bluuebunny/crossref_metadata_2025_split huggingface dataset:
Self-synergistic effect of Prussian blue nanoparticles for cancer therapy: driving photothermal therapy and reducing hyperthermia-induced side effects
Authors: Xie Xue , Gao Wei , Hao Junnian , Wu Jianrong , Cai Xiaojun , Zheng Yuanyi 
Published: May 2021

Abstract
Background
Photothermal therapy (PTT), involving application of localized hyperthermia to kill cancer cells, has attracted wide attention in cancer therapy. The production of reactive oxygen species (ROS) during PTT may cause irreversible damage to healthy tissues around the tumor. Simultaneously, hyperthermia can stimulate inflammatory response, thus promoting tumor recurrence and metastasis. Therefore, it is of paramount importance to reduce the undesired side effects for further development of PTT.

Results
Using a hydrothermal method, spherical Prussian blue nanoparticles (PBs) with uniform size were prepared. The PBs exhibited good dispersion and stability in saline with an average hydrodynamic size of 110 nm. The prepared PBs had a high photothermal conversion efficiency and photothermal stability. The PBs showed intrinsic ROS scavenging properties in vitro. Antioxidant and anti-inflammatory effects of PBs were also observed in vivo. Assessment of toxicity and endoplasmic reticulum stress-inducing ability showed that PBs did not induce an inflammatory response. Tissues of major organs of mice stained with hematoxylin–eosin showed no significant damage, indicating good biocompatibility and safety of PBs.

Conclusion
The designed single-component PBs with intrinsic ROS scavenging and anti-inflammatory properties could avoid inflammatory response and heat stress-induced ROS during PTT. Thus, further research on PBs is worthwhile to achieve their clinical translation and promote the development of PTT.
Exploiting the anticancer effects of a nitrogen bisphosphonate nanomedicine for glioblastoma multiforme
Authors: Jena Lynn N , Bennie Lindsey A , McErlean Emma M , Pentlavalli Sreekanth , Glass Kim , Burrows James F , Kett Vicky L , Buckley Niamh E , Coulter Jonathan A , Dunne Nicholas J , McCarthy Helen O 
Published: May 2021

AbstractGlioblastoma multiforme (GBM) is an incurable aggressive brain cancer in which current treatment strategies have demonstrated limited survival benefit. In recent years, nitrogen-containing bisphosphonates (N-BPs) have demonstrated direct anticancer effects in a number of tumour types including GBM. In this study, a nano-formulation with the RALA peptide was used to complex the N-BP, alendronate (ALN) into nanoparticles (NPs) < 200 nm for optimal endocytic uptake. Fluorescently labelled AlexaFluor®647 Risedronate was used as a fluorescent analogue to visualise the intracellular delivery of N-BPs in both LN229 and T98G GBM cells. RALA NPs were effectively taken up by GBM where a dose-dependent response was evidenced with potentiation factors of 14.96 and 13.4 relative to ALN alone after 72 h in LN229 and T98G cells, respectively. Furthermore, RALA/ALN NPs at the IC50,significantly decreased colony formation, induced apoptosis and slowed spheroid growthin vitro.In addition, H-Ras membrane localisation was significantly reduced in the RALA/ALN groups compared to ALN or controls, indicative of prenylation inhibition. The RALA/ALN NPs were lyophilised to enhance stability without compromising the physiochemical properties necessary for functionality, highlighting the suitability of the NPs for scale-up andin vivoapplication. Collectively, these data show the significant potential of RALA/ALN NPs as novel therapeutics in the treatment of GBM.
Systemic factors for enhancing intersectoral collaboration for the operationalization of One Health: a case study in India
Authors: Yasobant Sandul , Bruchhausen Walter , Saxena Deepak , Falkenberg Timo 
Published: May 2021

Abstract
Background
One Health is a collaborative, multisectoral, and transdisciplinary approach—working at the local, regional, national, and global levels—with the goal of achieving optimal health outcomes recognizing the interconnection between people, animals, plants, and their shared environment. Operationalization of the One Health approach is still unclear for various local health systems with their respective targets. In this scenario, the empirical study of intersectoral collaboration between the human and animal health systems provides an opportunity to investigate the appropriate strategies and their enabling factors at the local health system level. Thus, this study documented and validated the innovative strategy for intersectoral collaboration, focusing on effectual prevention and control of zoonotic diseases with its enabling factors for a city in western India, Ahmedabad.

Methods
This case study was conducted in three phases: phase I (qualitative data collection, i.e., vignette interview), phase II (quantitative data collection through modified policy Delphi), and phase III (participatory workshop). The vignette data were handled for content analysis, and the Delphi data, like other quantitative data, for descriptive statistics. The participatory workshop adapts the computerized Sensitivity Model® developed by Vester to analyse the health system dynamics.

Result
Out of the possible 36 strategies, this study validated the top 15 essential (must-have) and five preferred (should-have) strategies for the study area. For operationalization of the One Health approach, the enabling factors that were identified through the systems approach are micro-level factors at the individual level (trust, leadership, motivation, knowledge), meso-level factors at the organizational level (human resource, capacity-building, shared vision, decision-making capacity, laboratory capacity, surveillance), macro-level factors at the system level (coordinated roles, relationships, common platform), and external factors outside of the system (guidelines/policies, community participation, a specific budget, political will, smart technology).

Discussion
This study reveals that the micro-level factors at the individual level are potential levers of the health system. More attention to these factors could be beneficial for the operationalization of the One Health approach. This study recommends a systems approach through a bottom-up exploration to understand the local health system and its enabling factors, which should be accounted for in formulating future One Health policies.
TV advertising and dietary intake in adolescents: a pre- and post- study of Chile’s Food Marketing Policy
Authors: Jensen Melissa L. , Dillman Carpentier Francesca R. , Adair Linda , Corvalán Camila , Popkin Barry M. , Taillie Lindsey Smith 
Published: May 2021

AbstractBackgroundThe first phase of a comprehensive marketing policy was implemented in Chile in 2016. The policy restricted child-directed marketing of foods and beverages considered high in energy, total sugars, sodium or saturated fat (“high-in”). The objective of this study was to examine the role of high-in TV food advertising as a mediator in the association between policy implementation and consumption of high-in foods and beverages between 2016 and 2017.MethodsDietary data were from 24-hour diet recalls collected in 2016 and 2017 in a cohort of 12–14 y children (n = 721). Television use was assessed concurrently and linked to analyses of food advertisements on broadcast and paid television to derive individual-level estimates of exposure to high-in food advertising. A multilevel mediation analysis examined direct and indirect effects of the policy through advertising exposure.ResultsFollowing the policy implementation, high-in advertising exposure was significantly reduced (p < 0.01). High-in food intake decreased in adolescents with lower levels, but not higher levels, of high-in advertising at baseline. We did not find evidence of mediation by changes in high-in ad exposure.ConclusionsAdolescents’ exposure to high-in TV advertising decreased after the 2016 implementation of the Chilean Food Labeling and Marketing Law. However, evidence that changes in advertisement mediated dietary changes was not found. Further research is needed to understand how marketing changes will relate to dietary changes after full implementation of the law and in the long term.
Deconditioning does not explain orthostatic intolerance in ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome)
Authors: van Campen C. (Linda) M. C. , Rowe Peter C. , Visser Frans C. 
Published: May 2021

Abstract
Background
Orthostatic intolerance (OI) is a frequent finding in individuals with myalgic encephalomyelitis /chronic fatigue syndrome (ME/CFS). Published studies have proposed that deconditioning is an important pathophysiological mechanism in various forms of OI, including postural orthostatic tachycardia syndrome (POTS), however conflicting opinions exist. Deconditioning can be classified objectively using the predicted peak oxygen consumption (VO2) values from cardiopulmonary exercise testing (CPET). Therefore, if deconditioning is an important contributor to OI symptomatology, one would expect a relation between the degree of reduction in peak VO2during CPET and the degree of reduction in CBF during head-up tilt testing (HUT).

Methods and results
In 22 healthy controls and 199 ME/CFS patients were included. Deconditioning was classified by the CPET response as follows: %peak VO2 ≥ 85% = no deconditioning, %peak VO2 65–85% = mild deconditioning, and %peak VO2 < 65% = severe deconditioning. HC had higher oxygen consumption at the ventilatory threshold and at peak exercise as compared to ME/CFS patients (p ranging between 0.001 and < 0.0001). Although ME/CFS patients had significantly greater CBF reduction than HC (p < 0.0001), there were no differences in CBF reduction among ME/CFS patients with no, mild, or severe deconditioning. We classified the hemodynamic response to HUT into three categories: those with a normal heart rate and blood pressure response, postural orthostatic tachycardia syndrome, or orthostatic hypotension. No difference in the degree of CBF reduction was shown in those three groups.

Conclusion
This study shows that in ME/CFS patients orthostatic intolerance is not caused by deconditioning as defined on cardiopulmonary exercise testing. An abnormal high decline in cerebral blood flow during orthostatic stress was present in all ME/CFS patients regardless of their %peak VO2 results on cardiopulmonary exercise testing.
Optimizing the timing of diagnostic testing after positive findings in lung cancer screening: a proof of concept radiomics study
Authors: Wang Zixing , Li Ning , Zheng Fuling , Sui Xin , Han Wei , Xue Fang , Xu Xiaoli , Yang Cuihong , Hu Yaoda , Wang Lei , Song Wei , Jiang Jingmei 
Published: May 2021

AbstractBackgroundThe timeliness of diagnostic testing after positive screening remains suboptimal because of limited evidence and methodology, leading to delayed diagnosis of lung cancer and over-examination. We propose a radiomics approach to assist with planning of the diagnostic testing interval in lung cancer screening.MethodsFrom an institute-based lung cancer screening cohort, we retrospectively selected 92 patients with pulmonary nodules with diameters ≥ 3 mm at baseline (61 confirmed as lung cancer by histopathology; 31 confirmed cancer-free). Four groups of region-of-interest-based radiomic features (n = 310) were extracted for quantitative characterization of the nodules, and eight features were proven to be predictive of cancer diagnosis, noise-robust, phenotype-related, and non-redundant. A radiomics biomarker was then built with the random survival forest method. The patients with nodules were divided into low-, middle- and high-risk subgroups by two biomarker cutoffs that optimized time-dependent sensitivity and specificity for decisions about diagnostic workup within 3 months and about repeat screening after 12 months, respectively. A radiomics-based follow-up schedule was then proposed. Its performance was visually assessed with a time-to-diagnosis plot and benchmarked against lung RADS and four other guideline protocols.ResultsThe radiomics biomarker had a high time-dependent area under the curve value (95% CI) for predicting lung cancer diagnosis within 12 months; training: 0.928 (0.844, 0.972), test: 0.888 (0.766, 0.975); the performance was robust in extensive cross-validations. The time-to-diagnosis distributions differed significantly between the three patient subgroups,p < 0.001: 96.2% of high-risk patients (n = 26) were diagnosed within 10 months after baseline screen, whereas 95.8% of low-risk patients (n = 24) remained cancer-free by the end of the study. Compared with the five existing protocols, the proposed follow-up schedule performed best at securing timely lung cancer diagnosis (delayed diagnosis rate: < 5%) and at sparing patients with cancer-free nodules from unnecessary repeat screenings and examinations (false recommendation rate: 0%).ConclusionsTimely management of screening-detected pulmonary nodules can be substantially improved with a radiomics approach. This proof-of-concept study’s results should be further validated in large programs.
Metformin ameliorates scleroderma via inhibiting Th17 cells and reducing mTOR-STAT3 signaling in skin fibroblasts
Authors: Moon Jeonghyeon , Lee Seon-yeong , Choi Jeong Won , Lee A Ram , Yoo Jin Hee , Moon Su-Jin , Park Sung-Hwan , Cho Mi-La 
Published: May 2021

AbstractScleroderma is an autoimmune disease that causes dermal fibrosis. It occurs when collagen accumulates in tissue as a result of persistent inflammation. Th17 cells and pro-inflammatory cytokines such as IL-1β, IL-6, IL-17, and TNF-α play important roles in the pathogenesis of scleroderma. Because metformin, a medication used to treat diabetes, has effective immunoregulatory functions, we investigated its therapeutic function in scleroderma. Mice in a model of bleomycin-induced scleroderma were treated with metformin for 2 weeks. Histological assessment demonstrated protective effects of metformin against scleroderma. Metformin decreased the expression of pro-inflammatory factors in dermal tissue and lymphocytes. It also decreased mRNA expression of pro-inflammatory cytokines (IL-1β, IL-6, IL-17, and TNF-α) and fibrosis-inducing molecules both in vivo and in vitro. These results suggest that metformin treatment has anti-inflammatory effects on lymphocytes via the inhibition of IL-17 and cytokines related to Th17 differentiation, such as IL-1β, IL-6, and TNF-α. To investigate how metformin modulates the inflammatory process in skin fibroblasts, we measured mTOR-STAT3 signaling in skin fibroblasts and found that phosphorylated mTOR and phosphorylated STAT3 protein expression were decreased by metformin treatment. These results suggest that metformin has potential to treat scleroderma by inhibiting pro-inflammatory cytokines and anti-inflammatory activity mediated by mTOR-STAT3 signaling.
Severe COVID-19 in pediatric age: an update on the role of the anti-rheumatic agents
Authors: Costagliola Giorgio , Spada Erika , Consolini Rita 
Published: May 2021

AbstractBackgroundSARS-CoV-2 can induce an immune impairment and dysregulation, finally resulting in the massive release of inflammatory mediators (cytokine storm), strongly contributing to the pulmonary and systemic manifestations in severe coronavirus disease 2019 (COVID-19). As a consequence, different drugs active on the immune system have been proposed for the treatment of the disease in adults.Role of the anti-rheumatic agents in childrenChildren are more likely to develop a mild disease course, as the severe form of COVID-19 is identified in less than 5% of the pediatric patients. Moreover, in children a peculiar disease phenotype, defined as multisystem inflammatory syndrome in children (MIS-C) is observed, representing the most severe expression of the inflammatory dysregulation caused by SARS-CoV-2. The limited experience with the severe pediatric COVID-19 and MIS-C does not allow conclusions about the role of the immune pharmacological approach, and therefore the treatment of these conditions represents a considerable clinical challenge. The use of chloroquine, hydroxychloroquine, and colchicine in the early disease stages is not sufficiently supported by evidence, and there is an increasing interest in the role of biologic agents, including anti-IL-1 and anti-IL-6 agents, in the prevention and treatment of the severe manifestations of COVID-19.ConclusionThe therapeutic approach to pediatric COVID-19 is multidisciplinary, and anti-rheumatic agents have a prominent role in severe disease. This paper reviews the rationale for the use of anti-rheumatic agents in pediatric COVID-19 and MIS-C and the clinical experience with the single drugs. Finally, the areas of potential improvement in the use of anti-rheumatic agents, including the optimization of the drug choice and the timing of administration, are discussed.
The immune cell landscape of metastatic uveal melanoma correlates with overall survival
Authors: Tosi Anna , Cappellesso Rocco , Dei Tos Angelo Paolo , Rossi Valentina , Aliberti Camillo , Pigozzo Jacopo , Fabozzi Alessio , Sbaraglia Marta , Blandamura Stella , Del Bianco Paola , Chiarion-Sileni Vanna , Rosato Antonio 
Published: May 2021

Abstract
Background
Uveal melanoma (UM) represents the most common primary intra-ocular malignancy in adults. Up to 50% of the patients develop distant metastases within 10 years from diagnosis, with the liver as the most common site. Upon metastatization, life expectancy strongly reduces and immune checkpoint inhibitors that prove effective in cutaneous melanoma do not modify clinical outcome. To date, few studies have focused on deciphering the immunomodulatory features of metastatic UM microenvironment, and there are no prognostic models for clinical use. This highlights the urgent need to understand the delicate interplay between tumor and immune cells acting at the site of metastasis.

Methods
We collected a patient cohort comprising 21 metastatic UM patients. Hepatic and extra-hepatic UM metastasis samples were studied by multiplex immunofluorescence to assess the tumor immune cell composition. Quantitative analyses were performed to correlate immune cell densities with treatment response, metastasis site and patient survival.

Results
Compared to patients with progressive disease, those with controlled disease had a higher intra-tumoral/peritumoral ratio of CD8 + Granzyme B+ cells, higher density of intra-tumoral CD8+ cytotoxic T lymphocytes (CTL) and an increased percentage of UM cells in close proximity to T lymphocytes, reflecting a role of tumor-killing T cells in the disease. In liver metastases (LM), the intra-tumoral densities of CD163+ tumor-associated macrophages (TAM) and of total CD8+ T cells were higher than in extra-hepatic UM metastases, but the percentage of Granzyme B+ CTL was lower. Moreover, LM displayed more UM cells adjacent to both CTL and TAM, and also more T cells in proximity to TAM, all signs of an impaired immune response. The percentage of activated CTL within the tumor represented a prognostic indicator, as patients with a higher intra-tumoral percentage of CD8 + Granzyme B+ cells had the better outcome. A temptative Immunoscore was generated and proved capable to stratify patients with improved survival. Finally, CD4 + FoxP3+ T cells appeared a crucial population for response to immunotherapy.

Conclusion
The results of this study underly the clinical relevance and functional importance of composition and localization of antitumor effector cells for the progression of UM metastasis.
Ovarian endometrioid carcinoma and clear cell carcinoma: A 21-year retrospective study
Authors: Zhou Ling , Yao Liqing , Dai Lin , Zhu Honglan , Ye Xue , Wang Shang , Cheng Hongyan , Ma Ruiqiong , Liu Huiping , Cui Heng , Chang Xiaohong 
Published: May 2021

Abstract
Objective
This study aimed to identify the clinical characteristics of Chinese patients with ovarian endometrioid carcinoma (EC) and clear cell carcinoma (CCC) and to assess the impact of concurrent endometriosis on this group.

Methods
The present study reviewed the medical records of patients who received initial treatment and a postoperative pathological diagnosis of EC or CCC at our center in China between 1998 and 2018.

Results
Of 211 patients, 73 had pure EC, and 91 had pure CCC, and the remaining 47 had mixed cancer. The proportion of EC and CCC remained stable over past 21 years. The proportion of EC declined with aging and the age of EC onset to incline to the young. And the age of CCC onset had two peaks, namely, 36 and 77 years. After review by the pathologist, the number of endometriosis cases found in the pathological section of the analysis increased to 114, accounting for 54% of patients. As the stage progressed, the appearance of endometriosis became increasingly scarce in pathological sections(p = 0.001).
Compared with CCC, EC had a higher frequency of concurrent endometrial cancer (independent endometrial lesions) and estrogen and progesterone receptor expression(p = 0.000). And more patients were in premenopausal state in EC group(p = 0.040).
In the pure group, multivariate analysis showed that correlation existed between relevance to endometriosis and worse outcomes(p = 0.041). In patients with mixed cancer, mixed endometrioid histology was associated with better survival than other subtypes, even with stage III or poorly differentiated tumors(p = 0.001).

Conclusions
CCC and EC which are common in ovarian cancer patients who have associated with endometriosis have distinct clinicopathological characteristics. Attention should be paid to ovarian cancer patients with a history of endometriosis and those with concurrent endometriosis in pathological sections.
Short‐term rapamycin administration elevated testosterone levels and exacerbated reproductive disorder in dehydroepiandrosterone‐induced polycystic ovary syndrome mice
Authors: Guo Zaixin , Chen Xiaohan , Feng Penghui , Yu Qi 
Published: May 2021

Abstract
Background
Polycystic ovary syndrome (PCOS) is a multifactorial endocrinopathy that affects reproduction and metabolism. Mammalian target of rapamycin (mTOR) has been shown to participate in female reproduction under physiological and pathological conditions. This study aimed to investigate the role of mTOR complex 1 (mTORC1) signaling in dehydroepiandrosterone (DHEA)-induced PCOS mice.

Results
Female C57BL/6J mice were randomly assigned into three groups: control group, DHEA group, and DHEA + rapamycin group. All DHEA-treated mice were administered 6 mg/100 g DHEA for 21 consecutive days, and the DHEA + rapamycin group was intraperitoneally injected with 4 mg/kg rapamycin every other day for the last 14 days of the DHEA treatment. There was no obvious change in the expression of mTORC1 signaling in the ovaries of the control and DHEA groups. Rapamycin did not protect against DHEA-induced acyclicity and PCO morphology, but impeded follicle development and elevated serum testosterone levels in DHEA-induced mice, which was related with suppressed Hsd3b1, Cyp17a1, and Cyp19a1 expression. Moreover, rapamycin also exacerbated insulin resistance but relieved lipid metabolic disturbance in the short term.

Conclusions
Rapamycin exacerbated reproductive imbalance in DHEA-induced PCOS mice, which characterized by elevated testosterone levels and suppressed steroid synthesis. This underscores the need for new mTORC1-specific and tissue-specific mTOR-related drugs for reproductive disorders.