bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dose–response evaluation of urinary cadmium and kidney injury biomarkers in Chinese residents and dietary limit standards
Authors: Qing Ying , Yang Jiaqi , Zhu Yuanshen , Li Yongzhen , Zheng Weiwei , Wu Min , He Gengsheng 
Published: June 2021

Abstract
Background
Cadmium (Cd) is a common heavy metal that mainly causes renal damage. There is a lack of research on the large-scale and systematic evaluation of the association between urinary Cd (U-Cd) and various effect biomarkers among Chinese residents.

Methods
Based on the establishment process of dietary Cd limit standards by European Food Safety Authority (EFSA), the dose–response relationships between U-Cd and four biomarkers, β2-microglobulin (β2-MG), N-acetyl-β-glucosidase (NAG), microalbumin (mALB), and retinol binding Protein (RBP) were explored, respectively. Toxicokinetic model was used to derive the dietary Cd exposure limit for Chinese residents after critical U-Cd concentration was calculated.

Results
As the sensitive biomarkers of renal injury, β2-MG and NAG were selected to estimate the 95% confidence interval lower limit of the U-Cd benchmark dose (BMDL5) to be 3.07 and 2.98 μg/g Cr, respectively. Dietary Cd exposure limit was calculated to be 0.28 μg/kg bw/day (16.8 μg/day, based on the body weight of 60 kg), which was lower than the average Chinese Cd exposure (30.6 μg/day) by the China National Nutrient and Health Survey.

Conclusion
This study established an overall association between U-Cd and renal injury biomarkers, and explored the Chinese dietary Cd exposure limits, which helps improve Chinese Cd exposure risk assessment and provides a reference basis for formulating reasonable exposure standards.
Mesenchymal stem cell-derived extracellular vesicles prevent the development of osteoarthritis via the circHIPK3/miR-124-3p/MYH9 axis
Authors: Li Shenglong , Liu Jie , Liu Siyu , Jiao Weijie , Wang Xiaohong 
Published: June 2021

Abstract
Background
Extracellular vesicles (EVs) secreted by mesenchymal stem cells (MSCs) may play a vital role in a variety of biological processes, including cartilage regeneration. However, few studies reported their potential in the development of osteoarthritis (OA) previously. In this study, we explored the biological roles and underlying mechanism of MSCs-EVs in OA.

Results
Co-culture experiments revealed that MSCs-EVs could promote the expression of collagen type II alpha 1 chain (COL2A1), SRY-box transcription factor 9 (SOX9) and Aggrecan while negatively regulate the expression of chondrocyte hypertrophy markers matrix metallopeptidase 13 (MMP-13) and RUNX family transcription factor 2 (Runx2) in mouse chondrocytes in the OA model. Besides, the results of cell experiments indicated that MSCs-EVs could notably weaken the suppression of chondrocyte proliferation, migration and the promotion of chondrocyte apoptosis via interleukin1β (IL-1β) induction. In addition, MSCs-circHIPK3-EVs (EVs derived from MSCs overexpressing circHIPK3) considerably improved IL-1β-induced chondrocyte injury. Mechanistically, we elucidated that circHIPK3 could directly bind to miR-124-3p and subsequently elevate the expression of the target gene MYH9.

Conclusion
The findings in our study demonstrated that EVs-circHIPK3 participated in MSCs-EVs-mediated chondrocyte proliferation and migration induction and in chondrocyte apoptosis inhibition via the miR-124-3p/MYH9 axis. This offers a promising novel cell-free therapy for treating OA.

Graphic abstract
Broadening the biocompatibility of gold nanorods from rat to Macaca fascicularis: advancing clinical potential
Authors: Liao Jinfeng , Tian Taorang , Shi Sirong , Xie Xueping , Peng Shuanglin , Zhu Ying , Xiao Jingang , Lin Yunfeng 
Published: June 2021

Abstract
Background
The biomedical field has used gold nanorods (GNRs) for decades; however, clinical trials and translation is limited except gold nanoshells. The preparation of gold nanoshells is more complex than that of polyethylene glycol-modified GNRs (PEG-GNRs), and it is difficult to ensure uniform thickness. It is important to encourage and broaden the use of the star member (PEG-GNRs) of gold nanoparticles family for clinical translation. Existing studies on PEG-GNRs are limited with no relevant systematic progression in non-human primates. Herein, we assessed the systematic biocompatibility of PEG-GNRs in rats and clinically relevant Macaca fascicularis.

Results
In this small animal study, we administrated multiple doses of PEG-GNRs to rats and observed good biocompatibility. In the non-human primate study, PEG-GNRs had a longer blood half-life and produced a negligible immune response. Histological analysis revealed no significant abnormality.

Conclusions
PEG-GNRs were well-tolerated with good biocompatibility in both small animals and large non-human primates. The information gained from the comprehensive systemic toxicity assessment of PEG-GNRs in M. fascicularis will be helpful for translation to clinical trials.

Graphical abstract
Factors that influence enrollment in syringe services programs in rural areas: a qualitative study among program clients in Appalachian Kentucky
Authors: Ibragimov Umedjon , Cooper Katherine E. , Batty Evan , Ballard April M. , Fadanelli Monica , Gross Skylar B. , Klein Emma M. , Lockard Scott , Young April M. , Cooper Hannah L. F. 
Published: June 2021

Abstract
Background
Enrolling sufficient number of people who inject drugs (PWID) into syringe services programs (SSP) is important to curtail outbreaks of drug-related harms. Still, little is known about barriers and facilitators to SSP enrollment in rural areas with no history of such programs. This study’s purpose was to develop a grounded theory of the role of the risk environment and individual characteristics of PWID in shaping SSP enrollment in rural Kentucky.

Methods
We conducted one-on-one semi-structured interviews with 41 clients of 5 SSPs that were established in rural counties in Appalachian Kentucky in 2017–2018. Interviews covered PWID needs, the process of becoming aware of SSPs, and barriers and facilitators to SSP enrollment. Applying constructivist grounded theory methods and guided by the Intersectional Risk Environment Framework (IREF), we applied open, axial and selective coding to develop the grounded theory.

Results
Stigma, a feature of IREF’s meso-level social domain, is the main factor hampering SSP enrollment. PWID hesitated to visit SSPs because of internalized stigma and because of anticipated stigma from police, friends, family and healthcare providers. Fear of stigma was often mitigated or amplified by a constellation of meso-level environmental factors related to healthcare (e.g., SSPs) and social (PWID networks) domains and by PWID’s individual characteristics. SSPs mitigated stigma as a barrier to enrollment by providing low threshold services in a friendly atmosphere, and by offering their clients program IDs to protect them from paraphernalia charges. SSP clients spread positive information about the program within PWID networks and helped their hesitant peers to enroll by accompanying them to SSPs. Individual characteristics, including child custody, employment or high social status, made certain PWID more susceptible to drug-related stigma and hence more likely to delay SSP enrollment.

Conclusions
Features of the social and healthcare environments operating at the meso-level, as well as PWID’s individual characteristics, appear to enhance or mitigate the effect of stigma as a barrier to SSP enrollment. SSPs opening in locations with high stigma against PWID need to ensure low threshold and friendly services, protect their clients from police and mobilize PWID networks to promote enrollment.
Therapy of chronic hepatitis C in people who inject drugs: focus on adherence
Authors: Frankova Sona , Jandova Zuzana , Jinochova Gabriela , Kreidlova Miluse , Merta Dusan , Sperl Jan 
Published: June 2021

Abstract
Background
Intravenous drug use (IVDU) represents the major factor of HCV transmission, but the treatment uptake among people who inject drugs (PWID) remains low owing to a false presumption of low efficacy. The aim of our study was to assess treatment efficacy in PWID and factors determining adherence to therapy.

Methods
A total of 278 consecutive patients starting DAA (direct-acting antivirals) therapy were included, divided into two groups: individuals with a history of IVDU, PWID group (N = 101) and the control group (N = 177) without a history of IVDU.

Results
Sustained virological response 12 weeks after the end of therapy (SVR12) was achieved by 99/101 (98%) and 172/177 (98%) patients in the PWID and control group, respectively; in PWID group, two patients were lost to follow-up, and in the control group, four patients relapsed and one was lost to follow-up. PWID patients postponed appointments significantly more often, 29 (28.7%) in PWID versus 7 (4%) in the control group, p = 0.001. Thirteen of 101 (12.9%) and six of 177 (3.4%) patients in the PWID and in the control group, respectively, missed at least one visit (p < 0.01). However, postponing visits led to a lack of medication in only one PWID. In the PWID group, older age (p < 0.05; OR 1.07, 95% CI 1.00–1.20) and stable housing (p < 0.01; OR 9.70, 95% CI 2.10–56.20) were factors positively contributing to adherence. Contrarily, a stable job was a factor negatively influencing adherence (p < 0.05; OR 0.24, 95% CI 0.06–0.81). In the control group, none of the analyzed social and demographic factors had an impact on adherence to therapy.

Conclusions
In PWID, treatment efficacy was excellent and was comparable with SVR of the control group. Stable housing and older age contributed to a better adherence to therapy.
STAT3/HIF-1α signaling activation mediates peritoneal fibrosis induced by high glucose
Authors: Yang Xiaoxiao , Bao Manchen , Fang Yi , Yu Xiaofang , Ji Jun , Ding Xiaoqiang 
Published: June 2021

Abstract
Background
Epithelial-mesenchymal transition (EMT) of mesothelial cells is a key step in the peritoneal fibrosis (PF). Recent evidence indicates that signal transducer and activator of transcription 3 (STAT3) might mediate the process of renal fibrosis, which could induce the expression of hypoxia-inducible factor-1α (HIF-1α). Here, we investigated the effect of STAT3 activation on HIF-1α expression and the EMT of mesothelial cells, furthermore the role of pharmacological blockade of STAT3 in the process of PF during peritoneal dialysis (PD) treatment.

Methods
Firstly, we investigated the STAT3 signaling in human peritoneal mesothelial cells (HPMCs) from drained PD effluent. Secondly, we explored the effect of STAT3 signaling activation on the EMT and the expression of HIF-1α in human mesothelial cells (Met-5A) induced by high glucose. Finally, peritoneal fibrosis was induced by daily intraperitoneal injection with peritoneal dialysis fluid (PDF) so as to explore the role of pharmacological blockade of STAT3 in this process.

Results
Compared with the new PD patient, the level of phosphorylated STAT3 was up-regulated in peritoneal mesothelial cells from long-term PD patients. High glucose (60 mmol/L) induced over-expression of Collagen I, Fibronectin, α-SMA and reduced the expression of E-cadherin in Met-5A cells, which could be abrogated by STAT3 inhibitor S3I-201 pretreatment as well as by siRNA for STAT3. Furthermore, high glucose-mediated STAT3 activation in mesothelial cells induced the expression of HIF-1α and the profibrotic effect of STAT3 signaling was alleviated by siRNA for HIF-1α. Daily intraperitoneal injection of high-glucose based dialysis fluid (HG-PDF) induced peritoneal fibrosis in the mice, accompanied by the phosphorylation of STAT3. Immunostaining showed that phosphorylated STAT3 was expressed mostly in α-SMA positive cells in the peritoneal membrane induced by HG-PDF. Administration of S3I-201 prevented the progression of peritoneal fibrosis, angiogenesis, macrophage infiltration as well as the expression of HIF-1α in the peritoneal membrane induced by high glucose.

Conclusions
Taken together, these findings identified a novel mechanism linking STAT3/HIF-1α signaling to peritoneal fibrosis during long-term PD treatment. It provided the first evidence that pharmacological inhibition of STAT3 signaling attenuated high glucose-mediated mesothelial cells EMT as well as peritoneal fibrosis.
Molecular subtype identification and prognosis stratification by a metabolism-related gene expression signature in colorectal cancer
Authors: Lin Dagui , Fan Wenhua , Zhang Rongxin , Zhao Enen , Li Pansong , Zhou Wenhao , Peng Jianhong , Li Liren 
Published: June 2021

Abstract
Background
Metabolic reprograming have been associated with cancer occurrence and progression within the tumor immune microenvironment. However, the prognostic potential of metabolism-related genes in colorectal cancer (CRC) has not been comprehensively studied. Here, we investigated metabolic transcript-related CRC subtypes and relevant immune landscapes, and developed a metabolic risk score (MRS) for survival prediction.

Methods
Metabolism-related genes were collected from the Molecular Signatures Database and metabolic subtypes were identified using an unsupervised clustering algorithm based on the expression profiles of survival-related metabolic genes in GSE39582. The ssGSEA and ESTIMATE methods were applied to estimate the immune infiltration among subtypes. The MRS model was developed using LASSO Cox regression in the GSE39582 dataset and independently validated in the TCGA CRC and GSE17537 datasets.

Results
We identified two metabolism-related subtypes (cluster-A and cluster-B) of CRC based on the expression profiles of 539 survival-related metabolic genes with distinct immune profiles and notably different prognoses. The cluster-B subtype had a shorter OS and RFS than the cluster-A subtype. Eighteen metabolism-related genes that were mostly involved in lipid metabolism pathways were used to build the MRS in GSE39582. Patients with higher MRS had worse prognosis than those with lower MRS (HR 3.45, P < 0.001). The prognostic role of MRS was validated in the TCGA CRC (HR 2.12, P = 0.00017) and GSE17537 datasets (HR 2.67, P = 0.039). Time-dependent receiver operating characteristic curve and stratified analyses revealed the robust predictive ability of the MRS in each dataset. Multivariate Cox regression analysis indicted that the MRS could predict OS independent of TNM stage and age.

Conclusions
Our study provides novel insight into metabolic heterogeneity and its relationship with immune landscape in CRC. The MRS was identified as a robust prognostic marker and may facilitate individualized therapy for CRC patients.
SRPK1/AKT axis promotes oxaliplatin-induced anti-apoptosis via NF-κB activation in colon cancer
Authors: Huang Jing-Qiang , Li He-Feng , Zhu Jing , Song Jun-Wei , Zhang Xian-Bin , Gong Peng , Liu Qiu-Yu , Zhou Chun-Hui , Wang Liang , Gong Li-Yun 
Published: June 2021

Abstract
Background
Colorectal cancer is the third most common diagnosis. Oxaliplatin is used as first-line treatment of colon cancer. However, oxaliplatin resistance greatly reduces its therapeutic effect. SRPK1 involves in pre-mRNA splicing and tumorigenesis. How SRPK1 mediates drug resistance in colon cancer is unknown.

Methods
The expression of SRPK1 was analyzed in the TCGA and the CPTAC pan-cancer samples and detected in colon cancer cell lines and tissues by IHC and western blot. The MTT and TUNEL assay were used to verify the anti-apoptosis ability of colon cancer cell. The activation of NF-κB was determined by luciferase assay and qRT-PCR. AKT, IKK, IκB and their phosphorylation level were verified by western blot.

Results
We found that SRPK1 expression was the second highest in TCGA and the CPTAC pan-cancer samples. The mRNA and protein levels of SRPK1 were increased in tissues from patients with colon cancer. SRPK1 was associated with clinical stage and TNM classifications in 148 cases of colon cancer patients. High SRPK1 levels correlated with poor prognosis (p < 0.001). SRPK1 overexpression enhanced the anti-apoptosis ability of colon cancer cells, whereas SRPK1 silencing had the opposite effect under oxaliplatin treatment. Mechanistically, SRPK1 enhances IKK kinase and IκB phosphorylation to promote NF-κB nuclear translocation to confer oxaliplatin resistance.

Conclusions
Our findings suggest that SRPK1 participates in colon cancer progression and enhances the anti-apoptosis capacity to induce drug resistance in colon cancer cells via NF-κB pathway activation, and thus might be a potential pharmaceutically target for colon cancer treatment.
Association between serum advanced oxidation protein products and mortality risk in maintenance hemodialysis patients
Authors: Zhou Chun , Zhang Yuanyuan , Chen Jianghua , Mei Changlin , Xiong Fei , Shi Wei , Zhou Wei , Liu Xusheng , Sun Shiren , Tian Jianwei , Ye Ziliang , Wu Qimeng , Qin Xianhui , Jiang Jianping , Hou Fan Fan ,   CCSD (China Collaborative Study on Dialysis) group
Published: June 2021

AbstractBackgroundThe association between serum advanced oxidation protein products (AOPP) and mortality risk remains equivocal. We aimed to assess the correlation of serum AOPP levels with the risk of all-cause mortality in hemodialysis (HD) patients.MethodsA total of 1394 maintenance HD patients with complete data on AOPP and related parameters were included from China Collaborative Study on Dialysis (CCSD), a multi-center, prospective cohort study. The primary outcome was all-cause mortality, the secondary outcome was cardiovascular disease (CVD) mortality.ResultsDuring a median follow-up duration of 5.2 years (IQR, 2.1–5.4), all-cause mortality occurred in 492 (31.4%) participants. Overall, there was a reversed L-shaped association between serum AOPP and all-cause mortality in HD patients (Pfor nonlinearity = 0.04), with an inflection point at 87 µmol/L. Accordingly, there was no significant association between serum AOPP and all-cause mortality (per SD increment; HR, 0.94; 95%CI, 0.84, 1.05) in participants with AOPP < 87 µmol/L. However, there was a positive relationship of serum AOPP and all-cause mortality (per SD increment; HR, 1.24; 95%CI, 1.08, 1.42) in those with AOPP ≥ 87 µmol/L. Moreover, a similar trend was found for CVD mortality.ConclusionsElevated serum AOPP levels were associated with higher risk of all-cause mortality in Chinese maintenance HD patients.
A case of dermatomyositis in a patient with central core disease: unusual association with autoimmunity and genetic muscle disease
Authors: Kim Min Jung , Kim Mi Hyeon , Park Sung-Hye , Song Yeong Wook 
Published: June 2021

Abstract
Background
Dermatomyositis is an inflammatory muscle disease caused by immune-mediated muscle injury, and central core disease (CCD) is a congenital myopathy associated with disturbed intracellular calcium homeostasis and excitation-contraction coupling. To date, CCD has not been reported to have autoantibodies or coexist with inflammatory myopathy.

Case presentation
Here, we described the case of a 25-year-old woman who had progressive proximal muscle weakness, myalgia, pruritic macular rash, skin ulcers, and calcinosis. Dermatomyositis was initially suspected based on the clinical symptoms accompanied by elevated muscle enzyme levels, electromyography abnormalities, and a positive antinuclear antibody test. However, the patient’s muscle biopsy revealed the characteristic findings of both dermatomyositis and CCD, suggesting that dermatomyositis occurred in this patient with previously asymptomatic CCD. The patient did not have any pathogenic gene mutations associated with congenital myopathy, including RYR1 and SEPN1 in targeted next-generation sequencing. She received high-dose glucocorticoid therapy and azathioprine with a significant improvement in muscle strength.

Conclusions
We present a case of rare coexistence of dermatomyositis and CCD. Clinicians should be aware that patients with CCD may have inflammatory myopathy that responds well to immunosuppressive therapy.
Spatial heterogeneity in discontinuation of modern spacing method in districts of India
Authors: Nayak Soumya Ranjan , Mohanty Sanjay K. , Mahapatra Bidhubhusan , Sahoo Umakanta 
Published: June 2021

AbstractBackgroundDespite six decades of official family planning programme, the use of modern contraceptive method remained low in India. The discontinuation of modern spacing method (DMSM) has also increased from 42.3% in 2005−06 to 43.6% during 2015–16. Discontinuation rate is higher for Injectable (51%), followed by condom (47%), pill (42%) and lowest in IUD (26%).MethodsData from NFHS-4 (2015–16) comprising of 601,509 households, 699,686 women and a sample of 119,548 episode of modern spacing method was used for the analysis. Multiple decrement life table has used to estimate 12-month discontinuation rate of modern spacing methods (DMSM). Moran’s I statistics, Bivariate LISA cluster map has used to understand the spatial correlates and clustering the DMSM. OLS model and impact analysis has used to assess the significant associated covariates with discontinuation.ResultThe 12-month DMSM in India is 43.5%; largely due to desire for becoming pregnant and method failure. The high discontinuation rate was observed in most of the southern (62%) and central (46%) regions of India. DMSM has significantly and spatially associated with neighbouring districts of India (Moran’s I = 0.47, p-value = 0.00). The prevalence of modern spacing method is negatively associated with discontinuation in the neighbouring districts of India. The unmet need (β = 0.84, 95% CI 0.55–1.14), desire of children (β = 0.26, 95% CI − 0.05–0.57) and female sterilization (β = 0.54, 95% CI 0.14–0.95) were three main contributing factor to DMSM.ConclusionDistricts of high DMSM need programmatic intervention. More attention for counselling to client, health worker outreach to user and better quality care services will stimulate non-user of contraception.