bluuebunny/crossref_metadata_2025_split huggingface dataset:
Breast Cancer Therapeutics Based on Fusarochromanone and EGFR Inhibitors
Authors: Carroll Natalie , Smith Alena , Salvatore Brian A. , Mahdavian Elahe 
Published: March 2021

Abstract
Background: Fusarochromanone (FC101) is a small molecule with potent anti-cancer activity. It was originally derived from the fungal plant pathogen, Fusarium equiseti, and it has also been synthesized in non-racemic form in our lab. Numerous studies reveal the promising biological activity of FC101, including potent anti-angiogenic and anti-cancer activity. While FC101 is potent as a single drug treatment across many cancer cell lines, current cancer therapies often incorporate a combination of drugs in order to increase efficacy and decrease the development of drug resistance. In this study, we leverage drug combinations and cellular phenotypic screens to address important questions about FC101’s mode of action and its potential synergies as an anti-cancer therapeutic agent in triple negative breast cancer (TNBC).Method: We hypothesized that FC101’s activity against TNBC is similar to the known mTOR inhibitor, everolimus, because FC101 reduces the phosphorylation of two key mTOR substrates, S6K and S6. Since everolimus synergistically enhances the anti-cancer activities of known EGFR inhibitors (erlotinib or lapatinib) in TNBC, we performed analogous studies with FC101. Phenotypic cellular assays helped assess whether FC101 (in both single and combination treatments) acts similarly to everolimus.Results: FC101 outperformed all other single treatments in both cell proliferation and viability assays. Unlike everolimus, however, FC101 brought about a sustained decrease in cell viability in drug washout studies. None of the other drugs were able to maintain comparable effects upon removal of the treatment agents. Although we observed slightly additive effects when the TNBC cells were treated with FC101 and either EGFR inhibitor, those effects were not truly synergistic in the manner displayed with everolimus. Conclusion: Our results rule out direct inhibition of mTOR by FC101 and suggest that FC101 acts through a different mechanism than everolimus. This lays the foundation for the refinement of our hypothesis in order to better understand FC101’s mode of action as a novel anti-cancer agent.
A new discovery of genetic polymorphisms of important genes in WNT pathway (LPR5 and AXIN1) associated with osteoporosis susceptibility in Chinese Han population
Authors: Cui Yongsheng , Hu Xinglv , Zhang Chen , Wang Kunzheng 
Published: March 2021

Abstract
Background: genetic factors play a critical role in the pathogenesis of osteoporosis. The imbalance of WNT/β-catenin will cause the occurrence of osteoporosis. LPR5 and AXIN1 play an important role in the classical Wnt/β-catenin signaling pathway. Our study was aimed to determine the association between 5 candidate single nucleotide polymorphisms (SNPs) of LPR5 or AXIN1 and osteoporosis susceptibility in Chinese Han population. Methods: the association analysis was conducted between 5 candidate SNPs and osteoporosis susceptibility among 1198 participants. Agena MassARRAY was used to genotype SNPs. The association between SNPs and osteoporosis susceptibility in different genetic models was analyzed by logistic regression analysis. Multi-factor dimension reduction (MDR) was used to analyze the interaction of SNP-SNP in the osteoporosis risk. The difference of clinical indicators under different genotypes was completed by one-way analysis of variance.Results: we found that LPR5 rs11228240, AXIN1 rs2301522 and rs9921222 were significantly associated with the osteoporosis susceptibility. The results of subgroup analysis showed that LPR5 rs11228240 (protective factor) and AXIN1 rs2301522 (risk factor) were significantly associated with the susceptibility of osteoporosis among participants who were age > 60 years, female or BMI≤24; AXIN1 rs9921222 significantly increased the risk of osteoporosis among participants with BMI≤24. The results of Haplotype analysis showed that Ars2301522Crs9921222 could increase the susceptibility of osteoporosis. We also found that LRP5 rs11228219, AXIN1 rs2301522 and rs9921222 showed a potential association with some clinical indicators of osteoporosis.Conclusion: the SNPs of LPR5 and AXIN1 which are important genes in WNT classical pathway, have a potential association with osteoporosis susceptibility in Chinese Han population.
Rate of Decline in Kidney Function and Age-of-Onset or Duration of Type 2 Diabetes
Authors: Buyadaa Oyunchimeg , Salim Agus , Morton Jedidiah I , Magliano Dianna J , Shaw Jonathan E 
Published: March 2021

Abstract
The association between rate of kidney function decline and age-of-onset or duration of type 2 diabetes has not been well investigated. We aimed to examine whether rates of estimated glomerular filtration rate (eGFR) decline differ by age-of-onset or duration in people with type 2 diabetes. Using the Action to Control Cardiovascular Risk in Diabetes study dataset rates of eGFR decline were calculated using a joint-longitudinal-survival model and were compared among groups defined by the age-of-onset (0–39, 40–49, 50–59, 60–69 and > 70 years) and 5-year diabetes duration intervals. Changes in renal function were evaluated using median of 6 (interquartile range: 3–10) eGFR measurements per person. eGFR decline was the slowest in those with an age-at-diagnosis of 50 − 59 years or those with duration of diabetes < 5 years. The rates of eGFR decline were significantly greater in those with an age-of-onset < 40 years or those with duration of diabetes > 20 years compared to those diagnosed at 50 − 59 or those with duration of diabetes < 5 years (-1.98 vs -1.61 ml/min/year; -1.82 vs -1.52 ml/min/year; respectively (p < 0.001). Those with youngest age-of-onset or longest duration of type 2 diabetes had more rapid declines in eGFR compared to those diagnosed at middle age or those with shorter duration of diabetes.
Parthenolide induces autophagy and apoptosis of breast cancer cells associated with the PI3K/AKT/mTOR pathway
Authors: Han Yanyan , Yang Jinfeng , Sun Yan , Fan Shujun , Lu Ying , Li Lianhong 
Published: March 2021

Abstract
Background: Breast cancer is an aggressive malignancy that is unresponsive to conventional therapies. Parthenolide has been demonstrated to have anticancer effects against various types of cancer, including breast cancer. The aim of the present study was to investigate the effect and underlying mechanism of parthenolide in human breast cancer. Methods: Autophagy was measured through immunofluorescence and western blotting. DAPI staining and flow cytometry analysis were used to measure apoptosis. Western blot analysis was used to investigate the mechanism of autophagy induced by parthenolide on the expression levels of phosphoinositide 3‑kinase (PI3K), AKT, phosphorylated (p‑) AKT, mammalian target of rapamycin (mTOR), ATG13 and ATG14. Furthermore, apoptosis was confirmed via western blot analysis. Conclusion: Parthenolide inhibits breast cancer cell proliferation and induces autophagy and apoptosis, and suggested that the PI3K/AKT/mTOR pathway serves an important role in autophagy and apoptosis.
Novel neutralizing human monoclonal antibodies against tetanus neurotoxin
Authors: Minamitani Takeharu , Kiyose Karin , Otsubo Ryota , Ito Toshihiro , Akiba Hiroki , Furuta A. Rika , Inoue Tsuyoshi , Tsumoto Kouhei , Satake Masahiro , Yasui Teruhito 
Published: March 2021

Abstract
Tetanus is a fatal disease caused by tetanus neurotoxin (TeNT). TeNT is composed of a light chain (Lc) and a heavy chain, the latter of which is classified into two domains, N-terminus Hn and C-terminus Hc. Several TeNT-neutralizing antibodies have been reported, but it remains unclear which TeNT domains are involved in neutralization. To further understand the mechanism of these antibodies, we isolated TeNT-reactive human antibody clones from peripheral blood mononuclear cells. We then analyzed the reactivity of the isolated antibody clones to each protein domain and their inhibition of Hc-ganglioside GT1b binding, which is critical for TeNT toxicity. We also investigated the TeNT-neutralizing ability of isolated antibody clones and showed that Hn-reactive clones protected strongly against TeNT toxicity in mice. Furthermore, combination treatment of Hn-reactive antibody clones with both Hc-reactive and TeNT mix–reactive antibody clones enhanced the neutralizing effect. These results indicated that antibody clones targeting Hn effectively neutralized TeNT. In addition, the use of a cocktail composed of Hc-, Hn-, and TeNT mix–reactive antibodies provided enhanced protection compared to the use of each antibody alone.
Evaluation of a revised resuscitation protocol for out-of-hospital cardiac arrest patients due to COVID-19 safety protocols: A single-center retrospective study in Japan
Authors: Kandori Kenji , Okada Yohei , Ishii Wataru , Narumiya Hiromichi , Iizuka Ryoji 
Published: March 2021

Abstract
Background: This study aimed to determine the association between cardiopulmonary resuscitation (CPR) under the coronavirus 2019 (COVID-19) safety protocols in our hospital and the prognosis of out-of-hospital cardiac arrest (OHCA) patients, in an urban area tertiary critical care center, where the prevalence of COVID-19 infection is relatively low.Methods: This was a single-center, retrospective, observational, cohort study conducted at a tertiary critical care center in Kyoto City, Japan. Adult OHCA patients were included who were admitted to our emergency department while still in cardiac arrest at hospital arrival between January 1, 2019, and December 31, 2020. Our hospital implemented a revised resuscitation protocol for OHCA patients on April 1, 2020 to prevent COVID-19 disease transmission. This study defined the conventional CPR period as January 1, 2019 to March 31, 2020, and the COVID-19 safety protocol period as April 1, 2020 to December 31, 2020. The primary outcome was hospitalization survival. The secondary outcomes were return of spontaneous circulation after hospital admission and 1-month survival after OHCA occurrence. The adjusted odds ratios with 95% confidence intervals (CI) were calculated for outcomes to compare the two study periods, and the multivariable logistic model was used to adjust for six variables: age, presence of witness, presence of bystander CPR, initial cardiac rhythm at the scene, call–hospital interval, and the first documented cardiac rhythm at hospital arrival.Results: The study analyzed 443 patients, with a median age of 76 years (65–85), and included 261 men (58.9%). The percentage of hospitalization survivors during the entire research period was 16.9% (75/443 patients), with 18.7% (50/267) during the conventional CPR period and 14.2% (25/176) during the COVID-19 safety protocol period. The adjusted odds ratio for hospitalization survival during the COVID-19 safety protocol period was 0.61 (95% CI, 0.32–1.18), as compared with conventional CPR.Conclusions: There was no apparent difference in hospitalization survival between the OHCA patients resuscitated under the conventional CPR protocol compared with the current revised protocol for controlling COVID-19 disease transmission.
Osmotically Balanced, Large Unilamellar Liposomes for Sustained Bupivacaine Release: From the Development of Liposomes to Their in Vivo Application
Authors: Yoo Hyebin , Park Jun Seok , Oh Seung Soo , Kang Hyun 
Published: March 2021

Abstract
To efficiently prolong analgesic effects, we developed osmotically balanced, large unilamellar liposomes (~6 μm in diameter) in which highly concentrated bupivacaine (up to 30 mg/mL) was encapsulated, and their sustained bupivacaine release was highly effective in relieving postoperative pain over 24 h in a rat model. Our reverse-phase evaporation method based on non-toxic alcohol, ethanol, enabled simple and cost-effective production of bupivacaine-loaded liposomes, of which osmotic pressure was readily balanced to improve the structural stability of the enlarged unilamellar liposomes along with extension of their shelf life (> a month). The in vitro release profile verified that the release duration of the bupivacaine-loaded liposomes extended up to six days. For the in vivo study, male Sprague-Dawley rats were used for the incisional pain model, simulating postoperative pain, and the mechanical withdrawal threshold (MWT) was measured using a von Frey filament. Compared to the control group that received intraplantar administration of normal saline, the group of liposomal bupivacaine showed that the initially increased MWT gradually decreased up to 24 h, and importantly, the analgesic effect of the liposomal bupivacaine was maintained 6 times longer than that of bupivacaine only, proving the potential of effective long-acting anesthetics.
Socioeconomic factors contributing to antibiotic resistance in China: a panel data analysis
Authors: Zhen Xuemei , Chen Jingchunyu , Sun Xueshan , Sun Qiang , Guo Shasha , Lundborg Cecilia Stålsby 
Published: March 2021

Abstract

Background
The relationship between socioeconomic factors and ABR remains a knowledge gap in China. In this study, our aim was to examine the association between ABR proportion and socioeconomic factors across 30 provinces in mainland China.
Methods
We used two measures of ABR: the proportion of carbapenem-resistant Pseudomonas aeruginosa (CRPA), 3rd generation cephalosporin-resistant Klebsiella pneumoniae (3GCRKP), 3rd generation cephalosporin-resistant Escherichia coli (3GCREC), methicillin-resistant Staphylococcus aureus (MRSA); and the aggregate resistance. ABR proportion, education, gross domestic product (GDP) per capita, out-of-pocket (OOP) health expenditure, physician density, hospital bed density, access to water source, and number of public toilets per 10,000 population data during 2014 and 2018 in 30 provinces in mainland China were included. We examined the association between ABR level and potential contributing factors using panel data modelling. In addition, we explored this relationship from eastern, central, and western economic zone, respectively.
Results
Our results indicated that higher hospital bed density and physician density were significantly associated with lower levels of ABR. The issue of ABR was also related to socioeconomic factors such as GDP per capita, OOP health expenditure, education, which might depend on different resistant bacteria or different economic zones. GDP per capita was negatively associated with CRPA level, but positively associated with MRSA level. Higher OOP health expenditure was associated higher CRPA level. In addition, we only found that ABR prevalence was significantly negatively associated with education, and positively associated with OOP health expenditure in central economic zone, but not found in eastern and western economic zone.
Conclusions
Our study highlights that measures increasing hospital beds and physicians allocation to curb ABR should be implemented. Besides, intervention measures tackling the development and spread of ABR in China must better recognize and address the importance of social and economic determinants.
The effect of mobility restrictions on the SARS-CoV-2 diffusion: lessons from the first wave in Sweden, USA, France and Colombia.
Authors: Telle Olivier , Paul Richard , Benkimoun Samuel 
Published: March 2021

Abstract
The control of human mobility has quickly been targeted as a major leverage to contain the spread of SARS-CoV-2 in a great majority of countries worldwide. Using more than 151 million anonymized movements registered by one of the major social media platforms combined with spatial and temporal Covid-19 data, the objective of this research is to understand how mobility patterns and SARS-CoV-2 diffusion during the first wave are connected in four different countries: the west coast of the USA, Colombia, Sweden and France. In this research, we could demonstrate that introducing movement improved considerably the model. It underlines as well that mobility played an important role in the diffusion of SARS-CoV-2, even during the lockdown, suggesting a moderate impact of lockdown on virus diffusion. However, it suggests that government could better locate where disease mitigation would be the most effective by systematically analyzing real-time movements of population. Lockdown strategies and vaccination campaigns could, for example, be prioritized according to spatial vulnerability and connectivity to hotspots of viral circulation.
Differential Effects of Body Mass Index on Domain-Specific Cognitive Outcomes After Stroke
Authors: Lee Minwoo , Oh Mi Sun , Jung San , Lee Ju-Hun , Kim Chul-Ho , Jang Min Uk , Kim Young Eun , Bae Hee-Joon , Park Jaeseol , Kang Yeonwook , Lee Byung-Chul , Lim Jae-Sung , Yu Kyung-Ho 
Published: March 2021

Abstract
Background We aimed to investigate the association between body mass index (BMI) and domain-specific cognitive functions in post-ischemic stroke survivors.MethodsA total of 335 ischemic stroke patients were included in the study after completion of the Korean-Mini-Mental Status Examination (K-MMSE) and the K-VCIHS neuropsychological protocol at 3 months after stroke. Frontal lobe functions were analyzed using semantic/phonic fluency, processing speed, and mental set shifting. Our study participants were categorized into four groups according to BMI quartiles ResultsThe K-MMSE scores at 3 months differed significantly between the groups after adjustment for covariates with univariate p-value less than 0.1 (p = 0.003). Global cognitive function in stroke survivors in the Q1 BMI group was significantly lower than those in Q2 and Q4 BMI groups (K-MMSE scores, Q1: 22.9 ± 6.7 vs. Q2: 25.2 ± 5.2 and Q4: 25.1 ± 4.3). Controlled oral word association test findings indicated that phonemic and semantic word fluency was lower in Q4 BMI group participants than in Q2 BMI group participants (p = 0.012, and p=0.012 respectively). ConclusionsBMI might differentially affect cognitive domains after ischemic stroke. Although being underweight may negatively affect global cognition post-stroke, obesity could induce frontal lobe dysfunctions, specifically phonemic and semantic word fluency.
Optimizing reconstruction parameters for quantitative 124I-PET in the presence of therapeutic doses of 131I
Authors: Fanchon Louise , Beattie Brad , Pentlow Keith , Larson Steven , Humm John Laurence 
Published: March 2021

Abstract
Purpose To determine the accuracy of quantitative 124I PET imaging in the presence of therapeutic levels of 131I.Material and Methods Multiple PET images were acquired using a NEMA IEC phantom with spheres containing 0.4 MBq/cc of 124I and increasing amount of 131I activity in the phantom background (0 to 3.76 GBq). Acquisitions were performed on a GE Discovery 710 PET/CT scanner. At each 131I activity level two scans were acquired, one with the phantom at the center of the field of view (FOV) and one 11 cm off-center. Images were reconstructed with an ordered subset expectation maximization (OSEM) algorithm using between 1 and 25 iterations of 16 subsets. Results were evaluated visually and by comparing the 124I activity relative to the baseline PET performed in the absence of 131I.Results The presence of 131I within the PET FOV added to the random coincidence rate, to dead-time and to pile-up within the PET detectors. Using our standard clinical reconstruction parameters, the image quality and quantitative accuracy suffered at 131I background activities above 1.4 GBq. However, increasing the number of iterations resulted in dramatic improvements in image quality and quantitative accuracy. Projection space measurements suggest that the dead time corrections implemented on the scanner perform well even at the highest singles count rate tested (52 Mcps).Conclusion This study shows that 124I quantitative PET is feasible in the presence of large amounts of 131I on a GE D710. The high random coincidence fraction slows the reconstruction convergence rate, therefore iterations equivalent to at least 8x16 are recommended.
Immunomodulator FTY720 Rejuvenates β-cell and Ameliorates Cardiorenal Complications in Nonhuman Primate Model of Diabetes
Authors: Wang Yixin (Jim) , Wang Xiaoli , An Annie , Zang Mingfa , Xu Ling , Gong Kefeng , Xiao Yong-Fu , Yu Guoliang , Ma Zhongmin A. 
Published: March 2021

Abstract
Inadequate β-cell mass is essential for the pathogenesis of type 2 diabetes (T2D). Previous report showed that an immunomodulator FTY720, a sphingosine 1-phosphate (S1P) receptor modulator sustainably normalized hyperglycemia by stimulating β-cell in vivo regeneration in db/db mice. To further evaluate the therapeutic potential, we examined the effects of FTY720 on glucose homeostasis in a translational nonhuman primate (NHP) model of spontaneous diabetes. Daily administration of FTY720 (5 mg/kg) effectively lowered HbA1c, blood concentrations of fasting glucose (FBG) and insulin, hence, decreased homeostatic model assessment of insulin resistance (HOMA-IR); ameliorated glucose intolerance and restored glucose-stimulated insulin release, which was largely diminished in the vehicle-treated diabetic NHPs. Importantly, after discontinuation of FTY720, FBG and HbA1c remained at the reduced levels in washout period for 8 weeks. Accompanied by the glucose lowering effects, echocardiography revealed that FTY720 significantly improved cardiac left ventricular systolic function measured by increase in ejection fraction and fractional shortening, which was compromised in the diabetic NHPs. Finally, flow cytometry analysis detected that FTY720 significantly reduced CD4+ and increased DC cells. These data strongly suggest that immunomodulator FTY720 may be a novel immunotherapy to reverse T2D progression via rejuvenation of β-cell function with benefit to improve the cardiac function.
Stability of Flow Velocity and Intracoronary Resistance in the Intracoronary Electrocardiogram-triggered Pressure Ratio
Authors: Nakayama Masafumi , Tanaka Nobuhiro , Uchiyama Takashi , Ohkawauchi Takaaki , Tsuboko Yusuke , Iwasaki Kiyotaka , Kawase Yoshiaki , Matsuo Hitoshi 
Published: March 2021

Abstract
It has been found that the assessment of coronary artery lesions using the fractional flow reserve and instantaneous flow reserve measurements reduces the incidence of further cardiovascular events. Here, we investigated differences in the coronary flow velocity and resistance within the analysis interval between the instantaneous flow reserve (iFR) and the intracoronary electrocardiogram (IC-ECG)-triggered distal/aortic pressure (Pd/Pa) ratio (ICE-T). Thirty-three consecutive patients with stenoses that required coronary flow measurement were enrolled. ICE-T was defined as the average Pd/Pa ratio in the period corresponding to the isoelectric line of the IC-ECG. The index value, flow velocity, and intracoronary resistance during the analysis intervals of the iFR and ICE-T, both at rest and under hyperemia, were compared. The index value and intracoronary resistance of the ICE-T were found to be significantly lower, while the flow velocity was significantly higher, than those of the iFR (P < 0.001), and all fluctuations in ICE-T values were also significantly smaller than those in the iFR.In conclusion, the ICE-T is theoretically superior to pressure-dependent indices for analyzing phases with low and stable resistance, without an increase in invasiveness.