bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk Adapted Ablative Radiotherapy After Intensive Chemotherapy for Locally Advanced Pancreatic Cancer
Authors: Rossi Gabriella , Simoni Nicola , Paiella Salvatore , Rossi Roberto , Venezia Martina , Micera Renato , Malleo Giuseppe , Salvia Roberto , Giuliani Tommaso , Di Gioia Anthony , Auriemma Alessandra , Milella Michele , Guariglia Stefania , Cavedon Carlo , Bassi Claudio , Mazzarotto Renzo
Published: April 2021

Background and Objective

To assess the efficacy of a Risk-Adapted Ablative Radiotherapy (RAdAR) approach, after intensive induction chemotherapy, in patients with locally advanced pancreatic cancer (LAPC).

Material and Methods

Patients with LAPC who received RAdAR following induction chemotherapy from January 2017 to December 2019 were included in this observational study. The RAdAR approach consisted of an anatomy- and simultaneous integrated boost (SIB)-based dose prescription strategy. RAdAR was delivered with stereotactic ablative radiation therapy (SAbR), administering 30 Gy in 5 fractions to the tumor volume (PTVt) and 50 Gy SIB (BED10 100 Gy) to the vascular involvement, or with (hypo-)fractionated ablative radiotherapy (HART) prescribing 50.4 Gy in 28 fractions to the PTVt, with a vascular SIB of 78.4 Gy (BED10 100 Gy). Primary end points were freedom from local progression (FFLP), overall survival (OS), and progression-free survival (PFS).

Results

Sixty-four LAPC patients were included. Induction chemotherapy consisted of gemcitabine/nab-paclitaxel in 60.9% and FOLFIRINOX in 39.1% of cases. SAbR was used in 52 (81.2%) patients, and HART in 12 (18.8%). After RAdAR, surgery was performed in 17 (26.6%) patients. Median follow-up was 16.1 months. Overall local control (LC) rate was 78.1%, with no difference between resected and non-resected patients (2-year FFLP 75.3% vs 56.4%; p = 0.112). Median OS and PFS were 29.7 months and 8.7 months, respectively, for the entire cohort. Resected patients had a better median OS (not reached versus 26.1 months; p = 0.0001) and PFS (19 versus 5.6 months; p < 0.0001) compared to non-resected patients. In non-resected patients, no significant difference was found between SAbR and HART for median FFLP (28.1 versus 18.5 months; p = 0.614), OS (27.4 versus 25.3 months; p = 0.624), and PFS (5.7 versus 4.3 months; p = 0.486). One patient (1.6%) experienced acute grade 4 gastro-intestinal bleeding. No other acute or late grade ≥ 3 toxicities were observed.

Conclusions

The RAdAR approach, following intensive induction chemotherapy, is an effective radiation treatment strategy for selected LAPC patients, representing a promising therapeutic option in a multimodality treatment regimen.
Association Between the Pretreatment Albumin-to-Alkaline Phosphatase Ratio and Clinical Outcomes in Patients With Bladder Cancer Treated With Radical Cystectomy: A Retrospective Cohort Study
Authors: Li Shijie , Lu Shiyang , Liu Xuefeng , Chen Xiaonan
Published: April 2021

Objective

Serum albumin-to-alkaline phosphatase ratio (AAPR) has been proven to be a prognostic indicator of many malignant tumors. However, whether it can predict the prognosis of bladder cancer (BC) patients who underwent radical cystectomy (RC) remains unclear. This study was designed to assess the relationship between AAPR and clinical outcomes in patients with BC treated with RC.

Methods

The clinicopathological data of 199 BC patients receiving RC in our institution from January 2012 to December 2017 were retrospectively collected and analyzed. They were divided into three groups based on the optimal cut-off values and the association between AAPR groups and their clinical outcomes were evaluated.

Results

The average age of the patients was (64.0 ± 8.7) years and 79.9% were male. Based on the cut-off values of AAPR, patients were divided into three groups: low-AAPR group (AAPR < 0.37, n = 35), medium-AAPR group (AAPR = 0.37-0.59, n = 61) and high-AAPR group (AAPR > 0.59, n = 103). The median overall survival (OS) of each AAPR group was 12.5, 24, and 29 months, respectively (P value <0.0001). After adjusting the Cox proportional hazards model, medium- and high- AAPR groups showed a reduced risk trend of death, with a risk ratio of 0.44 (95% CI = 0.21-0.91) and 0.25 (95% CI = 0.12-0.49), respectively (P for trend <0.001). No nonlinear relationship was identified by smooth fitting curve between AAPR and OS. By subgroup analysis, we observed that compared to the low-AAPR group, the trends of the HRs in the medium- and high-AAPR group were decreased across nearly all subgroups after stratification. Moreover, the AAPR-based nomograms for OS, CSS and RFS were also constructed. The C-index showed a good predictive accuracy (OS, C-index 0.728, 95% CI 0.663-0.793; CSS, C-index 0.792, 95% CI 0.748-0.838; RFS, C-index 0.784, 95% CI 0.739-0.829).

Conclusion

Pretreatment AAPR is significantly associated with the prognosis of BC patients receiving RC, which can be conducive to the clinical decision-making and risk stratification in those patients. The nomogram based on AAPR is a reliable model for predicting survival of BC patients after RC.
Neurotoxicity of Unconjugated Bilirubin in Neonatal Hypoxic-Ischemic Brain Injury in vitro
Authors: Dani Carlo , Pratesi Simone , Mannaioni Guido , Gerace Elisabetta
Published: April 2021

Background: The pathophysiology of bilirubin neurotoxicity in course of hypoxic–ischemic encephalopathy (HIE) in term and preterm infants is still poorly understood. We hypothesized that oxidative stress may be a common mechanism that link hyperbilirubinemia and HIE.

Objectives: The objective of the present study was to evaluate whether unconjugated bilirubin (UCB) may enhance the HI brain injury by increasing oxidative stress and to test pioglitazone and allopurinol as new antioxidant therapeutic drugs in vitro.

Methods: The effects of UCB were tested on organotypic hippocampal slices subjected to 30 min oxygen-glucose deprivation (OGD), used as in vitro model of HIE. The experiments were performed on mature (14 days in culture) and immature (7 days in culture) slices, to mimic the brains of term and preterm infants, respectively. Mature and immature slices were exposed to UCB, human serum albumin (HSA), pioglitazone, and/or allopurinol for 24 h, immediately after 30 min OGD. Neuronal injury was assessed using propidium iodide (PI) fluorescence. ROS formation was quantified by using the 2′,7′-dichlorodihydrofluorescein diacetate (DCF-DA) method.

Results: In mature slices, we found that the neurotoxicity, as well as oxidative stress, induced by OGD were enhanced by UCB. HSA significantly prevented UCB-increased neurotoxicity, but had a slight reduction on ROS production. Allopurinol, but not pioglitazone, significantly reduced UCB-increased neurotoxicity induced by OGD. In immature slices exposed to OGD, no increase of neuronal death was observed, whereas oxidative stress was detected after UCB exposure. HSA, pioglitazone and allopurinol have no protective effects on both OGD-induced neuronal death and on UCB-induced oxidative stress. For this reason, UCB, pioglitazone and allopurinol was also tested on ischemic preconditioning protocol. We found that UCB abolished the neuroprotection induced by preconditioning and increased oxidative stress. These effects were restored by allopurinol but not pioglitazone.

Conclusions: UCB characterized a different path of neuronal damage and oxidative stress in mature and immature hippocampal slice model of HIE. Management of hyperbilirubinemia in a complex pathological condition, such as HIE and hyperbilirubinemia, should be very careful. Allopurinol could deserve attention as a novel pharmacological intervention for hyperbilirubinemia and HIE.
Empagliflozin Effectively Attenuates Olanzapine-Induced Body Weight Gain in Female Wistar Rats
Authors: Ashraf Ghulam Md , Alghamdi Badrah S. , Alshehri Fahad S. , Alam Mohammad Zubair , Tayeb Haythum O. , Tarazi Frank I.
Published: April 2021

Atypical antipsychotic drugs are commonly associated with undesirable side effects including body weight gain (BWG) and metabolic deficits. Many pharmacological interventions have been tested in an attempt to minimize or prevent these side effects. Preliminary evidence suggests that antidiabetic drugs may be effective in attenuating antipsychotic-induced BWG. In the current study, we examined the effect of an antidiabetic drug empagliflozin (EMPA) on BWG induced by anatypical antipsychotic drug olanzapine (Ola) in female and male Wistar rats. Rats were divided into six groups based on the dose they received: group 1 (female control), group 2 (female EMPA, 20 mg/kg; IG), group 3 (female Ola, 4 mg/kg; IP), group 4 (female Ola, 4 mg/kg; IP + EMPA, 20 mg/kg; IG), group 5 (male control), and group 6 (male Ola, 4 mg/kg; IP). Ola induced sustained increase in BWG. The subsequent treatment of Group 3 and 4 with EMPA attenuated the Ola-induced BWG in female Wistar rats. In terms of the gender difference between female and male Wistar rats, the male control group 5 gained more weight throughout the study as compared to the female control group 1. Similarly, the male Ola group 6 gained more weight throughout the study as compared to the female Ola group 3. However, Ola did not cause any weight difference between male rats treated with Ola in comparison with male control group, thus showing a significant gender difference regarding body weight between male and female Wistar rats regardless of Ola administration. In addition, the present findings showed that EMPA effectively attenuates the Ola induced BWG in female Wistar rats. These novel findings should help to better understand the underlying molecular and behavioral mechanisms contributing to the observed increase in body weight after treatment with Ola and other atypical antipsychotic drugs across male and female rats.
Blood Pressure Changes Following Antihypertensive Medication Reduction, by Drug Class and Dose Chosen for Withdrawal: Exploratory Analysis of Data From the OPTiMISE Trial
Authors: Sheppard James P. , Lown Mark , Burt Jenni , Ford Gary A. , Hobbs F. D. Richard , Little Paul , Mant Jonathan , Payne Rupert A. , McManus Richard J. ,   On behalf of the OPTiMISE Investigators
Published: April 2021

Aims: Deprescribing of antihypertensive drugs is recommended for some older patients with polypharmacy, but there is little evidence to inform which drug (or dose) should be withdrawn. This study used data from the OPTiMISE trial to examine whether short-term outcomes of deprescribing vary by drug class and dose of medication withdrawn.

Methods: The OPTiMISE trial included patients aged ≥80 years with controlled systolic blood pressure (SBP; <150 mmHg), receiving ≥2 antihypertensive medications. This study compared SBP control, mean change in SBP and frequency of adverse events after 12 weeks in participants stopping one medication vs. usual care, by drug class and equivalent dose of medication withdrawn. Equivalent dose was determined according to the defined daily dose (DDD) of each medication type. Drugs prescribed below the DDD were classed as low dose and those prescribed at ≥DDD were described as higher dose. Outcomes were examined by generalized linear mixed effects models.

Results: A total of 569 participants were randomized, aged 85 ± 3 years with controlled blood pressure (mean 130/69 mmHg). Within patients prescribed calcium channel blockers, higher dose medications were more commonly selected for withdrawal (90 vs. 10%). In those prescribed beta-blockers, low dose medications were more commonly chosen (87 vs. 13%). Withdrawal of calcium channel blockers was associated with an increase in SBP (5 mmHg, 95%CI 0–10 mmHg) and reduced SBP control (adjusted RR 0.89, 95%CI 0.80–0.998) compared to usual care. In contrast, withdrawal of beta-blockers was associated with no change in SBP (−4 mmHg, 95%CI −10 to 2 mmHg) and no difference in SBP control (adjusted RR 1.15, 95%CI 0.96–1.37). Similarly, withdrawal of higher dose medications was associated with an increase in SBP but no change in BP control. Withdrawal of lower dose medications was not associated with a difference in SBP or SBP control. There was no association between withdrawal of specific drug classes and adverse events.

Conclusion: These exploratory data suggest withdrawal of higher dose calcium channel blockers should be avoided if the goal is to maintain BP control. However, low dose beta-blockers may be removed with little impact on blood pressure over 12-weeks of follow-up. Larger studies are needed to confirm these associations.
Pure Total Flavonoids From Citrus Protect Against Nonsteroidal Anti-inflammatory Drug-Induced Small Intestine Injury by Promoting Autophagy in vivo and in vitro
Authors: Chen Shanshan , Jiang Jianping , Chao Guanqun , Hong Xiaojie , Cao Haijun , Zhang Shuo
Published: April 2021

Small intestine injury is an adverse effect of non-steroidal anti-inflammatory drugs (NSAIDs) that urgently needs to be addressed for their safe application. Although pure total flavonoids from citrus (PTFC) have been marketed for the treatment of digestive diseases, their effects on small intestine injury and the underlying mechanism of action remain unknown. This study aimed to investigate the potential role of autophagy in the mechanism of NSAID (diclofenac)-induced intestinal injury in vivo and in vitro and to demonstrate the protective effects of PTFC against NSAID-induced small intestine disease. The results of qRT-PCR, western blotting, and immunohistochemistry showed that the expression levels of autophagy-related 5 (Atg5), light chain 3 (LC3)-II, and tight junction (TJ) proteins ZO-1, claudin-1, and occludin were decreased in rats with NSAID-induced small intestine injury and diclofenac-treated IEC-6 cells compared with the control groups. In the PTFC group, Atg5 and LC3-II expression, TJ protein expression, and the LC3-II/LC3-I ratio increased. Furthermore, the mechanism by which PTFC promotes autophagy in vivo and in vitro was evaluated by western blotting. Expression levels of p-PI3K and p-Akt increased in the intestine disease-induced rat model group compared with the control, but decreased in the PTFC group. Autophagy of IEC-6 cells was upregulated after treatment with a PI3K inhibitor, and the upregulation was significantly more after PTFC treatment, suggesting PTFC promoted autophagy through the PI3K/Akt signaling pathway. In conclusion, PTFC protected intestinal barrier integrity by promoting autophagy, which demonstrates its potential as a therapeutic candidate for NSAID-induced small intestine injury.
8-Substituted Triazolobenzodiazepines: In Vitro and In Vivo Pharmacology in Relation to Structural Docking at the α1 Subunit-Containing GABAA Receptor
Authors: Golani Lalit K. , Platt Donna M. , Rüedi-Bettschen Daniela , Edwanker Chitra , Huang Shenming , Poe Michael M. , Furtmüller Roman , Sieghart Werner , Cook James M. , Rowlett James K.
Published: April 2021

In order to develop improved anxiolytic drugs, 8-substituted analogs of triazolam were synthesized in an effort to discover compounds with selectivity for α2/α3 subunit-containing GABAA subtypes. Two compounds in this series, XLi-JY-DMH (6-(2-chlorophenyl)-8-ethynyl-1-methyl-4H-benzo [f][1,2,4]triazolo[4,3-a][1,4]diazepine) and SH-TRI-108 [(E)-8-ethynyl-1-methyl-6-(pyridin-2-yl)-4H-benzo [f][1,2,4]triazolo[4,3-a][1,4]diazepine], were evaluated for in vitro and in vivo properties associated with GABAA subtype-selective ligands. In radioligand binding assays conducted in transfected HEK cells containing rat αXβ3γ2 subtypes (X = 1,2,3,5), no evidence of selectivity was obtained, although differences in potency relative to triazolam were observed overall (triazolam > XLi-JY-DMH > SH-TRI-108). In studies with rat αXβ3γ2 subtypes (X = 1,2,3,5) using patch-clamp electrophysiology, no differences in maximal potentiation of GABA-mediated Cl− current was obtained across subtypes for any compound. However, SH-TRI-108 demonstrated a 25-fold difference in functional potency between α1β3γ2 vs. α2β3γ2 subtypes. We evaluated the extent to which this potency difference translated into behavioral pharmacological differences in monkeys. In a rhesus monkey conflict model of anxiolytic-like effects, triazolam, XLi-JY-DMH, and SH-TR-108 increased rates of responding attenuated by shock (anti-conflict effect) but also attenuated non-suppressed responding. In a squirrel monkey observation procedure, both analogs engendered a profile of sedative-motor effects similar to that reported previously for triazolam. In molecular docking studies, we found that the interactions of the 8-ethynyl triazolobenzodiazepines with the C-loop of the α1GABAA site was stronger than that of imidazodiazepines XHe-II-053 and HZ-166, which may account for the non-sedating yet anxiolytic profile of these latter compounds when evaluated in previous studies.
Resveratrol Pretreatment Improved Heart Recovery Ability of Hyperglycemic Bone Marrow Stem Cells Transplantation in Diabetic Myocardial Infarction by Down-Regulating MicroRNA-34a
Authors: Zhang Fengyun , Wang Kun , Gao Fei , Xuan Yongli , Liu Xiaohong , Zhang Zhuoqi
Published: April 2021

AIM: To examine the effect of resveratrol (RSV) on bone marrow mesenchymal stem cells (BMSCs) under hyperglycemic conditions and on BMSCs transplantation in diabetic rats with myocardial infarction (MI).

METHODS:In vitro, BMSCs were isolated from 3-week-old male Sprague Dawley (SD) rats and cultured under hyperglycemic conditions for up to 28 days. Cell viability was analyzed by cell counting kit-8 (CCK-8) assays. The expression of miR-34a was measured by RT-qPCR. Western blotting was used to examine the protein expression of SIRT1, P21, P16, VEGF and HIF-1α. A senescence-associated β-galactosidase assay was used to examine the senescence level of each group. In vivo, a diabetes model was established by feeding rats a high-sugar and high-fat diet for 8 weeks, injecting the animals with streptozotocin (STZ) and continuing high-sugar and high-fat feeding for 4 additional weeks. Then, left anterior descending coronary artery (LAD) cessation was used to established the myocardial infarction (MI) models. Each group of rats was transplanted with differentially preconditioned BMSCs after myocardial infarction. Ultrasound was used to analyze cardiac function 1 and 3 weeks after the operation, and frozen heart sections were used for immunohistochemical analysis, Masson staining and CD31 measurement. In addition, ELISA analysis of serum cytokine levels was performed.

RESULTS: This study showed that the viability of BMSCs cultured under hyperglycemic conditions was decreased, the cells became senescent. Besides, an obviously increased in the expression of miR-34a was detected. Moreover, RSV preconditioning reduced the expression of miR-34a in BMSCs after high glucose stimulation and rejuvenated BMSCs under hyperglycemic conditions. Further analysis showed that the transplantation of RSV-BMSCs were benefit to heart recovery following infarction in diabetic rats, promoted proangiogenic factor release and increased arteriole and capillary densities.

CONCLUSION: RSV rejuvenated BMSCs after chronic hyperglycemia-induced senescence by interacting with miR-34a and optimized the therapeutic effect of BMSCs on diabetes with myocardial infarction.
Off-Patent Biological and Biosimilar Medicines in Belgium: A Market Landscape Analysis
Authors: Vandenplas Yannick , Simoens Steven , Van Wilder Philippe , Vulto Arnold G. , Huys Isabelle
Published: April 2021

Background and objective: Best-value biological medicines may generate competition in the off-patent biologicals market, resulting in having more resources available to provide patients with access to necessary medicines while maintaining high-quality care. Belgium is a country known to have low biosimilar market shares, suggesting a malfunctioning market for off-patent biologicals. This study aims to gain an in-depth understanding of the Belgian off-patent biologicals market, by looking at the evolution in volumes and costs of the relevant products in the market.

Methods: This study included a combination of quantitative and qualitative research methods. The quantitative part of this study consisted of the analysis of market data obtained by the National Institute for Health and Disability Insurance (NIHDI) for all relevant products in the Belgian off-patent biologicals market (i.e. TNF-inhibitors, insulins, granulocyte colony-stimulating factors, epoetins, rituximab, trastuzumab). In addition, for the qualitative part of this study, semi-structured interviews with Belgian stakeholders were conducted between December 2019 and March 2020.

Results: Belgian market data and stakeholder perceptions suggest a suboptimal market environment for off-patent biological and biosimilar medicines. Shifts are observed after loss of exclusivities of originator biologicals toward second-generation products or new therapeutic class products, at a higher cost and often limited added value. Moreover, cost reductions for off-patent biologicals after biosimilar market entry are mainly determined by mandatory price reductions applicable to both originator and biosimilar products, and not by lower prices induced by competition. For products used in the retail setting, significant mandatory price reductions for both originator and reference products with low biosimilar volumes were pointed out as the main reasons for the lack of price competition. For products dispensed in hospitals, the hospital financing system is important. First, it does not always encourage the use of lower cost alternatives. Second, competition mainly takes place at the level of confidential discounts in tenders. Most interviewees acknowledged the lack of a competitive environment, which is not supportive of a sustainable Belgian off-patent biologicals market.

Conclusion: Market data and stakeholder perceptions indicate that the sustainability of the Belgian market for off-patent biologicals is challenged. A sustainable market ensures access to biological therapies now and in the future.
Berberine-Loaded Carboxylmethyl Chitosan Nanoparticles Ameliorate DSS-Induced Colitis and Remodel Gut Microbiota in Mice
Authors: Zhao Luqing , Du Xueying , Tian Jiaxin , Kang Xiuhong , Li Yuxin , Dai Wenlin , Li Danyan , Zhang Shengsheng , Li Chao
Published: April 2021

Inflammatory bowel disease (IBD) is a refractory disorder characterized by chronic and recurrent inflammation. The progression and pathogenesis of IBD is closely related to oxidative stress and irregularly high concentrations of reactive oxygen species (ROS). A new oxidation-responsive nano prodrug was constructed from a phenylboronic esters-modified carboxylmethyl chitosan (OC-B) conjugated with berberine (BBR) that degrades selectively in response to ROS. The optimized micelles exhibited well-controlled physiochemical properties and stability in a physiological environment. OC-B-BBR micelles could effectively encapsulate the anti-inflammatory drug berberine and exhibit ideal H2O2-triggered release behavior as confirmed by in vitro drug loading and release studies. The in vivo anti-inflammatory effect and regulation of gut microbiota caused by it were explored in mice with colitis induced by dextran sodium sulfate (DSS). The results showed that OC-B-BBR significantly ameliorated colitis symptoms and colon damage by regulating the expression levels of IL-6 and remodeling gut microbiota. In summary, this study exhibited a novel BBR-loaded Carboxylmethyl Chitosan nano delivery system which may represent a promising approach for improving IBD treatment.
Circulating Galectin-1 and Galectin-3 in Sera From Patients With Systemic Sclerosis: Associations With Clinical Features and Treatment
Authors: Sundblad Victoria , Gomez Ramiro A. , Stupirski Juan C. , Hockl Pablo F. , Pino Maria S. , Laborde Hugo , Rabinovich Gabriel A.
Published: April 2021

Systemic Sclerosis (SSc) is a rheumatic disease characterized by fibrosis, microvascular damage and immune dysregulation. Two major subsets, limited cutaneous systemic sclerosis (lcSSc) and diffuse cutaneous systemic sclerosis (dcSSc) can be defined, according to the extent of skin involvement. Increasing evidence indicates a role for galectins in immune and vascular programs, extracellular matrix remodeling and fibrosis, suggesting their possible involvement in SSc. Here, we determined serum levels of galectin (Gal)-1 and Gal-3 in 83 SSc patients (dcSSc n = 17; lcSSc n = 64; ssSSc n = 2), and evaluated their association with clinical manifestations of the disease. Patients with dcSSc showed lower Gal-3 levels, compared to lcSSc (p = 0.003), whereas no considerable difference in Gal-1 levels was detected between groups. Remarkably, higher concentrations of Gal-1 were associated with the presence of telangiectasias (p = 0.015), and higher concentrations Gal-3 were associated with telangiectasias (p = 0.021), diarrhea (p = 0.039) and constipation (p = 0.038). Moreover, lower Gal-3 levels were associated with the presence of tendinous retractions (p = 0.005). Patients receiving calcium blockers (p = 0.048), methotrexate (p = 0.046) or any immunosuppressive treatment (p = 0.044) presented lower concentrations of Gal-3 compared to those not receiving such treatments. The presence of telangiectasia and the type of SSc maintained their statistical association with Gal-3 (β 0.25; p = 0.022 and β 0.26; p = 0.017, respectively) in multiple linear regression models. In conclusion, serum levels of Gal-3 are associated with clinical manifestations of SSc. Among them, the presence of telangiectasias could be explained by the central role of this lectin in the vascularization programs.
Fraxinellone Has Anticancer Activity by Inducing Osteosarcoma Cell Apoptosis via Promoting Excessive Autophagy Flux
Authors: He Bin , Zhang Wenkan , He Jiaming
Published: April 2021

Osteosarcoma is a malignant bone tumor that is easy to metastasize in the early stage and has a very poor prognosis. Fraxinellone (FRA) is one of the main components isolated from the D. dasycarpus plant. Its anti-inflammatory and neuroprotective effects have been confirmed, but the research on the anti-cancer effect of FRA and its potential mechanism is relatively scarce. In this study, we found that FRA inhibited the proliferation and migration of osteosarcoma cells HOS and MG63 in a dose-dependent manner. Immunofluorescence, fluorescence staining and western blotting analysis showed that FRA could simultaneously induce osteosarcoma cell apoptosis and increase autophagy flux. Subsequent turnaround experiments suggested that the pro-apoptotic effect of FRA was achieved through excessive autophagy flux. The results of the xenograft orthotopic model further supported the anti-cancer effects of FRA, indicating that FRA treatment inhibited the growth of osteosarcoma, and the pro-apoptotic and autophagy effects of FRA were also proved in vivo. These studies provide new ideas for the future treatment of osteosarcoma and offer theoretical support for the anti-cancer mechanism of FRA.
Oral Unsaturated Fat Load Impairs Postprandial Systemic Inflammation in Primary Hypercholesterolemia Patients
Authors: Collado Aida , Domingo Elena , Marques Patrice , Perello Eva , Martínez-Hervás Sergio , Piqueras Laura , Ascaso Juan F. , Real José T. , Sanz Maria-Jesus
Published: April 2021

Context: Primary hypercholesterolemia (PH) is a lipid disorder characterized by elevated levels of cholesterol and low-density lipoprotein (LDL). Low-grade systemic inflammation is associated with PH, which might explain the higher incidence of cardiovascular diseases in this setting.

Objective: To evaluate the effect of an oral unsaturated fat load (OUFL) on different immune parameters and functional consequences in patients with PH in postprandial state.

Design: A commercial liquid preparation of long-chain triglycerides (Supracal®; ω6/ω3 ratio >20/1, OUFL) was administered to 20 patients and 10 age-matched controls. Whole blood was collected before (fasting state) and 4 h after administration (postprandial state). Flow cytometry was employed to determine platelet and leukocyte activation, and the levels of circulating platelet-leukocyte aggregates. Soluble markers were determined by ELISA, and the parallel-plate flow chamber was employed to study leukocyte adhesion to the dysfunctional arterial endothelium.

Results: The PH group had a lower percentage of activated platelets and circulating type 1 monocytes, and blunted neutrophil activation after the OUFL, accompanied by a significant increase in the percentage of regulatory T lymphocytes. In this group, the OUFL led to a significant impairment of leukocyte adhesion to the dysfunctional [tumor necrosis factor α (TNFα)-stimulated] endothelium and reduced the plasma levels of soluble P-selectin, platelet factor-4 (PF-4)/CXCL4, CXCL8, CCL2, CCL5, and TNFα.

Conclusion: The OUFL has a beneficial impact on the pro-thrombotic and pro-inflammatory state of PH patients and might be a promising macronutrient approach to dampen the systemic inflammation associated with PH and the development of further cardiovascular events.
Uridine Diphosphate Promotes Rheumatoid Arthritis Through P2Y6 Activation
Authors: Wang Hongxing , Wu Hui , Fang Kehua , Chang Xiaotian
Published: April 2021

BACKGROUND: Uridine diphosphate (UDP) is an extracellular nucleotide signaling molecule implicated in diverse biological processes via specific activation of pyrimidinergic receptor P2Y, G Protein-Coupled, 6 (P2Y6). There is very little knowledge about the function and mechanism of UDP in rheumatoid arthritis (RA).

METHODS: This study used a quasi-targeted liquid chromatography-mass spectrometry (LC-MS) approach to investigate the unique expression of metabolites in RA synovial fluids (SF) (n = 10) with samples from osteoarthritis (OA) as controls (n = 10). RA fibroblast-like synoviocytes (FLSs) were collected from synovial tissues (n = 5) and cultured with UDP or MRS2578, a P2Y6 antagonist, and FLSs from OA were used as controls (n = 5). Rats with collagen-induced arthritis (CIA) were injected with UDP, MRS2578 or both (n = 9 for each group). P2Y6 expression was examined using real-time PCR, Western blotting and immunohistochemistry. Cell proliferation, apoptosis and migration of RA FLSs were measured using CCK-8 assay, real-time cell analysis, flow cytometry, wound healing assay and Transwell assay, respectively. The UDP levels in the culture medium, synovial fluid (n = 36) and peripheral blood (n = 36) of RA and CIA rats were measured using a Transcreener UDP Assay. Levels of proinflammatory cytokines were measured using a flow assay. Interleukin-6 (IL-6) levels were measured using ELISA and flow.

RESULTS: LC-MS analysis detected significantly increased UDP levels in RA SF compared with OA SF, and the level was positively correlated with anticyclic citrullinated peptide (anti-CCP) and rheumatoid factor (RF)levels in RA. The increased UDP concentration was verified in the blood and synovial fluids of RA patients compared with samples from OA patients and healthy volunteers, respectively. UDP stimulated cell proliferation, migration and IL-6 secretion in RA FLSs and inhibited their apoptosis in culture, and MRS2578 inhibited these effects of UDP. UDP injection accelerated CIA and stimulated IL-6 production rather than other proinflammatory cytokines in the rat model, but simultaneous injection of MRS2578 suppressed these effects and alleviated CIA. P2Y6 expression was increased in RA and CIA synovial tissues.

CONCLUSION: These results suggest that UDP is highly expressed in RA and stimulates RA pathogenesis by promoting P2Y6 activities to increase IL-6 production.
Therapeutic Strategies by Regulating Interleukin Family to Suppress Inflammation in Hypertrophic Scar and Keloid
Authors: Zhang Dan , Li Bo , Zhao Muxin
Published: April 2021

Hypertrophic scar (HS) and keloid are fibroproliferative disorders (FPDs) of the skin due to aberrant wound healing, which cause disfigured appearance, discomfort, dysfunction, psychological stress, and patient frustration. The unclear pathogenesis behind HS and keloid is partially responsible for the clinical treatment stagnancy. However, there are now increasing evidences suggesting that inflammation is the initiator of HS and keloid formation. Interleukins are known to participate in inflammatory and immune responses, and play a critical role in wound healing and scar formation. In this review, we summarize the function of related interleukins, and focus on their potentials as the therapeutic target for the treatment of HS and keloid.
Nonlinear Optical Properties of CdSe and CdTe Core-Shell Quantum Dots and Their Applications
Authors: Kalsoom Um e , Yi Rongxing , Qu Junle , Liu Liwei
Published: April 2021

The strong nonlinear optical behavior of low-dimensional materials, such as quantum dots and core-shell quantum dots, has been a topic of intense research in recent years. As quantum dots have tunable emission via changes in their sizes, they are potentially useful in photo-electronics, photovoltaic nonlinear optics, light-emitting diode fabrication, and laser protections. Variation among core and shell shape and size, along with the chemical composition of quantum dots, define their enhanced nonlinear optical properties. Some specific nonlinear optical properties, such as nonlinear refraction, optical limiting, saturable absorption, reverse saturable absorption of CdTe and CdSe quantum dots (QDs), as well as core-shell QDs and their applications, were assessed in this paper.
Large-Conductance Calcium-Activated Potassium Channels and Voltage-Dependent Sodium Channels in Human Cementoblasts
Authors: Kamata Satomi , Kimura Maki , Ohyama Sadao , Yamashita Shuichiro , Shibukawa Yoshiyuki
Published: April 2021

Cementum, which is excreted by cementoblasts, provides an attachment site for collagen fibers that connect to the alveolar bone and fix the teeth into the alveolar sockets. Transmembrane ionic signaling, associated with ionic transporters, regulate various physiological processes in a wide variety of cells. However, the properties of the signals generated by plasma membrane ionic channels in cementoblasts have not yet been described in detail. We investigated the biophysical and pharmacological properties of ion channels expressed in human cementoblast (HCEM) cell lines by measuring ionic currents using conventional whole-cell patch-clamp recording. The application of depolarizing voltage steps in 10 mV increments from a holding potential (Vh) of −70 mV evoked outwardly rectifying currents at positive potentials. When intracellular K+ was substituted with an equimolar concentration of Cs+, the outward currents almost disappeared. Using tail current analysis, the contributions of both K+ and background Na+ permeabilities were estimated for the outward currents. Extracellular application of tetraethylammonium chloride (TEA) and iberiotoxin (IbTX) reduced the densities of the outward currents significantly and reversibly, whereas apamin and TRAM-34 had no effect. When the Vh was changed to −100 mV, we observed voltage-dependent inward currents in 30% of the recorded cells. These results suggest that HCEM express TEA- and IbTX-sensitive large-conductance Ca2+-activated K+ channels and voltage-dependent Na+ channels.
Impairment of Cerebrovascular Hemodynamics in Patients With Severe and Milder Forms of Sickle Cell Disease
Authors: Afzali-Hashemi Liza , Baas Koen P. A. , Schrantee Anouk , Coolen Bram F. , van Osch Matthias J. P. , Spann Stefan M. , Nur Erfan , Wood John C. , Biemond Bart J. , Nederveen Aart J.
Published: April 2021

In patients with sickle cell disease (SCD), cerebral blood flow (CBF) is elevated to counteract anemia and maintain oxygen supply to the brain. This may exhaust the vasodilating capacity of the vessels, possibly increasing the risk of silent cerebral infarctions (SCI). To further investigate cerebrovascular hemodynamics in SCD patients, we assessed CBF, arterial transit time (ATT), cerebrovascular reactivity of CBF and ATT (CVRCBF and CVRATT) and oxygen delivery in patients with different forms of SCD and matched healthy controls. We analyzed data of 52 patients with severe SCD (HbSS and HbSβ0-thal), 20 patients with mild SCD (HbSC and HbSβ+-thal) and 10 healthy matched controls (HbAA and HbAS). Time-encoded arterial spin labeling (ASL) scans were performed before and after a vasodilatory challenge using acetazolamide (ACZ). To identify predictors of CBF and ATT after vasodilation, regression analyses were performed. Oxygen delivery was calculated and associated with hemoglobin and fetal hemoglobin (HbF) levels. At baseline, severe SCD patients showed significantly higher CBF and lower ATT compared to both the mild SCD patients and healthy controls. As CBFpostACZ was linearly related to CBFpreACZ, CVRCBF decreased with disease severity. CVRATT was also significantly affected in severe SCD patients compared to mild SCD patients and healthy controls. Considering all groups, women showed higher CBFpostACZ than men (p < 0.01) independent of baseline CBF. Subsequently, post ACZ oxygen delivery was also higher in women (p < 0.05). Baseline, but not post ACZ, GM oxygen delivery increased with HbF levels. Our data showed that baseline CBF and ATT and CVRCBF and CVRATT are most affected in severe SCD patients and to a lesser extent in patients with milder forms of SCD compared to healthy controls. Cerebrovascular vasoreactivity was mainly determined by baseline CBF, sex and HbF levels. The higher vascular reactivity observed in women could be related to their lower SCI prevalence, which remains an area of future work. Beneficial effects of HbF on oxygen delivery reflect changes in oxygen dissociation affinity from hemoglobin and were limited to baseline conditions suggesting that high HbF levels do not protect the brain upon a hemodynamic challenge, despite its positive effect on hemolysis.
Increase of Collectivistic Expression in China During the COVID-19 Outbreak: An Empirical Study on Online Social Networks
Authors: Han Nuo , Ren Xiaopeng , Wu Peijing , Liu Xiaoqian , Zhu Tingshao
Published: April 2021

The pathogen-prevalence hypothesis postulates that collectivism would be strengthened in the long term in tandem with recurrent attacks of infectious diseases. However, it is unclear whether a one-time pathogen epidemic would elevate collectivism. The outbreak of COVID-19 and the widespread prevalence of online social networks have provided researchers an opportunity to explore this issue. This study sampled and analyzed the posts of 126,165 active users on Weibo, a leading Chinese online social network. It used independent-sample t-tests to examine whether COVID-19 had an impact on Chinese collectivistic value-related behaviors by comparing the usage frequency of personal pronouns, group-related words, and relationship-related words before and after the outbreak. Overall, most collectivist words exhibited a significant upward trend after the outbreak. In turn, this tendency pointed to a rising sense of collectivism (versus individualism). Hence, this study confirmed the pathogen-prevalence hypothesis in real settings, finding that an outbreak of an infectious disease such as COVID-19 could exert an impact on collectivism and may deliver a theoretical basis for psychological protection against the threat of COVID-19. However, further evaluation is required to ascertain whether this trend is universal or culture-specific.
Sleep and its Association With Pain and Depression in Nursing Home Patients With Advanced Dementia – a Cross-Sectional Study
Authors: Blytt Kjersti Marie , Flo-Groeneboom Elisabeth , Erdal Ane , Bjorvatn Bjørn , Husebo Bettina S.
Published: April 2021

Objective: Previous research suggests a positive association between pain, depression and sleep. In this study, we investigate how sleep correlates with varying levels of pain and depression in nursing home (NH) patients with dementia.

Materials and methods: Cross-sectional study (n = 141) with sleep-related data, derived from two multicenter studies conducted in Norway. We included NH patients with dementia according to the Mini-Mental State Examination (MMSE ≤ 20) from the COSMOS trial (n = 46) and the DEP.PAIN.DEM trial (n = 95) whose sleep was objectively measured with actigraphy. In the COSMOS trial, NH patients were included if they were ≥65 years of age and with life expectancy >6 months. In the DEP.PAIN.DEM trial, patients were included if they were ≥60 years and if they had depression according to the Cornell Scale for Depression in Dementia (CSDD ≥ 8). In both studies, pain was assessed with the Mobilization-Observation-Behavior-Intensity-Dementia-2 Pain Scale (MOBID-2), and depression with CSDD. Sleep parameters were total sleep time (TST), sleep efficiency (SE), sleep onset latency (SOL), wake after sleep onset (WASO), early morning awakening (EMA), daytime total sleep time (DTS) and time in bed (TiB). We registered use of sedatives, analgesics, opioids and antidepressants from patient health records and adjusted for these medications in the analyses.

Results: Mean age was 86.2 years and 76.3% were female. Hierarchical regressions showed that pain was associated with higher TST and SE (p < 0.05), less WASO (p < 0.01) and more DTS (p < 0.01). More severe dementia was associated with more WASO (p < 0.05) and TiB (p < 0.01). More severe depression was associated with less TST (p < 0.05), less DTS (p < 0.01) and less TiB (p < 0.01). Use of sedative medications was associated with less TiB (p < 0.05).

Conclusion: When sleep was measured with actigraphy, NH patients with dementia and pain slept more than patients without pain, in terms of higher total sleep time. Furthermore, their sleep efficiency was higher, indicating that the patients had more sleep within the time they spent in bed. Patients with more severe dementia spent more time awake during the time spent in bed. Furthermore, people with more severe depression slept less at daytime and had less total sleep time Controlling for concomitant medication use did not affect the obtained results.
Association of Sleep Duration and Screen Time With Anxiety of Pregnant Women During the COVID-19 Pandemic
Authors: Zhang Yuan , Zhang Yuge , Deng Renli , Chen Min , Cao Rong , Chen Shijiu , Chen Kuntao , Jin Zhiheng , Bai Xue , Tian Jingyan , Zhou Baofeng , Tian Kunming
Published: April 2021

The COVID-19 pandemic has dramatically changed the patterns of lifestyle and posed psychological stress on pregnant women. However, the association of sleep duration and screen time with anxiety among pregnant women under the backdrop of the COVID-19 pandemic scenario has been poorly addressed. We conducted one large-scale, multicenter cross-sectional study which recruited 1794 pregnant women across middle and west China. Self-reported demographic characteristics, lifestyle, and mental health status were collected from 6th February to 8th May 2020. We investigated the association of sleep duration and screen time with the risk of anxiety by multivariable logistic regression analysis and linear regression analysis after adjusting potential confounders. The dose-response relationship of sleep duration and screen time with anxiety was visualized using a cubic spline plot. Our data revealed that almost 35% of pregnant women suffered from anxiety during the COVID-19 pandemic. Sleep duration was dose-dependently associated with a lower risk of anxiety among pregnant women (OR = 0.41, 95% CI: 0.27–0.63), while screen time exhibited a conversed effect (OR = 2.01, 95% CI:1.00–4.39). Notably, sleep duration (≥8 h/day) synergistically combined with screen time (3–7 h/day) to diminish the risk of anxiety (OR = 0.70, 95% CI: 0.50–0.99). Taken together, sleep duration and screen time were independently and jointly associated with anxiety (P < 0.05). Therefore, promoting a more active lifestyle and maintaining higher sleep quality could improve the mental health of pregnant women, especially under public health emergency.
A Novel User Emotional Interaction Design Model Using Long and Short-Term Memory Networks and Deep Learning
Authors: Chen Xiang , Huang Rubing , Li Xin , Xiao Lei , Zhou Ming , Zhang Linghao
Published: April 2021

Emotional design is an important development trend of interaction design. Emotional design in products plays a key role in enhancing user experience and inducing user emotional resonance. In recent years, based on the user's emotional experience, the design concept of strengthening product emotional design has become a new direction for most designers to improve their design thinking. In the emotional interaction design, the machine needs to capture the user's key information in real time, recognize the user's emotional state, and use a variety of clues to finally determine the appropriate user model. Based on this background, this research uses a deep learning mechanism for more accurate and effective emotion recognition, thereby optimizing the design of the interactive system and improving the user experience. First of all, this research discusses how to use user characteristics such as speech, facial expression, video, heartbeat, etc., to make machines more accurately recognize human emotions. Through the analysis of various characteristics, the speech is selected as the experimental material. Second, a speech-based emotion recognition method is proposed. The mel-Frequency cepstral coefficient (MFCC) of the speech signal is used as the input of the improved long and short-term memory network (ILSTM). To ensure the integrity of the information and the accuracy of the output at the next moment, ILSTM makes peephole connections in the forget gate and input gate of LSTM, and adds the unit state as input data to the threshold layer. The emotional features obtained by ILSTM are input into the attention layer, and the self-attention mechanism is used to calculate the weight of each frame of speech signal. The speech features with higher weights are used to distinguish different emotions and complete the emotion recognition of the speech signal. Experiments on the EMO-DB and CASIA datasets verify the effectiveness of the model for emotion recognition. Finally, the feasibility of emotional interaction system design is discussed.