bluuebunny/crossref_metadata_2025_split huggingface dataset:
The risk of consequent nephropathy following initial weight loss in diabetic patients treated with sodium glucose cotransporter 2 inhibitors
Authors: Chan Yi-Hsin , Chen Shao-Wei , Chao Tze-Fan , Kao Yi-Wei , Huang Chien-Ying , Chu Pao-Hsien 
Published: August 2021

Abstract
Background
There is a controversy over the association between obesity and the risk of renal events in patients with type 2 diabetes mellitus (T2DM). Furthermore, whether body weight (BW) loss following sodium glucose cotransporter 2 inhibitor (SGLT2i) treatment associated with risk of adverse renal events is unknown.

Methods
We used medical data from a multi-center healthcare provider in Taiwan, enrolling 8992 T2DM patients with a baseline/following-up BW data available after around 12 weeks of SGLT2i treatment, from June 1, 2016 to December 31, 2018. Patients were followed up until the occurrence of composite renal outcome (estimated glomerular filtration rate decline > 40% or end-stage kidney disease) or the end of study period, whichever occurred first.

Results
Participants were divided into six baseline BMI categories: < 18.5 (n = 55); 18.5–22.9 (n = 985); 23.0–24.9 (n = 1389); 25.0–29.9 (n = 3941); 30.0–34.9 (n = 1973); and ≥ 35.0 kg/m2 (n = 649). There were 38.9%, 23.5%, 24.7%, 8.4%, 2.7%, and 1.8% of patients experienced no-BW loss, initial BW loss of 0.0–2.4%, 2.5–4.9%, 5.0–7.4%, 7.5–9.9%, and ≥ 10.0%, associated with SGLT2i treatment, respectively. Compared with patients with normal BMI (BMI: 18.5–22.9 kg/m2), underweight (BMI: < 18.5 kg/m2) was associated with a higher risk of composite renal outcome (adjusted hazard ratio (aHR) [95% confidence intervals (CI)]: 2.17; [1.16–4.04]), whereas pre-obese (BMI: 25.0–29.9 kg/m2) associated with the lowest risk of composite renal outcome (0.52; [0.40–0.68]) after multivariate adjustment. Compared with those without BW loss after SGLT2i treatment, BW loss of 0.0–2.4% (0.55; [0.43–0.70]) and 2.5–4.9% (0.78; [0.63–0.98]) were associated with a lower risk, whereas BW loss ≥ 10.0% associated with a higher risk of composite renal outcome (1.61; [1.06–2.46]) after multivariate adjustment.

Conclusion
A modest BW loss of 0–5% associated with SGLT2i treatment was associated with a favorable renal outcome. Caution should be taken for whom are underweight at baseline or have a pronounced BW loss ≥ 10.0% associated with SGLT2i treatment, which was associated with a worse renal outcome.
Efficient conversion of phytosterols into 4-androstene-3,17-dione and its C1,2-dehydrogenized and 9α-hydroxylated derivatives by engineered Mycobacteria
Authors: Li Xin , Chen Tian , Peng Fei , Song Shikui , Yu Jingpeng , Sidoine Douanla Njimeli , Cheng Xiyao , Huang Yongqi , He Yijun , Su Zhengding 
Published: August 2021

Abstract4-Androstene-3,17-dione (4-AD), 1,4-androstadiene-3,17-dione (ADD) and 9α-hydroxyl-4-androstene-3,17-dione (9OH-AD), which are important starting compounds for the synthesis of steroidal medicines, can be biosynthetically transformed from phytosterols by Mycobacterium strains. Genomic and metabolic analyses have revealed that currently available 4-AD-producing strains maintain the ability to convert 4-AD to ADD and 9OH-AD via 3-ketosteroid-1,2-dehydrogenase (KstD) and 3-ketosteroid-9α-hydroxylase (Ksh), not only lowering the production yield of 4-AD but also hampering its purification refinement. Additionally, these 4-AD industrial strains are excellent model strains to construct ADD- and 9OH-AD-producing strains. We recently found that Mycobacterium neoaurum HGMS2, a 4-AD-producing strain, harbored fewer kstd and ksh genes through whole-genomic and enzymatic analyses, compared with other strains (Wang et al. in Microbial Cell Fact 19:187, 2020). In this study, we attempted to construct an efficient 4-AD-producing strain by knocking out the kstd and ksh genes from the M. neoaurum HGMS2 strain. Next, we used kstd- and ksh-default HGMS2 mutants as templates to construct ADD- and 9OH-AD-producing strains by knocking in active kstd and ksh genes, respectively. We found that after knocking out its endogenous kstd and ksh genes, one of these knockout mutants, HGMS2Δkstd211 + ΔkshB122, showed a 20% increase in the rate of phytosterol to 4-AD conversion, compared relative to the wild-type strain and an increase in 4-AD yield to 38.3 g/L in pilot-scale fermentation. Furthermore, we obtained the ADD- and 9OH-AD-producing strains, HGMS2kstd2 + Δkstd211+ΔkshB122 and HGMS2kshA51 + Δkstd211+ΔkshA226, by knocking in heterogenous active kstd and ksh genes to selected HGMS2 mutants, respectively. During pilot-scale fermentation, the conversion rates of the ADD- and 9OH-AD-producing mutants transforming phytosterol were 42.5 and 40.3%, respectively, and their yields reached 34.2 and 37.3 g/L, respectively. Overall, our study provides efficient strains for the production of 4-AD, ADD and 9OH-AD for the pharmaceutical industry and provides insights into the metabolic engineering of the HGMS2 strain to produce other important steroidal compounds.
DDX52 knockdown inhibits the growth of prostate cancer cells by regulating c-Myc signaling
Authors: Yu Wandong , Ma Hangbin , Li Junhong , Ge Jinchao , Wang Pengyu , Zhou Yinghao , Zhang Jun , Shi Guowei 
Published: August 2021

Abstract
Background
DDX52 is a type of DEAD/H box RNA helicase that was identified as a novel prostate cancer (PCa) genetic locus and possible causal gene in a European large-scale transcriptome-wide association study. However, the functions of DDX52 in PCa remain undetermined. The c-Myc oncogene plays a crucial role in the development of PCa, but the factors that regulate the activity of c-Myc in PCa are still unknown.

Methods
We determined DDX52 protein levels in PCa tissues using immunohistochemistry (IHC). DDX52 expression and survival outcomes in other PCa cohorts were examined using bioinformatics analysis. The inhibition of DDX52 via RNA interference with shRNA was used to clarify the effects of DDX52 on PCa cell growth in vitro and in vivo. Gene set enrichment analysis and RNA sequencing were used to explore the signaling regulated by DDX52 in PCa. Western blotting and IHC were used to determine the possible DDX52 signaling mechanism in PCa.

Results
DDX52 expression was upregulated in PCa tissues. Bioinformatics analysis showed that the level of DDX52 further increased in advanced PCa, with a high DDX52 level indicating a poor outcome. In vitro and in vivo experiments showed that downregulating DDX52 impeded the growth of PCa cells. High DDX52 levels contributed to activating c-Myc signaling in PCa patients and PCa cells. Furthermore, DDX52 expression was regulated by c-Myc and positively correlated with c-Myc expression in PCa.

Conclusion
DDX52 was overexpressed in PCa tissues in contrast to normal prostate tissues. DDX52 knockdown repressed the growth of PCa cells in vitro and in vivo. Deleting c-Myc inhibited DDX52 expression, which affected the activation of c-Myc signaling.
Identification of a robust signature for clinical outcomes and immunotherapy response in gastric cancer: based on N6-methyladenosine related long noncoding RNAs
Authors: Han Tenghui , Xu Dong , Zhu Jun , Li Jipeng , Liu Lei , Deng Yanchun 
Published: August 2021

Abstract
Background
Gastric cancer (GC) is a globally prevalent cancer, ranking fifth for incidence and fourth for mortality worldwide. The N6-methyladenosine (m6A) related long noncoding RNAs (lncRNAs) were widely investigated in recent studies. Nevertheless, the underlying prognostic implication and tumor immune mechanism of m6A-related lncRNA in GC remain unknown.

Methods
We systematically assessed the m6A modification expression of 407 GC clinical samples based on 23 m6A regulators and comprehensively associated these genes with lncRNAs. Then, we constructed a m6A-related lncRNA prognostic signature (m6A-LPS) to evaluate both status and prognosis of the disease. Immune-related mechanisms were explored via dissecting tumor-infiltrating cells as well as applying tumor immune dysfunction and the exclusion algorithm. Furthermore, we validated the latent regulative mechanism of m6A-related lncRNA in GC cell lines.

Results
The m6A-LPS containing nine hub lncRNAs was built, which possessed a superior capability to predict the outcomes of GC patients. Meanwhile, we found an intimate correlation between the m6A-LPS and tumor infiltrating cells, and that the low-risk group had a higher expression of immune checkpoints and responsed more to immunotherapy than the high-risk group. Clinically, these crucial lncRNAs expression levels were verified in ten pairs of GC samples. In in vitro experiments, the abilities of migration and proliferation were significantly enhanced via downregulating the lncRNA AC026691.1. Both migrative and proliferative capabilities of tumor cells were significantly enhanced via downregulating the lncRNA AC026691.1. in vitro.

Conclusions
Collectively, the m6A-LPS could provide a novel prediction insight into the prognosis of GC patients and serve as an independent clinical factor for GC. These m6A-related lncRNAs might remodel the tumor microenvironment and affect the anti-cancer ability of immune checkpoint blockers. Importantly, lncRNA AC026691.1 could inhibit both migration and proliferation of GC by means of FTO regulation.
Bisphenol-A exposure and risk of breast and prostate cancer in the Spanish European Prospective Investigation into Cancer and Nutrition study
Authors: Salamanca-Fernández Elena , Rodríguez-Barranco Miguel , Amiano Pilar , Delfrade Josu , Chirlaque Maria Dolores , Colorado Sandra , Guevara Marcela , Jimenez Ana , Arrebola Juan Pedro , Vela Fernando , Olea Nicolás , Agudo Antonio , Sánchez Maria-José 
Published: August 2021

AbstractBackgroundBisphenol A (BPA) is an endocrine disruptor that it is present in numerous products of daily use. The aim of this study was to assess the potential association of serum BPA concentrations and the risk of incident breast and prostate cancer in a sub-cohort of the Spanish European Prospective Investigation into Cancer and Nutrition (EPIC).MethodsWe designed a case-cohort study within the EPIC-Spain cohort. Study population consisted on 4812 participants from 4 EPIC-Spain centers (547 breast cancer cases, 575 prostate cancer cases and 3690 sub-cohort participants). BPA exposure was assessed by means of chemical analyses of serum samples collected at recruitment. Borgan II weighted Cox regression was used to estimate hazard ratios.ResultsMedian follow-up time in our study was 16.9 years. BPA geometric mean serum values of cases and sub-cohort were 1.12 ng/ml vs 1.10 ng/ml respectively for breast cancer and 1.33 ng/ml vs 1.29 ng/ml respectively for prostate cancer. When categorizing BPA into tertiles, a 40% increase in risk of prostate cancer for tertile 1 (p = 0.022), 37% increase for tertile 2 (p = 0.034) and 31% increase for tertile 3 (p = 0.072) was observed with respect to values bellow the limit of detection. No significant association was observed between BPA levels and breast cancer risk.ConclusionsWe found a similar percentage of detection of BPA among cases and sub-cohort from our population, and no association with breast cancer risk was observed. However, we found a higher risk of prostate cancer for the increase in serum BPA levels. Further investigation is needed to understand the influence of BPA in prostate cancer risk.
Park environment and moderate-to-vigorous physical activity in parks among adolescents in a high-density city: the moderating role of neighbourhood income
Authors: Zhang Ru , Zhang Chun-Qing , Lai Poh Chin , Cheng Wei , Schüz Benjamin , Kwan Mei-Po 
Published: August 2021

Abstract
Background
Urban parks are critical environmental resources in which adolescents engage in physical activity (PA). Evidence on the associations between park environmental characteristics and park-based PA in adolescents is mixed, particularly for high-density cities. Evidence is also lacking concerning the moderating role of neighbourhood socioeconomic status on the park-PA relationships. The current study aimed to examine the associations between park environmental characteristics and moderate-to-vigorous physical activity (MVPA) in parks among adolescents in Hong Kong and the moderating effect of neighbourhood income on these associations.

Methods
A cross-sectional study involving direct observations of adolescents was conducted in 32 randomly selected urban parks in Hong Kong. Park environmental characteristics were measured using the Community Park Audit Tool. Park-based MVPA among adolescents was measured using the System for Observation Play and Recreation in Communities. Neighbourhood income was extracted from the 2011 Hong Kong Population Census data on median household income.

Results
There was a significant positive association between the quality of amenities and park-based MVPA (metabolic equivalents per observation) in adolescents. However, the associations between the diversity of active facilities, greenness and adolescents’ park-based MVPA were not significant. Neighbourhood income moderated the association between adolescents’ park-based MVPA and park safety, where the relationship between park safety and park-based MVPA was significantly positive in low-income neighbourhoods but not significant in high-income neighbourhoods. An income-by-environment interaction was also observed concerning park aesthetics, with a negative relationship between park aesthetics and park-based MVPA in high-income neighbourhoods but not in low-income neighbourhoods.

Conclusion
Our findings provide evidence regarding how park environment and neighbourhood income impact adolescents’ park-based MVPA in Hong Kong. These findings can inform urban planning and policymakers who seek to improve urban park development in high-density cities.
Opioid overdose crises during the COVID-19 pandemic: implication of health disparities
Authors: Patel Ishika , Walter Lauren A. , Li Li 
Published: August 2021

Abstract
Background
Recent data suggest a disproportionate impact of opioid overdoses on Black Americans. The study aims to describe emergency department (ED) visits at a Southern, urban ED pertaining to opioid overdose and associated health disparities.

Methods
Patients presenting to the ED at the University of Alabama at Birmingham Hospital with opioid overdoses from January 1 to October 31, 2019, and from January 1 to October 31, 2020, were identified from electronic medical records.

Results
The total number of opioid overdose visits increased 9.7% (556 to 611) between January and October 2020 compared with 2019. Among patients who presented with opioid overdose, the mean ages were 50.3 years and 48.3 years, in 2019 and 2020, respectively. In both 2019 and 2020, more Blacks than whites were treated for opioid overdose in the ED (284 vs. 258 in 2019, and 306 vs. 271 in 2020) although 28 patients did not record their race in 2020. Consistently, more overdose deaths were observed in Blacks than in whites in 2020. More individuals seeking opioid overdose treatment were single in both years.

Conclusions
The study reported a greater number of visits for opioid overdoses from January to October of 2020 in an ED of a southeastern region, as well as higher overdose deaths in Blacks. Our findings highlight the importance of substance use treatment, harm reduction, and overdose prevention efforts that should be immediately present to reduce opioid overdose, especially for vulnerable populations in the South, i.e., Black community, and individuals experiencing singlehood.
Effects of LncRNA MEG3 on immunity and autophagy of non-small cell lung carcinoma through IDO signaling pathway
Authors: Wang Chuanqiang , Tao Xiangbo , Wei Jungong 
Published: August 2021

AbstractBackgroundThe study was done to investigate the effect of LncRNA MEG3 on the immunity and autophagy of non-small cell lung carcinoma through the IDO signaling pathway.MethodsA total of 78 cases of early NSCLC patients (research group; RG) and 69 cases of health controls (control group; CG) during the same time were included. The contents of LncRNA MEG3 and miR-543 in peripheral blood and tissues and their diagnostic values for NSCLC were detected. The relationship between LncRNA MEG3 and miR-543 and their posttreatment contents and influence on the prognosis of NSCLC patients were tested. The expression of LncRNA MEG3, miR-543, and IDO (IDO1, IDO2, and TDO proteins) in the lung tissue of rats and the immune function in the CG and the RG were detected. The effects of LncRNA MEG3 and miR-543 on the biological behavior of NSCLC cells were determined. The role of LncRNA MEG3, miR-543, and IDO in NSCLC was verified.ResultsLncRNA MEG3 was low in peripheral blood and tissues, while miR-543 was high (P < 0.05); both had good diagnostic values for NSCLC (P < 0.05). LncRNA MEG3 had a negative correlation with miR-543 (P < 0.05) and influenced the prognosis of NSCLC patients (P < 0.05). LncRNA MEG3 in the lung tissue of rats using IDO inhibitor was elevated compared with that of lung carcinoma model rats (P < 0.05). The level of miR-543 was declined compared with that of lung carcinoma model rats (P < 0.05). The levels of IDO1, IDO2, and TDO proteins were evidently declined compared with those of lung carcinoma model rats (P < 0.05). Compared with lung carcinoma model rats, CD3+, CD4+, and CD4+/CD8+of IDO inhibitor rats were elevated, while CD8+was declined (P < 0.05). Cell proliferation and invasion ability and IDO1, IDO2, TDO, Beclin-1, and LC3-II proteins were declined in the sh-LncRNA MEG3 group (P < 0.05), while those in the mimics-miR-543 group were evidently elevated (P < 0.05). However, the double luciferase activity detection and RIP experiment confirmed that there was targeted regulation among them (P < 0.05).ConclusionMEG3 has low expression in NSCLC and affects the immunity and autophagy of NSCLC cells via regulating the miR-543/IDO signaling pathway, which is effective for the treatment of NSCLC.
Deep learning-based predictive biomarker of pathological complete response to neoadjuvant chemotherapy from histological images in breast cancer
Authors: Li Fengling , Yang Yongquan , Wei Yani , He Ping , Chen Jie , Zheng Zhongxi , Bu Hong 
Published: August 2021

Abstract
Background
Pathological complete response (pCR) is considered a surrogate endpoint for favorable survival in breast cancer patients treated with neoadjuvant chemotherapy (NAC). Predictive biomarkers of treatment response are crucial for guiding treatment decisions. With the hypothesis that histological information on tumor biopsy images could predict NAC response in breast cancer, we proposed a novel deep learning (DL)-based biomarker that predicts pCR from images of hematoxylin and eosin (H&E)-stained tissue and evaluated its predictive performance.

Methods
In total, 540 breast cancer patients receiving standard NAC were enrolled. Based on H&E-stained images, DL methods were employed to automatically identify tumor epithelium and predict pCR by scoring the identified tumor epithelium to produce a histopathological biomarker, the pCR-score. The predictive performance of the pCR-score was assessed and compared with that of conventional biomarkers including stromal tumor-infiltrating lymphocytes (sTILs) and subtype.

Results
The pCR-score derived from H&E staining achieved an area under the curve (AUC) of 0.847 in predicting pCR directly, and achieved accuracy, F1 score, and AUC of 0.853, 0.503, and 0.822 processed by the logistic regression method, respectively, higher than either sTILs or subtype; a prediction model of pCR constructed by integrating sTILs, subtype and pCR-score yielded a mean AUC of 0.890, outperforming the baseline sTIL-subtype model by 0.051 (0.839, P  =  0.001).

Conclusion
The DL-based pCR-score from histological images is predictive of pCR better than sTILs and subtype, and holds the great potentials for a more accurate stratification of patients for NAC.
Microglia are involved in phagocytosis and extracellular digestion during Zika virus encephalitis in young adult immunodeficient mice
Authors: Enlow William , Bordeleau Maude , Piret Jocelyne , Ibáñez Fernando González , Uyar Olus , Venable Marie-Christine , Goyette Nathalie , Carbonneau Julie , Tremblay Marie-Eve , Boivin Guy 
Published: August 2021

AbstractBackgroundZika virus (ZIKV) has been associated with several neurological complications in adult patients.MethodsWe used a mouse model deficient in TRIF and IPS-1 adaptor proteins, which are involved in type I interferon production, to study the role of microglia during brain infection by ZIKV. Young adult mice were infected intravenously with the contemporary ZIKV strain PRVABC59 (1 × 105PFUs/100 µL).ResultsInfected mice did not present overt clinical signs of the disease nor body weight loss compared with noninfected animals. However, mice exhibited a viremia and a brain viral load that were maximal (1.3 × 105genome copies/mL and 9.8 × 107genome copies/g of brain) on days 3 and 7 post-infection (p.i.), respectively. Immunohistochemistry analysis showed that ZIKV antigens were distributed in several regions of the brain, especially the dorsal hippocampus. The number of Iba1+/TMEM119+microglia remained similar in infectedversusnoninfected mice, but their cell body and arborization areas significantly increased in thestratum radiatumandstratum lacunosum-molecularelayers of the dorsal hippocampuscornu ammoni(CA)1, indicating a reactive state. Ultrastructural analyses also revealed that microglia displayed increased phagocytic activities and extracellular digestion of degraded elements during infection. Mice pharmacologically depleted in microglia with PLX5622 presented a higher brain viral load compared to untreated group (2.8 × 1010versus8.5 × 108genome copies/g of brain on day 10 p.i.) as well as an increased number of ZIKV antigens labeled with immunogold in the cytoplasm and endoplasmic reticulum of neurons and astrocytes indicating an enhanced viral replication. Furthermore, endosomes of astrocytes contained nanogold particles together with digested materials, suggesting a compensatory phagocytic activity upon microglial depletion.ConclusionsThese results indicate that microglia are involved in the control of ZIKV replication and/or its elimination in the brain. After depletion of microglia, the removal of ZIKV-infected cells by phagocytosis could be partly compensated by astrocytes.