bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chinese never smokers with adenocarcinoma of the lung are younger and have fewer lymph node metastases than smokers
Authors: Shan Longyu , Zhang Liang , Zhu Xiaolei , Wang Zhilin , Fang Shaohan , Lin Junfeng , Wang Jianweng , Li Ning , Liu Hongming , Zhang Xiaowen , Feng Yihui , Liu Jingwei , Pan Jianyun , Ye Guanzhi , Yu Xiuyi , Tufman Amanda , Katalinic Alexander , Goldmann Torsten , Petersen Frank , Jiang Jie , Geng Guojun , Yu Xinhua 
Published: October 2022

Abstract
Background
Lung cancers arising in never smokers have been suggested to be substantially different from lung cancers in smokers at an epidemiological, genetic and molecular level. Focusing on non-small cell lung cancer (NSCLC), we characterized lung cancer patients in China looking for demographic and clinical differences between the smoking and never-smoking subgroups.

Methods
In total, 891 patients with NSCLC, including 841 with adenocarcinoma and 50 with squamous cell carcinoma, were recruited in this study. Association of smoking status with demographic and clinical features of NSCLC was determined, and risk factors for lymph node metastasis and TNM stage were evaluated using Multivariate logistic regression analysis.

Results
In patients with adenocarcinoma, never smokers showed a younger age at diagnosis (54.2 ± 12.7vs. 59.3 ± 9.4, padjusted<0.001), a lower risk for lymph node metastasis than smokers (7,6% vs. 19.5%, padjusted<0.001) and less severe disease as indicated by lower percentages of patients with TNM stage of III or IV (5.5% vs. 14.7%, padjusted<0.001 ). By contrast, these associations were not observed in 50 patients with squamous cell carcinoma. Multivariate logistic regression analysis showed that smoking status was a risk factor for lymph node metastasis (OR = 2.70, 95% CI: 1.39–5.31, p = 0.004) but not for TNM stage (OR = 1.18, 95% CI: 0.09–14.43, p = 0.896) in adenocarcinoma.

Conclusion
This study demonstrates that lung adenocarcinoma in never smokers significantly differ from those in smokers regarding both age at diagnosis and risk of lymph node metastasis, supporting the notion that they are distinct entries with different etiology and pathogenesis.
End-of-life care for idiopathic pulmonary fibrosis patients with acute exacerbation
Authors: Akiyama Norimichi , Fujisawa Tomoyuki , Morita Tatsuya , Koyauchi Takafumi , Matsuda Yoshinobu , Mori Masanori , Miyashita Mitsunori , Tachikawa Ryo , Tomii Keisuke , Tomioka Hiromi , Hagimoto Satoshi , Kondoh Yasuhiro , Inoue Yoshikazu , Suda Takafumi 
Published: October 2022

Abstract
Background
Acute exacerbation (AE) is a major cause of death in patients with idiopathic pulmonary fibrosis (IPF). AE-IPF patients require optimal palliative care; however, the real-world clinical situations are poorly understood. We aimed to survey the palliative care received by AE-IPF patients, especially with respect to opioid use for dyspnea and the end-of-life discussions (EOLd).

Methods
Self-administered questionnaires were dispatched to 3423 of the certified pulmonary physicians in Japan. They were asked to report a care report form of one patient each with AE-IPF who died very recently about opioid use for dyspnea and EOLd. We further explored the factors associated with the early use of opioids for dyspnea.

Results
Among the 3423 physicians, 1226 (35.8%) returned the questionnaire with the report forms of 539 AE-IPF patients. Of 539 AE-IPF patients, 361 (67.0%) received opioids for dyspnea. Of the 361 patients, 72 (20.0%) received opioids during the initial treatment with an intention of recovery (early use), while 289 (80.0%) did when the recovery was deemed impossible. EOLd was held before the onset of AE in 124 patients (23.0%); however, the majority of patients had EOLd after the admission for AE-IPF. EOLd before the onset of AE was significantly associated with the early use of opioids.

Conclusion
In terminally ill AE-IPF patients, opioids are usually administered when the recovery is deemed impossible, and EOLd are rarely held before the onset of AE. Further studies are warranted on the efficacy of opioids for dyspnea and the appropriate timing of EOLd.
Prognostic value of coronary microvascular dysfunction assessed by coronary angiography-derived index of microcirculatory resistance in diabetic patients with chronic coronary syndrome
Authors: Zhang Wen , Singh Shekhar , Liu Lu , Mohammed Abdul-Quddus , Yin Guoqing , Xu Siling , Lv Xian , Shi Tingting , Feng Cailin , Jiang Rong , Mohammed Ayman A. , Mareai Redhwan M. , Xu Yawei , Yu Xuejing , Abdu Fuad A. , Che Wenliang 
Published: October 2022

Abstract
Background
Coronary microvascular dysfunction (CMD) is common and is associated with unfavorable cardiovascular events in patients with diabetes mellitus (DM). Coronary angiography-derived index of microcirculatory resistance (caIMR) is a recently developed wire- and hyperemic agent-free method to assess CMD. We aimed to investigate the prognostic impact of CMD assessed by caIMR on clinical outcomes in patients with DM and chronic coronary syndrome (CCS).

Methods
CCS patients who underwent coronary angiography between June 2015 to May 2018 were included. Coronary microvascular function was measured by caIMR, and CMD was defined as caIMR ≥ 25U. The primary endpoint was major adverse cardiac events (MACE). Kaplan-Meier analysis and Cox proportional hazards models were used to assess the relationship between caIMR and the risk of MACE.

Results
Of 290 CCS patients, 102 patients had DM. Compared with non-diabetic patients, CMD (caIMR ≥ 25U) was higher among DM patients (57.8% vs. 38.3%; p = 0.001). During a mean 35 months follow-up, 40 MACE had occurred. Patients with caIMR ≥ 25 had a higher rate of MACE than patients with caIMR < 25 (20.6% vs. 8.2%, p = 0.002). Of these, the MACE rate was higher among DM patients with caIMR ≥ 25 than those with caIMR < 25 (33.9% vs. 14.0%; p = 0.022). In multivariable Cox analysis, caIMR ≥ 25 was independently associated with MACE in the DM patients but not in non-DM patients (HR, 2.760; 95% CI, 1.066–7.146; P = 0.036).

Conclusion
CMD assessed by caIMR was common and is an independent predictor of MACE among diabetic patients with CCS. This finding potentially enables a triage of higher-risk patients to more intensive therapy.
Long-term cardiovascular outcomes of gestational diabetes mellitus: a prospective UK Biobank study
Authors: Lee Seung Mi , Shivakumar Manu , Park Ji Won , Jung Young Mi , Choe Eun Kyung , Kwak Soo Heon , Oh Sohee , Park Joong Shin , Jun Jong Kwan , Kim Dokyoon , Yun Jae-Seung 
Published: October 2022

Abstract
Background
Previous studies showed that gestational diabetes mellitus (GDM) can be a risk factor for subsequent atherosclerotic cardiovascular disease. However, there is a paucity of information regarding diverse cardiovascular outcomes in elderly women after GDM. In the current study, we examined whether women with a history of GDM have an increased risk for long-term overall cardiovascular outcomes.

Methods
Among the UK participants, we included 219,330 women aged 40 to 69 years who reported at least one live birth. The new incidence of diverse cardiovascular outcomes was compared according to GDM history by multivariable Cox proportional hazard models. In addition, causal mediation analysis was performed to examine the contribution of well-known risk factors to observed risk.

Results
After enrollment, 13,094 women (6.0%) developed new overall cardiovascular outcomes. Women with GDM history had an increased risk for overall cardiovascular outcomes [adjusted HR (aHR) 1.36 (95% CI 1.18–1.55)], including coronary artery disease [aHR 1.31 (1.08–1.59)], myocardial infarction [aHR 1.65 (1.27–2.15)], ischemic stroke [aHR 1.68 (1.18–2.39)], peripheral artery disease [aHR 1.69 (1.14–2.51)], heart failure [aHR 1.41 (1.06–1.87)], mitral regurgitation [aHR 2.25 (1.51–3.34)], and atrial fibrillation/flutter [aHR 1.47 (1.18–1.84)], after adjustment for age, race, BMI, smoking, early menopause, hysterectomy, prevalent disease, and medication. In mediation analysis, overt diabetes explained 23%, hypertension explained 11%, and dyslipidemia explained 10% of the association between GDM and overall cardiovascular outcome.

Conclusions
GDM was associated with more diverse cardiovascular outcomes than previously considered, and conventional risk factors such as diabetes, hypertension, and dyslipidemia partially contributed to this relationship.
LncRNA XIST from the bone marrow mesenchymal stem cell derived exosome promotes osteosarcoma growth and metastasis through miR-655/ACLY signal
Authors: Zhu Guanghui , Xia Yu , Zhao Ziyue , Li Aoyu , Li Hui , Xiao Tao 
Published: October 2022

Abstract
Background
Long non-coding RNA X-inactive specific transcript (XIST) regulates the progression of a variety of tumors, including osteosarcoma. Bone marrow mesenchymal stem cells (BMSCs) can be recruited into osteosarcoma tissue and affect the progression by secreting exosomes. However, whether BMSCs derived exosomes transmit XIST to regulate the growth and metastasis of osteosarcoma and the related mechanism are still unclear.

Method
In this study, BMSCs derived exosomes were used to treat human osteosarcoma cells MG63 and 143B, and the level of XIST in BMSCs was intervened by siRNA. CCK-8, EdU, transwell assays were used to analyze the changes of cell proliferation, migration and invasion. Bioinformatics analysis, RNA pulldown and dual-luciferase reporter gene assays validated the targeted relationship of XIST with miR-655 and the interaction between miR-655 and ACLY 3’-UTR. 143B/LUC cell line was used to establish an animal model of in situ osteosarcoma to verify the found effects of XIST on osteosarcoma. Oil Red O staining, Western blot and so on were used to detect the changes of lipid deposition and protein expression.

Results
It was found that BMSCs derived exosomes promoted the proliferation, migration and invasion of osteosarcoma cells, and the down-regulation of XIST inhibited this effect. miR-655 mediated the role of BMSCs derived exosomal XIST in promoting the progression of osteosarcoma and down-regulation of miR-655 could reverse the effects of inhibiting XIST on the proliferation, migration and invasion of osteosarcoma cells. Meanwhile, animal level results confirmed that BMSCs derived exosomal XIST could promote osteosarcoma growth and lung metastasis by combining with miR-655. In-depth mechanism study showed that BMSCs derived exosomal XIST combined with miR-655 to increase the protein level of ACLY, which led to lipid deposition and activate β-catenin signal to promote the proliferation, migration and invasion of osteosarcoma cells.

Conclusion
This study showed that BMSCs derived exosomal XIST could enter osteosarcoma cells, bind and down-regulates the level of miR-655, resulting in an increase in the level of ACLY, thus increasing the lipid deposition and the activity of β-catenin signal to promote the growth and metastasis of osteosarcoma.
Human amniotic epithelial cells exert anti-cancer effects through secretion of immunomodulatory small extracellular vesicles (sEV)
Authors: Bolouri Mohammad-Reza , Ghods Roya , Zarnani Kayhan , Vafaei Sedigheh , Falak Reza , Zarnani Amir-Hassan 
Published: October 2022

AbstractWe identified here mechanism by which hAECs exert their anti-cancer effects. We showed that vaccination with live hAEC conferred effective protection against murine colon cancer and melanoma but not against breast cancer in an orthotopic cancer cell inoculation model. hAEC induced strong cross-reactive antibody response to CT26 cells, but not against B16F10 and 4T1 cells. Neither heterotopic injection of tumor cells in AEC-vaccinated mice nor vaccination with hAEC lysate conferred protection against melanoma or colon cancer. Nano-sized AEC-derived small-extracellular vesicles (sEV) (AD-sEV) induced apoptosis in CT26 cells and inhibited their proliferation. Co-administration of AD-sEV with tumor cells substantially inhibited tumor development and increased CTL responses in vaccinated mice. AD-sEV triggered the Warburg’s effect leading to Arginine consumption and cancer cell apoptosis. Our results clearly showed that it is AD-sEV but not the cross-reactive immune responses against tumor cells that mediate inhibitory effects of hAEC on cancer development. Our results highlight the potential anti-cancer effects of extracellular vesicles derived from hAEC.
Mechanistic insights into the health benefits of fish-oil supplementation against fine particulate matter air pollution: a randomized controlled trial
Authors: Zhou Lu , Jiang Yixuan , Lin Zhijing , Chen Renjie , Niu Yue , Kan Haidong 
Published: October 2022

Abstract
Background:
Dietary fish-oil supplementation might attenuate the associations between fine particulate matter (PM2.5) and subclinical biomarkers. However, the molecular mechanisms remain to be elucidated. This study aimed to explore the molecular mechanisms of fish-oil supplementation against the PM2.5-induced health effects.

Methods:
We conducted a randomized, double-blinded, and placebo-controlled trial among healthy college students in Shanghai, China, from September 2017 to January 2018. A total of 70 participants from the Fenglin campus of Fudan University were included. We randomly assigned participants to either supplementation of 2.5-gram fish oil (n = 35) or sunflower-seed oil (placebo) (n = 35) per day and conducted four rounds of health measurements in the last two months of the trial. As a post hoc exploratory study, the present untargeted metabolomics analysis used remaining blood samples collected in the previous trial and applied a Metabolome-Wide Association Study framework to compare the effects of PM2.5 on the metabolic profile between the sunflower-seed oil and fish oil groups.

Results:
A total of 65 participants completed the trial (34 of the fish oil group and 31 of the sunflower-seed oil group). On average, ambient PM2.5 concentration on the day of health measurements was 34.9 µg/m3 in the sunflower-seed oil group and 34.5 µg/m3 in the fish oil group, respectively. A total of 3833 metabolites were significantly associated with PM2.5 in the sunflower-seed oil group and 1757 in the fish oil group. Of these, 1752 metabolites showed significant between-group differences. The identified differential metabolites included arachidonic acid derivatives, omega-3 fatty acids, omega-6 fatty acids, and omega-9 fatty acids that were related to unsaturated fatty acid metabolism, which plays a role in the inflammatory responses.

Conclusion:
This trial suggests fish-oil supplementation could mitigate the PM2.5-induced inflammatory responses via modulating fatty acid metabolism, providing biological plausibility for the health benefits of fish-oil supplementation against PM2.5 exposure.

Trial registration:
This study is registered at ClinicalTrails.gov (NCT03255187).
Pitfalls in methods to study colocalization of nanoparticles in mouse macrophage lysosomes
Authors: Moreno-Echeverri Aura Maria , Susnik Eva , Vanhecke Dimitri , Taladriz-Blanco Patricia , Balog Sandor , Petri-Fink Alke , Rothen-Rutishauser Barbara 
Published: October 2022

Abstract
Background
In the field of nanoscience there is an increasing interest to follow dynamics of nanoparticles (NP) in cells with an emphasis on endo-lysosomal pathways and long-term NP fate. During our research on this topic, we encountered several pitfalls, which can bias the experimental outcome. We address some of these pitfalls and suggest possible solutions. The accuracy of fluorescence microscopy methods has an important role in obtaining insights into NP interactions with lysosomes at the single cell level including quantification of NP uptake in a specific cell type.

Methods
Here we use J774A.1 cells as a model for professional phagocytes. We expose them to fluorescently-labelled amorphous silica NP with different sizes and quantify the colocalization of fluorescently-labelled NP with lysosomes over time. We focus on confocal laser scanning microscopy (CLSM) to obtain 3D spatial information and follow live cell imaging to study NP colocalization with lysosomes.

Results
We evaluate different experimental parameters that can bias the colocalization coefficients (i.e., Pearson’s and Manders’), such as the interference of phenol red in the cell culture medium with the fluorescence intensity and image post-processing (effect of spatial resolution, optical slice thickness, pixel saturation and bit depth). Additionally, we determine the correlation coefficients for NP entering the lysosomes under four different experimental set-ups. First, we found out that not only Pearson’s, but also Manders’ correlation coefficient should be considered in lysosome-NP colocalization studies; second, there is a difference in NP colocalization when using NP of different sizes and fluorescence dyes and last, the correlation coefficients might change depending on live-cell and fixed-cell imaging set-up.

Conclusions
The results summarize detailed steps and recommendations for the experimental design, staining, sample preparation and imaging to improve the reproducibility of colocalization studies between the NP and lysosomes.

Graphical Abstract
Nanoparticle-mediated selective Sfrp-1 silencing enhances bone density in osteoporotic mice
Authors: García-García Patricia , Reyes Ricardo , García-Sánchez Daniel , Pérez-Campo Flor María , Rodríguez-Rey José Carlos , Évora Carmen , Díaz-Rodríguez Patricia , Delgado Araceli 
Published: October 2022

AbstractOsteoporosis (OP) is characterized by a loss in bone mass and mineral density. The stimulation of the canonical Wnt/β-catenin pathway has been reported to promote bone formation, this pathway is controlled by several regulators as secreted frizzled-related protein-1 (Sfrp-1), antagonist of the pathway. Thus, Sfrp-1 silencing therapies could be suitable for enhancing bone growth. However, the systemic stimulation of Wnt/β-catenin has been correlated with side effects. This work hypothesizes the administration of lipid-polymer NPs (LPNPs) functionalized with a MSC specific aptamer (Apt) and carrying a SFRP1 silencing GapmeR, could favor bone formation in OP with minimal undesired effects. Suitable SFRP1 GapmeR-loaded Apt-LPNPs (Apt-LPNPs-SFRP1) were administered in osteoporotic mice and their biodistribution, toxicity and bone induction capacity were evaluated. The aptamer functionalization of the NPs modified their biodistribution profile showing a four-fold increase in the bone accumulation and a ten-fold decrease in the hepatic accumulation compared to naked LPNPs. Moreover, the histological evaluation revealed evident changes in bone structure observing a more compact trabecular bone and a cortical bone thickness increase in the Apt-LPNPs-SFRP1 treated mice with no toxic effects. Therefore, these LPNPs showed suitable properties and biodistribution profiles leading to an enhancement on the bone density of osteoporotic mice.
Circulating Anti-Müllerian hormone in a cohort-study of women with severe obesity with and without polycystic ovary syndrome and the effect of a one-year weight loss intervention
Authors: Kataoka Josefin , Larsson Ingrid , Lindgren Eva , Kindstrand Li Oskarson , Schmidt Johanna , Stener-Victorin Elisabet 
Published: October 2022

Abstract
Background
Women with polycystic ovary syndrome (PCOS) have high circulating anti-Müllerian hormone (AMH) levels which is correlated with antral follicle count and polycystic ovarian morphology and negatively correlated with body mass index (BMI). Moreover, diet-induced weight loss in women with PCOS and overweight or obesity, reduce or normalize AMH-levels. There is, however, no previous study investigating the circulating AMH levels in women with severe obesity and how a structured diet-induced weight loss program affects circulating AMH levels in these women. Therefore, this study aims to investigate circulating AMH levels in a population of women with severe obesity (BMI ≥ 35 kg/m2) with and without PCOS, as diagnosed by the NIH-criteria, and to investigate the effect of a one-year weight loss program with a very low-energy diet (VLED) on circulating levels of AMH.

Methods
In a prospective cohort-study, were 246 women with severe obesity were screened for PCOS diagnosis with the NIH-criteria, circulating AMH and anthropometry were measured at baseline and after a 12-month weight loss intervention with very low-energy diet (VLED).

Results
Mean BMI was 39.9 ± 4.7 (PCOS), 39.6 ± 4.3 (non-PCOS) P = 0.960. Circulating AMH was higher in women with PCOS (5.47 ± 4.89 µg/L) compared with non-PCOS (2.66 ± 3.71 µg/L) P < 0.001 and was positively correlated with circulating total testosterone in both groups. Next, we performed ROC-analyses, and show that circulating AMH could not discriminate women with PCOS and severe obesity from non-PCOS women with severe obesity. Finally, a one-year weight reduction program does not affect circulating AMH levels despite significant weight loss neither in women with PCOS, nor without PCOS and severe obesity.

Conclusion
Women with severe obesity and PCOS have elevated levels of circulating AMH compared to women without the syndrome. AMH-levels could not discriminate women with PCOS from non-PCOS because of low sensitivity and specificity. Significant weight loss was not associated with changes in circulating AMH levels, neither in women with, nor without PCOS and severe obesity. These results imply that in women with severe obesity, a greater weight loss may be needed to improve reproductive features, independent of PCOS diagnosis.

Trial registration number:
Clinical trial.gov: NCT01319162.
Silencing eL31 suppresses the progression of colorectal cancer via targeting DEPDC1
Authors: Sharen Gaowa , Li Xiongfeng , Sun Jiaxin , Zhang Lei , Xi Wen , Zhao Xiaodong , Han Fei , Jia Longlong , A Rong , Cheng Haidong , Hou Mingxing 
Published: October 2022

Abstract
Background
Colorectal cancer (CRC) is one of the most commonly diagnosed human malignancies. Ribosomal protein L31 (RPL31, aka eL31) is a component of the 60S large ribosomal subunit, and its expression pattern and functional role in CRC have not been reported.

Methods
Herein, we identified that eL31 protein level was dramatically increased in CRC tissues through using IHC analysis. More notably, elevated eL31 was associated with larger tumor size and shorter overall survival. Besides, we evaluated the effects of eL31 depletion on CRC cell phenotypes in vitro.

Results
The data indicated that eL31 knockdown restricted CRC cell proliferation, migration and colony formation whilst enhancing cell apoptosis. Importantly, eL31 was also essential for CRC tumor growth in vivo, as demonstrated by impaired tumor growth markers and reduced Ki67 levels in xenografts from eL31-depleted cells. In addition, our evidence indicated that DEP domain containing 1 (DEPDC1) was a potential downstream target of eL31 in regulating CRC. Consistently, DEPDC1 depletion restrained CRC cell proliferation and migration, as well as facilitated cell apoptosis. More interestingly, DEPDC1 depletion could reverse the promotion effects of eL31 elevation on CRC cells.

Conclusions
Identification of eL31’s function in CRC may pave the way for future development of more specific and more effective targeted therapy strategies against CRC.