bluuebunny/crossref_metadata_2025_split huggingface dataset:
How well do doctors understand a scientific article in English when it is not their first language? A randomised controlled trial
Authors: Rostadmo Martine , Strømme Siri Lunde , Nylenna Magne , Gulbrandsen Pal , Hem Erlend , Skovlund Eva , Brean Are , Orstavik Ragnhild 
Published: June 2021

IntroductionEnglish is thelingua francaof science. How well doctors understand English is therefore crucial for their understanding of scientific articles. However, only 5% of the world’s population have English as their first language.MethodsObjectives: To compare doctors’ comprehension of a scientific article when read in their first language (Norwegian) versus their second language (English). Our hypothesis was that doctors reading the article in Norwegian would comprehend the content better than those reading it in English.Design: Parallel group randomised controlled trial. We randomised doctors to read the same clinical review article in either Norwegian or English, before completing a questionnaire about the content of the article.Setting: Conference in primary care medicine in Norway, 2018.Participants: 130 native Norwegian-speaking doctors, 71 women and 59 men. One participant withdrew before responding to the questionnaire and was excluded from the analyses.Interventions: Participants were randomly assigned to read a review article in either Norwegian (n=64) or English (n=66). Reading time was limited to 7 min followed by 7 min to answer a questionnaire.Main outcome measures: Total score on questions related to the article content (potential range −9 to 20).ResultsDoctors who read the article in Norwegian had a mean total score of 10.40 (SD 3.96) compared with 9.08 (SD 3.47) among doctors who read the article in English, giving a mean difference of 1.32 (95% CI 0.03 to 2.62; p=0.046). Age was independently associated with total score, with decreased comprehension with increasing age.ConclusionThe difference in comprehension between the group who read in Norwegian and the group who read in English was statistically significant but modest, suggesting that the language gap in academia is possible to overcome.
Stroke care and case fatality in people with and without schizophrenia: a retrospective cohort study
Authors: Kapral Moira K , Kurdyak Paul , Casaubon Leanne K , Fang Jiming , Porter Joan , Sheehan Kathleen A 
Published: June 2021

BackgroundSchizophrenia is associated with an increased risk of death following stroke; however, the magnitude and underlying reasons for this are not well understood.ObjectiveTo determine the association between schizophrenia and stroke case fatality, adjusting for baseline characteristics, stroke severity and processes of care.DesignRetrospective cohort study used linked clinical and administrative databases.SettingAll acute care institutions (N=152) in the province of Ontario, Canada.ParticipantsAll patients (N=52 473) hospitalised with stroke between 1 April 2002 and 31 March 2013 and included in the Ontario Stroke Registry. Those with schizophrenia (n=612) were identified using validated algorithms.Main outcomes and measuresWe compared acute stroke care in those with and without schizophrenia and used Cox proportional hazards models to examine the association between schizophrenia and mortality, adjusting for demographics, comorbidity, stroke severity and processes of care.ResultsCompared with those without schizophrenia, people with schizophrenia were less likely to undergo thrombolysis (10.1% vs 13.4%), carotid imaging (66.3% vs 74.0%), rehabilitation (36.6% vs 46.6% among those with disability at discharge) or be treated with antihypertensive, lipid-lowering or anticoagulant therapies. After adjustment for age and other factors, schizophrenia was associated with death from any cause at 1 year (adjusted HR (aHR) 1.33, 95% CI 1.14 to 1.54). This was mainly attributable to early deaths from stroke (aHR 1.47, 95% CI 1.20 to 1.80, with survival curves separating in the first 30 days), and the survival disadvantage was particularly marked in those aged over 70 years (1-year mortality 46.9% vs 35.0%).ConclusionsSchizophrenia is associated with increased stroke case fatality, which is not fully explained by stroke severity, measurable comorbid conditions or processes of care. Future work should focus on understanding this mortality gap and on improving acute stroke and secondary preventive care in people with schizophrenia.
Protocol for a realist synthesis of health systems responsiveness in low-income and middle-income countries
Authors: Mirzoev Tolib , Cronin de Chavez Anna , Manzano Ana , Agyepong Irene Akua , Ashinyo Mary Eyram , Danso-Appiah Anthony , Gyimah Leveana , Yevoo Lucy , Awini Elizabeth , Ha Bui Thi Thu , Do Thi Hanh Trang , Nguyen Quynh-Chi Thai , Le Thi Minh , Le Vui Thi , Hicks Joseph Paul , Wright Judy M , Kane Sumit 
Published: June 2021

IntroductionHealth systems responsiveness is a key objective of any health system, yet it is the least studied of all objectives particularly in low-income and middle-income countries. Research on health systems responsiveness highlights its multiple elements, for example, dignity and confidentiality. Little is known, however, about underlying theories of health systems responsiveness, and the mechanisms through which responsiveness works. This realist synthesis contributes to bridging these two knowledge gaps.Methods and analysisIn this realist synthesis, we will use a four-step process, comprising: mapping of theoretical bases, formulation of programme theories, theory refinement and testing of programme theories using literature and empirical data from Ghana and Vietnam. We will include theoretical and conceptual pieces, reviews, empirical studies and grey literature, alongside the primary data. We will explore responsiveness as entailing external and internal interactions within health systems. The search strategy will be purposive and iterative, with continuous screening and refinement of theories. Data extraction will be combined with quality appraisal, using appropriate tools. Each fragment of evidence will be appraised as it is being extracted, for its relevance to the emerging programme theories and methodological rigour. The extracted data pertaining to contexts, mechanisms and outcomes will be synthesised to identify patterns and contradictions. Results will be reported using narrative explanations, following established guidance on realist syntheses.Ethics and disseminationEthics approvals for the wider RESPONSE (Improving health systems responsiveness to neglected health needs of vulnerable groups in Ghana and Vietnam) study, of which this review is one part, were obtained from the ethics committees of the following institutions: London School of Hygiene and Tropical Medicine (ref: 22981), University of Leeds, School of Medicine (ref: MREC19-051), Ghana Health Service (ref: GHS-ERC 012/03/20) and Hanoi University of Public Health (ref: 020-149/DD-YTCC).We will disseminate results through academic papers, conference presentations and stakeholder workshops in Ghana and Vietnam.PROSPERO registration numberCRD42020200353. Full record:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020200353.
SARS-CoV-2 seroprevalence in students and teachers: a longitudinal study from May to October 2020 in German secondary schools
Authors: Kirsten Carolin , Unrath Manja , Lück Christian , Dalpke Alexander H , Berner Reinhard , Armann Jakob 
Published: June 2021

ObjectiveTo quantify the number of SARS-CoV-2 infections in secondary schools after their reopening in May 2020.DesignRepeated SARS-CoV-2 seroprevalence study after the reopening of schools and 4 months later.SettingSecondary school in Dresden, Germany.Participants1538 students grades 8–12 and 507 teachers from 13 schools.InterventionsSerial blood sampling and SARS-CoV-2 IgG antibody assessment.Primary and secondary outcome measureSeroprevalence of SARS-CoV-2 antibodies in study population. Number of undetected cases.Results1538 students and 507 teachers were initially enrolled, and 1334 students and 445 teachers completed both study visits. The seroprevalence for SARS-CoV-2 antibodies was 0.6% in May/June and the same in September/October. Even in schools with reported COVID-19 cases before the lockdown of 13 March, no clusters could be identified. Of 12 persons with positive serology five had a known history of confirmed COVID-19; 23 out of 24 participants with a household history of COVID-91 were seronegative.ConclusionsSchools do not play a crucial role in driving the SARS-CoV-2 pandemic in a low-prevalence setting. Transmission in families occurs very infrequently, and the number of unreported cases is low in this age group. These observations do not support school closures as a strategy fighting the pandemic in a low-prevalence setting.Trial registration numberDRKS00022455.
Tocilizumab decreases T cells but not macrophages in the synovium of patients with rheumatoid arthritis while it increases the levels of serum interleukin-6 and RANKL
Authors: Chatzidionysiou Katerina , Circiumaru Alexandra , Rethi Bence , Joshua Vijay , Engstrom Marianne , Hensvold Aase , af Klint Erik , Catrina Anca 
Published: June 2021

ObjectivesOur knowledge about the effect of tocilizumab (TCZ) on the synovium in rheumatoid arthritis (RA) is limited. The aim of this study was to investigate the effect of TCZ on citrullination and on inflammation in the synovial tissue and in the peripheral blood.Methods15 patients with RA underwent synovial biopsy before and 8 weeks after TCZ initiation. Clinical evaluation was performed at baseline and at 8 weeks. Using immunohistochemistry, we evaluated the expression of CD68, CD3, CD20, osteoprotegerin (OPG) and receptor activator for nuclear factor-κB ligand (RANKL) before and after treatment with TCZ. We also analysed the expression of protein arginine deiminase (PAD)-2 and PAD-4 enzymes in the synovial tissue and protein citrullination patterns with the help of anticitrullinated protein antibody (ACPA) clones 1325:04C03 and 1325:01B09. Serum levels of interleukin-6 (IL-6), IL-8, RANKL, OPG and C-terminal crosslinked telopeptide type II collagen were measured by ELISA. Paired-wise Wilcoxon signed-rank test was used to compare median values before and after treatment.ResultsDisease activity in patients was reduced from baseline to 8 weeks. Although PAD-2 and PAD-4 expressions remained unchanged after TCZ treatment, the binding of one ACPA clone decreased in the synovial tissue. TCZ did not affect the number of CD68+ macrophages or CD20+ B cells but induced significant decrease in the number of CD3+ T cells. RANKL and OPG expression remained unchanged in the synovial tissue. A significant increase in the levels of IL-6 and RANKL was observed in the serum. This increase was statistically significant in patients who responded to TCZ (achieving Clinical Disease Activity Index low disease activity or remission) but not in non-responders.ConclusionsTCZ reduced synovial T-cell counts but not macrophages. A significant increase of serum IL-6 was observed in responders.
Abstract A05: Context-dependent transformation with activated Ras isoforms in human normal epithelial cells
Authors: Kumazaki Minami , Yamamoto Yusuke 
Published: June 2021

Abstract
The classical mammalian ras genes exist three isoforms K-, H- and N-Ras. Ras mutations are genetic events that have been detected in 30 % of all human cancers. Unfortunately, mutated Ras tumors have not responded to chemotherapy, an IgG1 chimeric monoclonal antibody and tyrosine-kinase inhibitors against EGFR. Therefore, there is need for development of new therapeutic strategies to mutated Ras tumors. Although the function of three Ras isoforms is considered to be almost the same, the occurrence of Ras mutation is largely different in human each tissue. For example, APC and BRACA1 genes are associated with a high risk of developing tissue specific cancer. APC mutation caused familial adenomatous polyposis. Affected people have a nearly 100% lifetime risk of developing colorectal cancer, whereas other tumor types are rare. Such genes are therefore considered as tissue-specific cancer genes. Whether Ras genes have tissue specificity has not been clarified. In this study, we thought to elucidate whether mutated Ras isoform has tissue specificity and there is a difference in the function among three mutated Ras isoforms by using human normal epithelial cell lines (prostate, small airway, mammary, skin and bronchus). In clinical data, skin and bronchus frequently occurred H-Ras mutation, others occurred K-Ras mutation. Firstly, we induced immortalization of these cell lines by introduction of human papillomavirus E6/E7 and mutant c-myc (T58A). These cell lines could stably culture and were expressed cytokeratin 5, which is basal cell marker of epidermis. We analyzed the carcinogenesis efficiency by soft-agar assay when the cells infected with retrovirus of three mutated Ras in five immortalized cell lines. As a result, carcinogenesis efficiency was different for each cell line. These results were mostly consistent with clinical data. Also, we identified downstream signaling of Ras (PI3K-AKT and MAPK signaling) involved in carcinogenesis by performing Western blot analysis when the cells infected with mutated Ras, which induced highest carcinogenesis efficiency in each cell lines. As a result, the protein expression level that associated with growth-related PI3K/AKT and MAPK signaling affected differently in each mutated Ras isoform. These results indicated that mutated Ras isoform have tissue specificity and specific functions involved in carcinogenesis. Taken together, we concluded that these events present the possibility of new therapeutic target for mutated Ras tumors.
Citation Format: Minami Kumazaki, Yusuke Yamamoto. Context-dependent transformation with activated Ras isoforms in human normal epithelial cells [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr A05.
Abstract A13: KRAS4A directly regulates hexokinase 1
Authors: Mahaffety James P. , Amendola Caroline R. , Chen Wei-Ching , Kimmelman Alec , Balmain Allan , Philips Mark R. 
Published: June 2021

Abstract
The KRAS oncogene is alternatively spliced, yielding KRAS4A and KRAS4B, which differ only in their membrane-targeting sequences. Tumors that harbor mutant KRAS manifest enhanced glucose utilization. We report a direct, GTP-dependent interaction between KRAS4A and hexokinase 1 (HK1) that alters the activity of the kinase, establishing HK1 as an effector of KRAS4A. The interaction is unique to KRAS4A because the palmitoylation/depalmitoylation cycle of this RAS isoform permits colocalization with HK1 on the outer mitochondrial membrane. Our findings constitute the first demonstration of direct regulation of a metabolic enzyme by a RAS protein and the first biochemical distinction between the KRAS splice variants. KRAS4A expression in cancer may drive unique metabolic vulnerabilities that can be therapeutically exploited.
Citation Format: James P. Mahaffety, Caroline R. Amendola, Wei-Ching Chen, Alec Kimmelman, Allan Balmain, Mark R. Philips. KRAS4A directly regulates hexokinase 1 [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr A13.
Abstract A15: Axl-mediated activation of TBK1 drives epithelial plasticity in pancreatic cancer
Authors: Cruz Victoria H. , Arner Emily N. , Du Wenting , Bremauntz Alberto E. , Brekken Rolf A. 
Published: June 2021

Abstract
Pancreatic ductal adenocarcinoma (PDA) is characterized by an activating mutation in KRAS, which is critical for the biology of PDA progression. Direct inhibition of KRAS through pharmacologic means remains a challenge; however, targeting key KRAS effectors has therapeutic potential. Higher levels of TANK-binding kinase 1 (TBK1) mRNA, a critical downstream effector of mutant active KRAS, are associated with poorer overall survival in human PDA patients. We report that TBK1 supports the growth and metastasis of KRAS mutant PDA by driving an epithelial plasticity program in tumor cells that enhances invasive and metastatic capacity. Further, we identify that the receptor tyrosine kinase Axl induces TBK1 activity in a Ras-RalB-dependent manner. These findings demonstrate that TBK1 is central to Axl-driven EMT in KRAS mutant PDA and suggest that interruption of the Axl-TBK1 signaling cascade above or below KRAS has potential therapeutic efficacy in this recalcitrant disease.
Citation Format: Victoria H. Cruz, Emily N. Arner, Wenting Du, Alberto E. Bremauntz, Rolf A. Brekken. Axl-mediated activation of TBK1 drives epithelial plasticity in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr A15.
Abstract A29: The gastric cancer-associated mutations R5W and Y42C in the RAS homologous RHOA protein cause distinct biochemical alterations, exhibit gain-of-function signaling and oncogenic activities
Authors: Schaefer Antje , Hodge Richard G. , Blake Devon R. , Zhang Haisheng , Bass Adam J. , Der Channing J. 
Published: June 2021

Abstract
Missense mutations of the RAS homologous RHOA gene have recently been identified in ~25% of diffuse gastric cancer (DGC). Unexpectedly, in contrast to the gain-of-function hotspot mutations found in RAS in cancer, DGC-associated RHOA mutations (e.g., R5W, Y42C) are localized at different hotspots that instead suggest loss-of-function alterations. First, we utilized bacterially expressed recombinant proteins and determined the biochemical consequences of these mutations on RHOA function. We found that RHOA WT and Y42C, but not R5W nucleotide exchange, was catalyzed by the ECT2 RhoGEF. Similarly, WT and Y42C, but not R5W GTP hydrolysis activity, was stimulated by the p190RhoGAP. Surprisingly, Y42C and to a lesser degree R5W exhibited impaired intrinsic GTP hydrolysis activity. Interestingly, Y42C showed both loss- and gain-of-function interaction with effectors. Second, we ectopically expressed WT and mutant RHOA proteins in NIH/3T3 fibroblast, and surprisingly, found that Y42C and R5W, similar to the lab-generated constitutively GTP-bound Q63L mutant (analogous to RAS Q61L), stimulated actin stress fiber formation and focal adhesion assembly. Finally, when ectopically expressed in beta-catenin-deficient (another mutation found in gastric cancer) mouse gastric organoids, Y42C disrupted the 3D architecture and induced a DGC-like phenotype in vitro and in vivo. In summary, our studies suggest mutation-specific biochemical defects that act as gain-of-function oncogenic RHOA mutations.
Citation Format: Antje Schaefer, Richard G. Hodge, Devon R. Blake, Haisheng Zhang, Adam J. Bass, Channing J. Der. The gastric cancer-associated mutations R5W and Y42C in the RAS homologous RHOA protein cause distinct biochemical alterations, exhibit gain-of-function signaling and oncogenic activities [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr A29.
Abstract A44: SHP2 inhibition overcomes RTK-mediated pathway reactivation in KRAS-mutant tumors treated with MEK inhibitors
Authors: Lu Hengyu , Liu Chen , Velazquez Roberto , Wang Hongyun , Dunkl Lukas M. , Kazic-Legueux Malika , Haberkorn Anne , Billy Eric , Manchado Eusebio , Brachmann Saskia M. , Moody Susan , Engelman Jeffrey A. , Hammerman Peter S. , Caponigro Giordano , Mohseni Morvarid , Hao Huai-Xiang 
Published: June 2021

Abstract
FGFR1 was recently shown to be activated as part of a compensatory response to prolonged treatment with MEK inhibitor trametinib in several KRAS-mutant lung and pancreatic cancer cell lines. We hypothesize that other receptor tyrosine kinases (RTKs) are also feedback activated in this context. Herein, we profile a large panel of KRAS-mutant cancer cell lines for the contribution of RTKs to the feedback activation of phospho-MEK following MEK inhibition, using a SHP2 inhibitor (SHP099) that blocks RAS activation mediated by multiple RTKs. We find that RTK-driven feedback activation widely exists in KRAS mutant cancer cells and involves several RTKs including EGFR, FGFR, and MET. We further demonstrate this pathway feedback activation is mediated through mutant KRAS. Finally, SHP099 and MEK inhibitors exhibit combination benefits inhibiting KRAS mutant cancer cell proliferation in vitro and in vivo. These findings provide a rationale for exploration of combining SHP2 and MAPK pathway inhibitors for treating KRAS-mutant cancers in the clinic.
Citation Format: Hengyu Lu, Chen Liu, Roberto Velazquez, Hongyun Wang, Lukas M. Dunkl, Malika Kazic-Legueux, Anne Haberkorn, Eric Billy, Eusebio Manchado, Saskia M. Brachmann, Susan Moody, Jeffrey A. Engelman, Peter S. Hammerman, Giordano Caponigro, Morvarid Mohseni, Huai-Xiang Hao. SHP2 inhibition overcomes RTK-mediated pathway reactivation in KRAS-mutant tumors treated with MEK inhibitors [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr A44.
Abstract A47: Targeting glutaminolysis potentiates the efficacy of chemotherapy in RAS-driven pancreatic cancers
Authors: Mukhopadhyay Suman , Adiseshaiah Pavan , Goswami Debanjan , Nissley Dwight V. , McCormick Frank 
Published: June 2021

Abstract
Pancreatic cancer is an extremely aggressive and deadly malignancy. Despite a detailed understanding of pancreatic ductal adenocarcinoma (PDAC)’s biology, the outcome of the current therapeutic regimen remains grim. Chemotherapeutic treatment is one of the first-line systemic treatments for PDAC. However, creating resistance against chemotherapy remains a major challenge. Oncogenic K-Ras mutation is one of the most common events responsible for the initiation and progression of PDAC. K-Ras mutation also promotes the activation of a transcription factor called NRF2 that is crucial for tumor development and pancreatic cancer proliferation. Our study detects differential basal levels of NRF2 in a panel of PDAC cell lines. We hypothesized that this phenomenon might reflect a greater intrinsic capacity of PDAC cells to become resistant to chemotherapy. We then demonstrated that upregulation of NRF2 creates resistance against chemotherapy in PDAC cells. Consequently, NRF2 activation rewires metabolic pathway networks. Importantly, our metabolomics analysis revealed that, upon NRF2 activation, several metabolic pathways are reprogrammed. Recent advances in tumor metabolism signify the critical role of glutamine as a key regulator of cancer therapy. Moreover, we observed that inhibiting glutamine metabolism enhances the efficacy of chemotherapeutic drugs in PDAC cells. Taken together, our finding holds promise as a novel combination therapy for patients with pancreatic cancer marked by developed resistance against chemotherapy. Finally, this treatment strategy further establishes the potential for exploiting metabolic changes in RAS-driven cancer cells that confer novel therapeutic opportunities.
Citation Format: Suman Mukhopadhyay, Pavan Adiseshaiah, Debanjan Goswami, Dwight V. Nissley, Frank McCormick. Targeting glutaminolysis potentiates the efficacy of chemotherapy in RAS-driven pancreatic cancers [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr A47.