bluuebunny/crossref_metadata_2025_split huggingface dataset:
The FAM3C locus that encodes interleukin-like EMT inducer (ILEI) is frequently co-amplified in MET-amplified cancers and contributes to invasiveness
Authors: Schmidt Ulrike , Heller Gerwin , Timelthaler Gerald , Heffeter Petra , Somodi Zsolt , Schweifer Norbert , Sibilia Maria , Berger Walter , Csiszar Agnes 
Published: January 2021

Abstract
Background Gene amplification of MET, which encodes for the receptor tyrosine kinase c-MET, occurs in a variety of human cancers. High c-MET levels often correlate with poor cancer prognosis. Interleukin-like EMT inducer (ILEI) is also overexpressed in many cancers and is associated with metastasis and poor survival. The gene for ILEI, FAM3C, is located close to MET on chromosome 7q31 in an amplification “hotspot”, but it is unclear whether FAMC3 amplification contributes to elevated ILEI expression in cancer. In this study we have investigated FAMC3 copy number gain in different cancers and its potential connection to MET amplifications.Methods FAMC3 and MET copy numbers were investigated in various cancer samples and 200 cancer cell lines. Copy numbers of the two genes were correlated with mRNA levels, with relapse-free survival in lung cancer patient samples as well as with clinicopathological parameters in primary samples from 49 advanced stage colorectal cancer patients. ILEI knock-down and c-MET inhibition effects on proliferation and invasiveness of five cancer cell lines and growth of xenograft tumors in mice were then investigated. Results FAMC3 was amplified in strict association with MET amplification in several human cancers and cancer cell lines. Increased FAM3C and MET copy numbers were tightly linked and correlated with increased gene expression and poor survival in human lung cancer and with extramural invasion in colorectal carcinoma. Stable ILEI shRNA knock-down did not influence proliferation or sensitivity towards c-MET-inhibitor induced proliferation arrest in cancer cells, but impaired both c-MET-independent and -dependent cancer cell invasion. c-MET inhibition reduced ILEI secretion, and shRNA mediated ILEI knock-down prevented c-MET-signaling induced elevated expression and secretion of matrix metalloproteinase (MMP)-2 and MMP-9. Combination of ILEI knock-down and c-MET-inhibition significantly reduced the invasive outgrowth of NCI-H441 and NCI-H1993 lung tumor xenografts by inhibiting proliferation, MMP expression and E-cadherin membrane localization.Conclusions These novel findings suggest MET amplifications are often in reality MET-FAM3C co-amplifications with tight functional cooperation. Therefore, the clinical relevance of this frequent cancer amplification hotspot, so far dedicated purely to c-MET function, should be re-evaluated to include ILEI as a target in the therapy of c-MET-amplified human carcinomas.
Data-driven FDG-PET subtypes of Alzheimer’s disease-related neurodegeneration
Authors: Levin Fedor , Ferreira Daniel , Lange Catharina , Dyrba Martin , Westman Eric , Buchert Ralph , Teipel Stefan , Grothe Michel 
Published: January 2021

Abstract
Background

Previous research has described distinct subtypes of Alzheimer’s disease (AD) based on differences in regional patterns of brain atrophy on MRI. We conducted a data-driven exploration of distinct AD neurodegeneration subtypes using FDG-PET as a sensitive molecular imaging marker of neurodegenerative processes.

Methods

Hierarchical clustering of voxel-wise FDG-PET data from 177 amyloid-positive patients with AD dementia enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) was used to identify distinct hypometabolic subtypes of AD, which were then further characterized with respect to clinical and biomarker characteristics. We then classified FDG-PET scans of 217 amyloid-positive patients with mild cognitive impairment (‘prodromal AD’) according to the identified subtypes and studied their domain-specific cognitive trajectories and progression to dementia over a follow-up interval of up to 72 months.

Results

Three main hypometabolic subtypes were identified: (i) “typical” (48.6%), showing a classic posterior temporo-parietal hypometabolic pattern, (ii) “limbic-predominant” (44.6%), characterized by old age and a memory-predominant cognitive profile, and (iii) a relatively rare “cortical-predominant” subtype (6.8%) characterized by younger age and more severe executive dysfunction. Subtypes classified in the prodromal AD sample demonstrated similar subtype characteristics as in the AD dementia sample and further showed differential courses of cognitive decline.

Conclusions

These findings complement recent research efforts on MRI-based identification of distinct AD atrophy subtypes and may provide a potentially more sensitive molecular imaging tool for early detection and characterization of AD-related neurodegeneration variants at prodromal disease stages.
Human Drug Efflux Transporter ABCC5 Confers Acquired Resistance to Pemetrexed in Breast Cancer
Authors: Chen Jihui , Wang Zhipeng , Gao Shouhong , Wu Kejin , Bai Fang , Zhang Qiqiang , Wang Hongyu , Ye Qin , Xu Fengjing , Sun Hong , Lu Yunshu , Liu Yan 
Published: January 2021

Abstract
AimPemetrexed, a new generation antifolate drug, is approved for the treatment for locally advanced or metastatic breast cancer, but factors affecting the efficacy and resistance of it have yet to be fully explicit. ATP-binding cassette (ABC) transporters have been reported as prognostic and adverse effects predictors of many xenobiotics. This study was designed to explore whether ABC transporters affect pemetrexed resistance and may contribute to treatment regimen optimization for breast cancer.MethodsFirstly, the expression of ABC transporters family members was measured in cell lines, thereafter examined the potential role of ABC transporter in conferring resistance to pemetrexed in primary cancer cell lines isolated from 34 breast cancer patients, and then the role of ABCC5 in mediating transport of pemetrexed and apoptosis pathway in MCF-7 cell line was assessed. Finally, the functions of ABCC5 on therapeutic effect of pemetrexed was evaluated in breast cancer bearing mice.ResultsThe expressions of ABCC2, ABCC4, ABCC5 and ABCG2 were significantly increased in pan-resistance cell line, and the ABCC5, the most obvious one, was 5.21 times higher than that of the control group. The expression of ABCC5 was inversely correlated with sensitivity (IC50) of pemetrexed (r = 0.741; p<0.001) in breast cancer cells from 34 patients. Furthermore, we found that the expression of ABCC5 influenced the efflux and cytotoxicity of pemetrexed in MCF-7 cell line, and the IC50 were 0.06 μg/ml and 0.20 μg/ml in ABCC5 knock-down and over-expression cells, respectively. In in vivo study, we found ABCC5 affected the sensitivity of pemetrexed in breast cancer bearing mice, and the tumor volume was much larger in ABCC5 over-expression group than that in control group (2.7 folds vs 1.3 folds).ConclusionsOur results indicated ABCC5 expression was associated with pemetrexed resistance in vitro and in vivo, and may be a biomarker for regimen optimization of pemetrexed in breast cancer treatment.
The Investigational Clinical Center: a clinical-supportive and patient-centered trial unit model. Ten years of experience through normal and pandemic times of a large pediatric Trial Center in Italy.
Authors: Pontrelli Giuseppe , Ciabattini Marco , De Crescenzo Franco , Biondi Isabella , Cocchiola Rossana , Copponi Giorgia , Frillici Claudia , Molinari Francesca , Rocchi Francesca , Simonetti Alessandra , Rossi Paolo , Livadiotti Susanna 
Published: January 2021

Abstract
Evidence-based medicine relies on appropriately designed, conducted and reported clinical trials (CTs) to provide the best proofs of efficacy and safety for pharmacological and non-pharmacological treatments. Modern clinical research features high complexity and requires a high workload for the management of trials-related activities, often hampering physicians’ participation to clinical trials. Dealing with children in clinical research adds complexity: rare diseases, parents or legal guardian reluctance to engage and recruitment difficulties are major reasons of pediatric trials failure. However, because in pediatrics many treatments are prescribed off-label or are lacking, well-designed clinical trials are particularly needed. Clinical Trial Units (CTUs) are indeed an important asset in the implementation of clinical trials, but their support to investigators is limited to administrative and non-clinical tasks. In this paper we present the model of the Investigational Clinical Center (ICC) of the Bambino Gesù Children’s Hospital in Rome. The ICC includes clinicians supporting the Principal Investigators for clinical management of enrolled patients in compliance of Good Clinical Practice, the legal framework of Clinical Trials. Furthermore, we present ten years’ experience in pediatric clinical trials and how it has been affected in 2020 by the COVID-19 pandemic. The activity of the ICC has been evaluated according to specific metrics of performance. The ICC model offers a complete support, helping investigators, patients and their families to overcome majority of barriers linked to clinical research, even in time of pandemic. We propose this organization as an innovative model for total-supportive and patient-centered clinical trial implementation.
Impact of an acute Care Surgery Model on the Management of acute Appendicitis in South Korea: A Retrospective Cohort Study
Authors: Yi Gun-Hee , Lee Hak-Jae , Lee Seul , Yoon Jong-Hee , Hong Suk-Kyung 
Published: January 2021

Abstract
Background The acute care surgery (ACS) system is a new model for the prompt management of diseases that require rapid treatment in patients with acute abdomen. This study compared the outcomes and characteristics of the ACS system and traditional on-call system (TROS) for acute appendicitis in South Korea. Methods This single-center, retrospective study included all patients (aged ≥18 years) who underwent surgery for acute appendicitis in 2016 and 2018. The TROS and ACS system were used for the 2016 and 2018 groups, respectively. We retrospectively obtained data on each patient from the electrical medical records. The independent samples t-test and Mann-Whitney U-test were used for continuous and non-normally distributed data, respectively.Results In total, 126 patients were included. The time taken to get from the emergency room admission to the operating room, operation times, and postoperative complication rates were similar between both groups. However, the length of the hospital stay was shorter in the ACS group than in the TROS group (4.3±3.2 days vs. 7.2±9.6 days, p=0.039).Conclusions Since the introduction of the ACS system, the length of hospital stay for surgical patients has decreased. This may be due to the application of an integrated medical procedure, such as a new clinical pathway, rather than differences in the surgical techniques.Trial registration: Retrospectively registered.
A climate investment trap in developing economies
Authors: Ameli Nadia , Dessens Olivier , Winning Matthew , Cronin Jennifer , Chenet Hugues , Drummond Paul , Calzadilla Alvaro , Anandarajah Gabrial , Grubb Michael 
Published: January 2021

Abstract
Finance is vital for the green energy transition, but the access to low cost finance is uneven as the cost of capital differs substantially between regions. This study shows how modelled decarbonisation pathways of developing economies are disproportionately impacted by assumptions around their cost of capital (WACC). For example, representing regionally specific WACC values indicates 35% lower green electricity production in Africa for a cost-optimal 2°C pathway. Moreover, results show that early convergence of WACC values for green and brown technologies in 2050 would allow Africa to reach net-zero emissions approximately 10 years earlier than when convergence is not considered. A “climate investment trap” arises for developing economies when climate-related investments remain chronically insufficient. Elements of sustainable finance frameworks currently present barriers to these finance flows and radical changes are needed so that capital is better allocated to the regions that most need it.
Towards health equity for people experiencing chronic pain and social marginalization
Authors: Wallace Bruce , Varcoe Colleen , Holmes Cindy , Moosa-Mitha Mehmoona , Moor Gregg , Hudspith Maria , Craig Kenneth D 
Published: January 2021

Abstract
Objective: For people who experience social inequities and structural violence, pain and related care are inexorably linked to experiences of injustice and stigma. The purpose of this study was to examine in greater depth the experiences of pain and discrimination and stigma across diverse marginalized communities in order to recommend equity-oriented healthcare approaches. Methods: This community-based qualitative study reports on four focus groups that included 36 people living with pain. All participants identified with one of three groups known to experience high levels of inequities and structural violence including an Indigenous group, a LGBTQ2S group, and two newcomer and refugee groups. Results: Pain was entangled with and shaped by: social locations and identities, experiences of violence, trauma and related mental health issues, experiences of discrimination, stigma and dismissal, experiences of inadequate and ineffective health care, and the impacts of these intersecting experiences. Conclusions: Equity-oriented responses to chronic pain would recognize pain not only as a biomedical issue but as a social justice issue. The EQUIP Framework is an approach to integrating trauma- and violence-informed care; culturally-safe care; and harm reduction in health care that may hold promise for being tailored to people experiencing pain and social marginalization.
Treadmill running regulates adult neurogenesis, spatial and non-spatial learning by ErbB4 signaling
Authors: Yi Yandong , Song Yuanlong , Liu Bo , Lu Yisheng 
Published: January 2021

Abstract
Recent studies have shown exercise is effective for adult hippocampus neurogenesis and memory. However, the molecular mechanism of exercise is unclear. In this study, AG1478, an ErbB4 inhibitor, was used to explore the involvement of ErbB4 receptors. Four weeks post-running, cognitive impairment was analyzed using T-maze, Morris water maze (MWM) and contextual fear discrimination learning tests, followed by histological assessment of the proliferation and survival of hippocampal neurons using Ki67, NeuN and BrdU immunostaining respectively. Expression of total and phosphate ErbB4 protein level was evaluated by Western blotting. The results showed that AG1478 significantly impaired the performances in T-maze and MWM (spatial learning and memory), contextual fear conditioning and discrimination learning paradigm (non-spatial working and reference memory), enhanced neurogenesis loss, downregulated the expression of p-ErbB4 and total ErbB4 protein, which could be reversed by running. Taken together, our study suggested that running ameliorates cognitive impairment and neurogenesis via ErbB4 signaling.
Airway Pseudomonas aeruginosa Density in Mechanically Ventilated Patients: Clinical Impact and Relation to Therapeutic Efficacy of Antibiotics
Authors: Migiyama Yohei , Sakata Shinya , Iyama Shinji , Tokunaga Kentaro , Saruwatari Koichi , Tomita Yusuke , Saeki Sho , Okamoto Shinichiro , Ichiyasu Hidenori , Sakagami Takuro 
Published: January 2021

Abstract
Background: The bacterial density of Pseudomonas aeruginosa (PA) is closely related to its pathogenicity. We evaluated the effect of airway PA density on the clinical course of mechanically ventilated patients and the therapeutic efficacy of antibiotics.Methods: We retrospectively analyzed data of intensive care unit (ICU) mechanically ventilated patients with PA isolated from endotracheal aspirates. Patients were divided into three groups according to the peak PA density during ICU stay: low-PA (≤ 104 colony-forming units [cfu]/mL), moderate-PA (105‒106 cfu/mL), and high-PA (≥ 107 cfu/mL) groups. The relationship between PA density and weaning from mechanical ventilation, risk factors for high-PA isolation, and antibiotic efficacy were investigated using multivariate and propensity score-matched analyses.Results: A total of 461 patients were enrolled. Patients with high-PA had higher inflammation marker levels and developed more severe respiratory infections. High PA was independently associated with fewer ventilator-free days on day 28 (P < 0.01) and increased ICU mortality (P = 0.047). Risk factors for high PA were prolonged mechanical ventilation (odds ratio [OR] 3.07, 95% confidence interval [CI] 1.35‒6.97), non-antipseudomonal cephalosporins (OR 2.17, 95% CI 1.35‒3.49), hyperglycemia (OR 2.01, 95% CI 1.26‒3.22) during ICU stay, and respiratory diseases (OR 1.9, 95% CI 1.12‒3.23). Isolation of commensal colonizers was associated with lower risks of high PA (OR 0.43, 95% CI 0.26‒0.73). Propensity score-matched analyses revealed that antibiotic therapy for patients with ventilator-associated tracheobronchitis improved weaning from mechanical ventilation only in the high-PA group.Conclusions: High PA significantly affected the clinical course of mechanically ventilated patients and could be a good therapeutic indicator for ventilator-associated tracheobronchitis treatment.
ITPR3 facilitates tumor growth, metastasis and stemness by inducing the NF-ĸB/CD44 pathway in urinary bladder carcinoma
Authors: Zhang Mengzhao , Wang Lu , Yue Yangyang , Zhang Lu , Liu Tianjie , Jing Minxuan , Liang Xiao , Ma Minghai , Xu Shan , Wang Ke , Wang Xinyang , Fan Jinhai 
Published: January 2021

Abstract
Background: Bladder carcinoma is one of the most common urological cancers. ITPR3, as a ubiquitous endoplasmic reticulum calcium channel protein, was reported to be involved in the development and progression of various types of cancer. However, the potential roles and molecular mechanism of ITPR3 in bladder cancer are still unclear. Herein, we elucidated a novel role of ITPR3 in regulating the proliferation, metastasis, and stemness of bladder cancer cells.Methods: The expression of ITPR3 in bladder cancer was analyzed using public databases and bladder cancer tissue microarrays. To demonstrate the role of ITPR3 in regulating the NF-ĸB/CD44 pathway and the progression of bladder cancer, a series of molecular biology and biochemistry methods was performed on clinical tissues, along with in vivo and in vitro experiments. The methods used included western blot assay, quantitative RT-PCR assay, immunofluorescence assay, immunohistochemistry (IHC) assays, wound healing assay, Transwell assay, colony formation assay, tumorsphere formation assay, cell flow cytometry analysis, EdU assay, MTT assay, cell transfection, bisulfite sequencing PCR (BSP), a xenograft tumor model and a tail vein cancer metastasis model.Results: Higher ITPR3 expression was found in bladder cancer tissues and bladder cancer cells compared with the corresponding normal peritumor tissues and SV-HUC-1 cells, which was attributed to demethylation in the ITPR3 promoter region. ITPR3 promoted the proliferation of bladder cancer by accelerating cell cycle transformation and promoted local invasion and distant metastasis by inducing epithelial-to-mesenchymal transition (EMT). Meanwhile, ITPR3 maintained the cancer stemness phenotype by regulating CD44 expression. NF-κB, which is upstream of CD44, also played a critical role in this process.Conclusions: Our study clarifies that ITPR3 serves as an oncogene in bladder cancer cells and represents a novel candidate for bladder cancer diagnosis and treatment.
First Evidence for Nicotiana (Tobacco) and its Human Use in Pleistocene North America
Authors: Duke Daron , Wohlgemuth Eric , Adams Karen , Armstrong-Ingram Angela , Rice Sarah , Young D. 
Published: January 2021

Abstract
Current studies on cultigens emphasize the protracted and intimate human interactions with wild species that defined paths to domestication and, for certain plants, profoundly impacted humanity1,2. Tobacco (Nicotiana) is one such plant. Tobacco arguably has had more impact on global patterns in history than any other psychoactive substance, but how deep its cultural ties trace back is widely debated. Adding to the puzzle is whether the distribution of tobacco in North America occurred naturally or if humans themselves were responsible for its expansion across the continent3. Archaeological excavations at the Wishbone site, directed at the hearth-side activities of the early inhabitants of North America’s desert west, have uncovered evidence for tobacco approximately 12,300 years ago, 9,000 years earlier than previously documented4. Here we detail the preservation context of the site, discuss its cultural affiliation, and consider the ways that the tobacco may have been used. Researchers have long suspected that human use extends earlier in time than can been readily demonstrated by such fragile remains3–7, so the finding reinvigorates research on the driving cultural forces behind tobacco’s use, cultivation, and subsequent domestication. This has implications for our understanding of deep-time human use of plant intoxicants, the intersection of non-food plant domestication with that of food crops, and the trajectory of selective, potentially independent, interactions with tobacco from a broad cultural milieu in ancient North America to a place of worldwide cross-cultural significance.
Association Between Social Media and Psychological Effects Among Adolescents: A School Based Cross-Sectional Study in Kathmandu City of Nepal
Authors: Paudel Ashok , Chhetri Muni , Baidya Prinisha 
Published: January 2021

Abstract
Background: Social media are comprised of websites and software applications that enable users to create and share content or to participate in social networking. Inappropriate use of social media may lead to negative psychological effects. This study aimed to assess the psychological effects of social media among adolescent students of Grade 9 and 10 in Kathmandu city of Nepal. Methods: A Cross-sectional school-based study done among randomly sampled adolescent students (10-19 yrs) of Grade 9 and 10. Total 318 sample size derived using the formula: n=z²pq/e2. Social Media Addiction Scale Student Form and Short Mood and Feelings Questionnaire were the self-administered data collection tools. The purpose of the study was explained to respondents. Ethical approval was obtained through the Ethical Review Board of Nepal Health Research Council. Data were analyzed on Scientific Package for Social Science version-20. Results: About sixty-two percent of the adolescents had their cell phones and 88.1 percent had internet facilities in their houses. Forty-six percent of adolescents were addicted to social media and 68.2 percent were depressed. Out of depressed adolescents, 64.4 percent of them had social media addiction. The significant association observed between adolescents with their cell phone and social media addiction (p=0.037); social media addiction and depression (p= 0.000). Conclusions: Adolescents with their cell phone is associated with social media addiction and social media addiction is associated with depression, suggesting an urgent need to develop policies and programs to mitigate negative psychological effects of cell phones and social media addiction.