7.1 ± 0.2). In vivo anti-inflammatory studies proved that Cur-loaded nanoemulgel displayed the lowest percent of swelling (26.6% after 12 h). Conclusions: The obtained data confirmed the potential of the nanoemulgel dosage form and established the synergism of myrrh oil and Cur as an advanced anti-inflammatory drug.
The In Vivo Selection Method in Breast Cancer Metastasis

Metastasis is a complex event in cancer progression and causes most deaths from cancer. Repeated transplantation of metastatic cancer cells derived from transplanted murine organs can be used to select the population of highly metastatic cancer cells; this method is called as in vivo selection. The in vivo selection method and highly metastatic cancer cell lines have contributed to reveal the molecular mechanisms of cancer metastasis. Here, we present an overview of the methodology for the in vivo selection method. Recent comparative analysis of the transplantation methods for metastasis have revealed the divergence of metastasis gene signatures. Even cancer cells that metastasize to the same organ show various metastatic cascades and gene expression patterns by changing the transplantation method for the in vivo selection. These findings suggest that the selection of metastasis models for the study of metastasis gene signatures has the potential to influence research results. The study of novel gene signatures that are identified from novel highly metastatic cell lines and patient-derived xenografts (PDXs) will be helpful for understanding the novel mechanisms of metastasis.
Plasma Xanthine Oxidoreductase Activity Is Associated with a High Risk of Cardiovascular Disease in a General Japanese Population

The purpose of this study was to investigate the association between xanthine oxidoreductase (XOR) activity and a high risk of cardiovascular disease (CVD) in a general Japanese population. The Iwate Tohoku Medical Megabank Organization pooled individual participant data from a general population-based cohort study in Iwate prefecture. The cardiovascular risk was calculated using the Framingham Risk Score (FRS). A total of 1605 of the 1631 participants (98.4%) had detectable XOR activity. Multiple regression analysis demonstrated that XOR activity was independently associated with body mass index (β = 0.26, p < 0.001), diabetes (β = 0.09, p < 0.001), dyslipidemia (β = 0.08, p = 0.001), and uric acid (β = 0.13, p < 0.001). Multivariate analysis showed that the highest quartile of XOR activity was associated with a high risk for CVD (FRS ≥ 15) after adjustment for baseline characteristics (OR 2.93, 95% CI 1.16–7.40). The area under the receiver operating characteristic curves of the FRS with XOR activity was 0.81 (p = 0.008). XOR activity is associated with a high risk for CVD, suggesting that high XOR activity may indicate cardiovascular risk in a general Japanese population.
Shape Fidelity of 3D-Bioprinted Biodegradable Patches

There is high demand in the medical field for rapid fabrication of biodegradable patches at low cost and high throughput for various instant applications, such as wound healing. Bioprinting is a promising technology, which makes it possible to fabricate custom biodegradable patches. However, several challenges with the physical and chemical fidelity of bioprinted patches must be solved to increase the performance of patches. Here, we presented two hybrid hydrogels made of alginate-cellulose nanocrystal (CNC) (2% w/v alginate and 4% w/v CNC) and alginate-TEMPO oxidized cellulose nanofibril (T-CNF) (4% w/v alginate and 1% w/v T-CNC) via ionic crosslinking using calcium chloride (2% w/v). These hydrogels were rheologically characterized, and printing parameters were tuned for improved shape fidelity for use with an extrusion printing head. Young’s modulus of 3D printed patches was found to be 0.2–0.45 MPa, which was between the physiological ranges of human skin. Mechanical fidelity of patches was assessed through cycling loading experiments that emulate human tissue motion. 3D bioprinted patches were exposed to a solution mimicking the body fluid to characterize the biodegradability of patches at body temperature. The biodegradation of alginate-CNC and alginate-CNF was around 90% and 50% at the end of the 30-day in vitro degradation trial, which might be sufficient time for wound healing. Finally, the biocompatibility of the hydrogels was tested by cell viability analysis using NIH/3T3 mouse fibroblast cells. This study may pave the way toward improving the performance of patches and developing new patch material with high physical and chemical fidelity for instant application.
Telehealth Use in Geriatrics Care during the COVID-19 Pandemic—A Scoping Review and Evidence Synthesis

Introduction: Globally, the COVID-19 pandemic has affected older people disproportionately. Prior to the pandemic, some studies reported that telehealth was an efficient and effective form of health care delivery, particularly for older people. There has been increased use of telehealth and publication of new literature on this topic during the pandemic, so we conducted a scoping review and evidence synthesis for telehealth use in geriatric care to summarize learning from these new data. Methods: We searched PubMed, Embase, and the World Health Organization’s COVID-19 global research database for articles published between 1 January and 20 August 2020. We included 79 articles that met our inclusion criteria. The information collected has been synthesized and presented as descriptive statistics. Strengths, weaknesses, opportunities, and threats (SWOT) have also been discussed. Results: The articles included in our review provide some evidence of effective provision of preventive, curative, and rehabilitative telehealth services for older people, but they highlight a greater focus on curative services and are mostly concentrated in high-income countries. We identified convenience and affordability as the strengths of telehealth use in geriatric care. Weaknesses identified include the inability of telehealth to cater to the needs of older people with specific physical and cognitive limitations. While the threats of increasing inequity and the lack of standardization in the provision of age-friendly telehealth services remain, we identified opportunities for technologic advancements driven by simplicity and user-friendliness for older people. Conclusion: Telehealth offers futuristic promise for the provision of essential health care services for older people worldwide. However, the extent of these services via telehealth appears to be currently limited in low and low-middle income countries. Optimizing telehealth services that can be accessed by older people requires greater government investments and active engagement by broader participation of older people, their caregivers, physicians and other health care providers, technology experts, and health managers.
Seasonal Biomass Accumulation and Nutrient Uptake of Canola, Mustard, and Flax on a Black Chernozem Soil in Saskatchewan

ABSTRACT Seed yield and nutrient use efficiency are related to biomass accumulation and nutrient uptake in the growing season. Biomass accumulation and nutrient uptake of canola (Brassica napus L. and Brassica rapa L.), mustard (Brassica juncea L.) and flax (Linum usitatissimum L.) and the relationship to days after emergence (DAE) or growing degree days (GDD) were determined during the 1998 and 1999 growing seasons in field experiments at Melfort, Saskatchewan, Canada. In general, biomass accumulation and nutrient uptake increased with time at early growth stages and reached a maximum at late growth stages. Significant R2 values for both biomass accumulation and nutrient uptake indicated that a cubic polynomial type equation was suitable to represent these parameters as a function of DAE. All oilseed crops maximized biomass at mid way to the end of pod forming stages (74–84 DAE or 750–973 GDD). Maximum biomass accumulation rate occurred at the early to late bud forming stage (42–49 DAE or 390–498 GDD), and it was 146–190 kg ha−1d−1 for canola, 158–182 kg ha−1d−1 for mustard, and 174–189 kg ha−1d−1 for flax. Maximum nutrient uptake occurred during flowering to early ripening (59–82 DAE or 597–945 GDD). Maximum nutrient uptake rate normally occurred at branching to early bud formation (21–42 DAE or 142–399 GDD). There was a close correlation between biomass accumulation and nutrient uptake, and among nutrients, suggesting interrelated absorption. For nitrogen (N), phosphorus (P), potassium (K), sulfur (S), and boron (B), respectively, maximum nutrient uptake rate was 2.3–4.5, 0.3–0.5, 2.5–5.7, 0.7–1.1, and 0.005–0.008 kg ha−1d−1 for canola; 2.3–3.9, 0.4–0.5, 2.6–4.9, 1.2–1.4, and 0.006–0.008 kg ha−1d−1 for mustard; and 3.2–4.0, 0.3–0.4, 2.9–4.1, 0.3–0.5, and 0.004–0.009 kg ha−1d−1 for flax. In general, maximum nutrient uptake rate and amount occurred earlier than maximum biomass accumulation rate and amount, and maximum rates of both nutrient uptake and biomass accumulation occurred earlier than their maximum amounts. The findings suggest that for high seed yields, there should be adequate supply of nutrients for plants, particularly to sustain high nutrient uptake rate at branching to bud forming stage and high biomass accumulation rate at early to late bud forming stage.
The Influence of Zinc Waste Filler on the Tribological and Mechanical Properties of Silicone-Based Composites

Silicones are often used for various types of coatings, but due to their poor mechanical properties, they often require modification to meet specific requirements. At the same time, various production processes throughout the world generate different types of waste, the disposal of which is harmful to the environment. One possible solution is to use production waste as a filler. In this paper, the authors investigated how the use of metallurgical production waste products as fillers changed the mechanical properties of silicone composites prepared by casting. Composite samples were characterized using tensile tests, resilience, pin-on-disc, Schopper–Schlobach abrasion, hardness, and density measurements. Based on the obtained results, the authors assessed the effect of each of the fillers used in different weight proportions. The results showed that the silicone composite filled with 5 wt% zinc dust showed the lowest decrease in tensile strength and Young’s modulus, with a simultaneous significant reduction in abrasion compared with the reference sample. This research shows that zinc waste can be successfully introduced into a silicone matrix in cases where it is important to reduce abrasive wear.
A Low-Carbohydrate Ketogenic Diet and Treadmill Training Enhanced Fatty Acid Oxidation Capacity but Did Not Enhance Maximal Exercise Capacity in Mice

The low-carbohydrate ketogenic diet (LCKD) is a dietary approach characterized by the intake of high amounts of fat, a balanced amount of protein, and low carbohydrates, which is insufficient for metabolic demands. Previous studies have shown that an LCKD alone may contribute to fatty acid oxidation capacity, along with endurance. In the present study, we combined a 10-week LCKD with an 8-week forced treadmill running program to determine whether training in conjunction with LCKD enhanced fatty acid oxidation capacity, as well as whether the maximal exercise capacity would be affected by an LCKD or training in a mice model. We found that the lipid pool and fatty acid oxidation capacity were both enhanced following the 10-week LCKD. Further, key fatty acid oxidation related genes were upregulated. In contrast, the 8-week training regimen had no effect on fatty acid and ketone body oxidation. Key genes involved in carbohydrate utilization were downregulated in the LCKD groups. However, the improved fatty acid oxidation capacity did not translate into an enhanced maximal exercise capacity. In summary, while favoring the fatty acid oxidation system, an LCKD, alone or combined with training, had no beneficial effects in our intensive exercise-evaluation model. Therefore, an LCKD may be promising to improve endurance in low- to moderate-intensity exercise, and may not be an optimal choice for those partaking in high-intensity exercise.
Dietary Quality in Vegetarian and Omnivorous Female Students in Germany: A Retrospective Study

Vegetarian diets have gained in popularity, especially among highly educated women, and are considered beneficial to health. Comparative studies assessing the diet of vegetarians against omnivores are rather limited and often provide ambivalent results. Therefore, this study examined the nutrient intake and nutritional quality of vegetarian and omnivorous diets in a group of 61 female students in Germany. Habitual dietary intake was evaluated using a validated graphical online food frequency questionnaire (FFQ). Differences in nutrient intakes were analyzed by Mann–Whitney-U-Tests. Odds Ratios (OR) were calculated for vegetarians exceeding dietary reference values (DRV) compared to omnivores. The overall nutritional quality was assessed using the Healthy-Eating-Index-2015 (HEI-2015). In omnivores, intakes of total energy from saturated fatty acids (SFA), monounsaturated fatty acids (MUFA), long-chain omega-3 polyunsaturated fatty acids (LC-n3-PUFA), cholesterol, sucrose, lactose, retinol, and cobalamin were significantly higher than in vegetarians. Significantly lower intakes were observed for fiber, magnesium, and beta-carotene. Significant OR were detected for total fat (OR = 0.29), SFA (OR = 0.04), beta-carotene (OR = 4.55), and cobalamin (OR = 0.32). HEI-2015 scores were higher for vegetarians than for omnivores (79 points versus 74 points) and significant differences were recorded for the HEI-2015 components dairy, seafood & plant proteins, fatty acids, added sugars, and saturated fatty acids.
Atorvastatin Inhibits Endothelial PAI-1-Mediated Monocyte Migration and Alleviates Radiation-Induced Enteropathy

Intestinal injury is observed in cancer patients after radiotherapy and in individuals exposed to radiation after a nuclear accident. Radiation disrupts normal vascular homeostasis in the gastrointestinal system by inducing endothelial damage and senescence. Despite advances in medical technology, the toxicity of radiation to healthy tissue remains an issue. To address this issue, we investigated the effect of atorvastatin, a commonly prescribed hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor of cholesterol synthesis, on radiation-induced enteropathy and inflammatory responses. We selected atorvastatin based on its pleiotropic anti-fibrotic and anti-inflammatory effects. We found that atorvastatin mitigated radiation-induced endothelial damage by regulating plasminogen activator inhibitor-1 (PAI-1) using human umbilical vein endothelial cells (HUVECs) and mouse model. PAI-1 secreted by HUVECs contributed to endothelial dysfunction and trans-endothelial monocyte migration after radiation exposure. We observed that PAI-1 production and secretion was inhibited by atorvastatin in irradiated HUVECs and radiation-induced enteropathy mouse model. More specifically, atorvastatin inhibited PAI-1 production following radiation through the JNK/c-Jun signaling pathway. Together, our findings suggest that atorvastatin alleviates radiation-induced enteropathy and supports the investigation of atorvastatin as a radio-mitigator in patients receiving radiotherapy.
Aquaporins in Immune Cells and Inflammation: New Targets for Drug Development

The mammalian immune system senses foreign antigens by mechanisms that involve the interplay of various kinds of immune cells, culminating in inflammation resolution and tissue clearance. The ability of the immune cells to communicate (via chemokines) and to shift shape for migration, phagocytosis or antigen uptake is mainly supported by critical proteins such as aquaporins (AQPs) that regulate water fluid homeostasis and volume changes. AQPs are protein channels that facilitate water and small uncharged molecules’ (such as glycerol or hydrogen peroxide) diffusion through membranes. A number of AQP isoforms were found upregulated in inflammatory conditions and are considered essential for the migration and survival of immune cells. The present review updates information on AQPs’ involvement in immunity and inflammatory processes, highlighting their role as crucial players and promising targets for drug discovery.
Comparative Evaluation of Different Chitosan Species and Derivatives as Candidate Biomaterials for Oxygen-Loaded Nanodroplet Formulations to Treat Chronic Wounds

Persistent hypoxia is a main clinical feature of chronic wounds. Intriguingly, oxygen-loaded nanodroplets (OLNDs), filled with oxygen-solving 2H,3H-decafluoropentane and shelled with polysaccharides, have been proposed as a promising tool to counteract hypoxia by releasing a clinically relevant oxygen amount in a time-sustained manner. Here, four different types of chitosan (low or medium weight (LW or MW), glycol-(G-), and methylglycol-(MG-) chitosan) were compared as candidate biopolymers for shell manufacturing. The aim of the work was to design OLND formulations with optimized physico-chemical characteristics, efficacy in oxygen release, and biocompatibility. All OLND formulations displayed spherical morphology, cationic surfaces, ≤500 nm diameters (with LW chitosan-shelled OLNDs being the smallest), high stability, good oxygen encapsulation efficiency, and prolonged oxygen release kinetics. Upon cellular internalization, LW, MW, and G-chitosan-shelled nanodroplets did not significantly affect the viability, health, or metabolic activity of human keratinocytes (HaCaT cell line). On the contrary, MG-chitosan-shelled nanodroplets showed very poor biocompatibility. Combining the physico-chemical and the biological results obtained, LW chitosan emerges as the best candidate biopolymer for future OLND application as a skin device to treat chronic wounds.
2020 FDA TIDES (Peptides and Oligonucleotides) Harvest

2020 has been an extremely difficult and challenging year as a result of the coronavirus disease 2019 (COVID-19) pandemic and one in which most efforts have been channeled into tackling the global health crisis. The US Food and Drug Administration (FDA) has approved 53 new drug entities, six of which fall in the peptides and oligonucleotides (TIDES) category. The number of authorizations for these kinds of drugs has been similar to that of previous years, thereby reflecting the consolidation of the TIDES market. Here, the TIDES approved in 2020 are analyzed in terms of chemical structure, medical target, mode of action, and adverse effects.