bluuebunny/crossref_metadata_2025_split huggingface dataset:
Incidence, comorbidity and mortality in patients with necrotising soft-tissue infections, 2005–2018: a Danish nationwide register-based cohort study
Authors: Hedetoft Morten , Madsen Martin Bruun , Madsen Lærke Bruun , Hyldegaard Ole 
Published: October 2020

ObjectiveTo assess the incidence, comorbidities, treatment modalities and mortality in patients with necrotising soft-tissue infections (NSTIs) in Denmark.DesignNationwide population-based registry study.SettingDenmark.ParticipantsDanish residents with NSTI between 1 January 2005 and 31 August 2018.Main outcome measureIncidence of disease per 100 000 person/year and all-cause mortality at day 90 obtained from Danish National Patient Registry and the Danish Civil Registration System.Results1527 patients with NSTI were identified, yielding an incidence of 1.99 per 100 000 person/year. All-cause 30-day, 90-day and 1-year mortality were 19.4% (95% CI 17.4% to 21.5%), 25.2% (95% CI 23.1% to 27.5%) and 30.4% (95% CI 28.0% to 32.8%), respectively. Amputation occurred in 7% of the individuals. Diabetes was the most predominant comorbidity affecting 43% of the cohort, while 26% had no comorbidities. Higher age, female sex and increasing comorbidity index were found to be independent risk factors of mortality. Admission to high-volume hospitals was associated with improved survival (OR 0.59, 95% CI 0.45 to 0.77). Thirty-six per cent received hyperbaric oxygen therapy (HBOT) as an adjunctive therapy. No change in overall mortality was found over the studied time period.ConclusionThe present study found that in Denmark, the incidence of NSTI increased; mortality rates remained high and largely unaltered. Diabetes was the most common comorbidity, while higher age, female sex and increasing comorbidity index were associated to increased mortality. Survival was improved in those admitted to hospitals with more expertise in treating NSTI. In high-volume hospital, HBOT was associated with decreased odds for mortality.
The Food provision, cUlture and Environment in secondary schooLs (FUEL) study: protocol of a mixed methods evaluation of national School Food Standards implementation in secondary schools and their impact on pupils’ dietary intake and dental health
Authors: Murphy Marie , Pallan Miranda , Lancashire Emma , Duff Rhona , Adamson Ashley J , Bartington Suzanne , Frew Emma , Griffin Tania , Hurley Kiya L , Parry Jayne , Passmore Sandra , Ravaghi Vahid , Sitch Alice J , Spence Suzanne , Rowland Maisie K , Wheeldon Scott , Adab Peymane 
Published: October 2020

IntroductionExcess free sugar intake is associated with obesity and poor dental health. Adolescents consume substantially more free sugar than is recommended. National (UK) School Food Standards (SFS) are in place but are not mandatory in all schools, and their impact on the diets of secondary school pupils is unknown. We aim to evaluate how SFS and wider healthy eating recommendations (from the national School Food Plan (SFP)) are implemented in secondary schools and how they influence pupils’ diets and dental health.Methods and analysisSecondary-level academies/free schools in the West Midlands, UK were divided into two groups: SFS mandated and SFS non-mandated. Using propensity scores to guide sampling, we aim to recruit 22 schools in each group. We will compare data on school food provision and sales, school food culture and environment, and the food curriculum from each group, collected through: school staff, governor, pupil, parent surveys; school documents; and observation. We will explore the implementation level for the SFS requirements and SFP recommendations and develop a school food typology. We aim to recruit 1980 pupils aged 11–15 years across the 44 schools and collect dietary intake (24-hour recall) and dental health data through self-completion surveys. We will compare free sugar/other dietary intake and dental health across the two SFS groups and across the identified school types. School type will be further characterised in 4–8 case study schools through school staff interviews and pupil focus groups. Evaluation of economic impact will be through a cost-consequence analysis and an exploratory cost–utility analysis.Ethics and disseminationEthical approval was obtained from the University of Birmingham Ethical Review Committee (ERN_18-1738). Findings will be disseminated to key national and local agencies, schools and the public through reports, presentations, the media and open access publications.Trial registration numberISRCTN 68757496 (registered 17 October 2019).
Targeted deep sequencing of DNA from multiple tissue types improves the diagnostic rate and reveals a highly diverse phenotype of mosaic neurofibromatosis type 2
Authors: Teranishi Yu , Miyawaki Satoru , Hongo Hiroki , Dofuku Shogo , Okano Atsushi , Takayanagi Shunsaku , Ota Takahiro , Yoshimura Jun , Qu Wei , Mitsui Jun , Nakatomi Hirofumi , Morishita Shinichi , Tsuji Shoji , Saito Nobuhito 
Published: October 2020

BackgroundAlthough 60% of patients with de novo neurofibromatosis type 2 (NF2) are presumed to have mosaic NF2, the actual diagnostic rate of this condition remains low at around 20% because of the existing difficulties in detecting NF2 variants with low variant allele frequency (VAF). Here, we examined the correlation between the genotype and phenotype of mosaic NF2 after improving the diagnostic rate of mosaic NF2.MethodsWe performed targeted deep sequencing of 36 genes including NF2 using DNA samples from multiple tissues (blood, buccal mucosa, hair follicle and tumour) of 53 patients with de novo NF2 and elucidated their genotype–phenotype correlation.ResultsTwenty-four patients (45.2%) had the NF2 germline variant, and 20 patients with NF2 (37.7%) had mosaic NF2. The mosaic NF2 phenotype was significantly different from that in patients with NF2 germline variant in terms of distribution of NF2-related disease, tumour growth rate and hearing outcome. The behaviour of schwannoma correlated to the extent of VAF with NF2 variant in normal tissues unlike meningioma.ConclusionWe have improved the diagnostic rate of mosaic NF2 compared with that of previous studies by targeted deep sequencing of DNA from multiple tissues. Many atypical patients with NF2 diagnosed with ‘unilateral vestibular schwannoma’ or ‘multiple meningiomas’ presumably have mosaic NF2. Finally, we suggest that the highly diverse phenotype of NF2 could result not only from the type and location of NF2 variant but also the extent of VAF in the NF2 variant within normal tissue DNA.
A germline 1;3 translocation disrupting the VHL gene: a novel genetic cause for von Hippel-Lindau
Authors: Ricketts Christopher J , Vocke Cathy D , Lang Martin , Chen Xiongfong , Zhao Yongmei , Tran Bao , Tandon Mayank , Schmidt Laura S , Ball Mark W , Linehan W Marston 
Published: October 2020

Von Hippel-Lindau (VHL) disease is an autosomal dominant hereditary tumour susceptibility disease caused by germline pathogenic variation of the VHL tumour suppressor gene. Affected individuals are at risk of developing multiple malignant and benign tumours in a number of organs.In this report, a male patient in his 20s who presented to the Urologic Oncology Branch at the National Cancer Institute with a clinical diagnosis of VHL was found to have multiple cerebellar haemangioblastomas, bilateral epididymal cysts, multiple pancreatic cysts, and multiple, bilateral renal tumours and cysts. The patient had no family history of VHL and was negative for germline VHL mutation by standard genetic testing. Further genetic analysis demonstrated a germline balanced translocation between chromosomes 1 and 3, t(1;3)(p36.3;p25) with a breakpoint on chromosome 3 within the second intron of the VHL gene. This created a pathogenic germline alteration in VHL by a novel mechanism that was not detectable by standard genetic testing.Karyotype analysis is not commonly performed in existing genetic screening protocols for patients with VHL. Based on this case, protocols should be updated to include karyotype analysis in patients who are clinically diagnosed with VHL but demonstrate no detectable mutation by existing genetic testing.
Tobacco industry targeting of health-conscious youth with ‘lighter’ cigarettes: the case of Singapore
Authors: van der Eijk Yvette , Tan Grace Ping Ping 
Published: October 2020

BackgroundDespite Singapore’s strict tobacco control policies, smoking rates have not decreased since 2004. We examined the primary targets, motivations and strategies behind targeted marketing activities in Singapore from the tobacco industry’s perspective to understand how tobacco companies continue to target people in their marketing.MethodsSnowball search in the Truth Tobacco Industry Documents Library for documents covering the industry’s targeted marketing activities in Singapore. Information from the documents was subsequently triangulated with market data obtained from the Euromonitor Passport database, analysed for trends by tar segment and data from cigarette packs purchased from Singapore retailers, analysed in terms of product positioning.ResultsIn the 1970s and 1980s, as young people in Singapore became more health-conscious, tobacco companies positioned ‘light’ cigarettes for growth in the 1990s. Many of these ‘lights’ contained similar tar and nicotine levels as regular brands; they were only light in their branding. In the 1990’s, ‘lights’ became more popular in Singapore and this demand was largely youth driven. Into the 2010s, while the low tar (<6 mg) segment comprised only a small portion of Singapore’s cigarette market, most cigarette variants were marketed as ‘lighter’ or as having harm reductive benefits to appeal to more health-conscious people.ConclusionsThe differentiation of ‘lighter’ cigarettes remains an important marketing tool for tobacco companies amidst Singapore’s strict regulations. Legislation to remove all remaining avenues for tobacco companies to make harm reduction claims on their products, explicit or implicit, coupled with improving health literacy and exposing industry deception, could help to further bring down smoking prevalence in Singapore.
Disambiguating Arabic Words According to Their Historical Appearance in the Document Based on Recurrent Neural Networks
Authors: Laatar Rim , Aloulou Chafik , Belguith Lamia Hadrich 
Published: October 2020

How can we determine the semantic meaning of a word in relation to its context of appearance? We eventually have to grabble with this difficult question, as one of the paramount problems of Natural Language Processing (NLP). In other words, this issue is commonly defined as Word Sense Disambiguation (WSD). The latter is one of the crucial difficulties within the NLP field. In this respect, word vectors extracted from a neural network model have been successfully applied for resolving the WSD problem. Accordingly, this article presents an unprecedented method to disambiguate Arabic words according to both their contextual appearance in a source text and the era in which they emerged. In fact, in the few previous decades, many researchers have been grabbling with Arabic Word Sense Disambiguation.
It should be noted that the Arabic language can be divided into three major historical periods: old Arabic, middle-age Arabic, and contemporary Arabic. Actually, contemporary Arabic has proved to be the greatest concern of many researchers. The main gist of our work is to disambiguate Arabic words according to the historical period in which they appeared. To perform such a task, we suggest a method that deploys contextualized word embeddings to better gather valid syntactic and semantic information of the same word by taking into account its contextual uses. The preponderant thing is to convert both the senses and the contextual uses of an ambiguous item to vectors, then determine which of the possible conceptual meanings of the target word is closer to the given context.
Long Noncoding RNA TINCR-Mediated Regulation of Acetyl-CoA Metabolism Promotes Nasopharyngeal Carcinoma Progression and Chemoresistance
Authors: Zheng Zi-Qi , Li Zhi-Xuan , Guan Jia-Li , Liu Xu , Li Jun-Yan , Chen Yue , Lin Li , Kou Jia , Lv Jia-Wei , Zhang Lu-Lu , Zhou Guan-Qun , Liu Rui-Qi , Chen FoPing , He Xiao-Jun , Li Ying-Qin , Li Feng , Xu Si-Si , Ma Jun , Liu Na , Sun Ying 
Published: October 2020

Abstract

Frontier evidence suggests that dysregulation of long noncoding RNAs (lncRNA) is ubiquitous in all human tumors, indicating that lncRNAs might have essential roles in tumorigenesis. Therefore, an in-depth study of the roles of lncRNA in nasopharyngeal carcinoma (NPC) carcinogenesis might be helpful to provide novel therapeutic targets. Here we report that lncRNA TINCR was significantly upregulated in NPC and was associated positively with poor survival. Silencing TINCR inhibited NPC progression and cisplatin resistance. Mechanistically, TINCR bound ACLY and protected it from ubiquitin degradation to maintain total cellular acetyl-CoA levels. Accumulation of cellular acetyl-CoA promoted de novo lipid biosynthesis and histone H3K27 acetylation, which ultimately regulated the peptidyl arginine deiminase 1 (PADI1)–MAPK–MMP2/9 pathway. In addition, insulin-like growth factor 2 mRNA-binding protein 3 interacted with TINCR and slowed its decay, which partially accounted for TINCR upregulation in NPC. These findings demonstrate that TINCR acts as a crucial driver of NPC progression and chemoresistance and highlights the newly identified TINCR–ACLY–PADI1–MAPK–MMP2/9 axis as a potential therapeutic target in NPC.

Significance:
TINCR-mediated regulation of a PADI1–MAPK–MMP2/9 signaling pathway plays a critical role in NPC progression and chemoresistance, marking TINCR as a viable therapeutic target in this disease.
Evolution of the Epigenetic Landscape in Childhood B Acute Lymphoblastic Leukemia and Its Role in Drug Resistance
Authors: Saint Fleur-Lominy Shella , Evensen Nikki A. , Bhatla Teena , Sethia Gunjan , Narang Sonali , Choi Jun H. , Ma Xiaotu , Yang Jun J. , Kelly Stephen , Raetz Elizabeth , Harvey Richard C. , Willman Cheryl , Loh Mignon L. , Hunger Stephen P. , Brown Patrick A. , Getz Kylie M. , Meydan Cem , Mason Christopher E. , Tsirigos Aristotelis , Carroll William L. 
Published: October 2020

Abstract

Although B-cell acute lymphoblastic leukemia (B-ALL) is the most common malignancy in children and while highly curable, it remains a leading cause of cancer-related mortality. The outgrowth of tumor subclones carrying mutations in genes responsible for resistance to therapy has led to a Darwinian model of clonal selection. Previous work has indicated that alterations in the epigenome might contribute to clonal selection, yet the extent to which the chromatin state is altered under the selective pressures of therapy is unknown. To address this, we performed chromatin immunoprecipitation, gene expression analysis, and enhanced reduced representation bisulfite sequencing on a cohort of paired diagnosis and relapse samples from individual patients who all but one relapsed within 36 months of initial diagnosis. The chromatin state at diagnosis varied widely among patients, while the majority of peaks remained stable between diagnosis and relapse. Yet a significant fraction was either lost or newly gained, with some patients showing few differences and others showing massive changes of the epigenetic state. Evolution of the epigenome was associated with pathways previously linked to therapy resistance as well as novel candidate pathways through alterations in pyrimidine biosynthesis and downregulation of polycomb repressive complex 2 targets. Three novel, relapse-specific superenhancers were shared by a majority of patients including one associated with S100A8, the top upregulated gene seen at relapse in childhood B-ALL. Overall, our results support a role of the epigenome in clonal evolution and uncover new candidate pathways associated with relapse.

Significance:
This study suggests a major role for epigenetic mechanisms in driving clonal evolution in B-ALL and identifies novel pathways associated with drug resistance.
RNA-Binding RING E3-Ligase DZIP3/hRUL138 Stabilizes Cyclin D1 to Drive Cell-Cycle and Cancer Progression
Authors: Kolapalli Srinivasa P. , Sahu Rinku , Chauhan Nishant R. , Jena Kautilya K. , Mehto Subhash , Das Saroj K. , Jain Ashish , Rout Manaswini , Dash Rupesh , Swain Rajeeb K. , Lee David Y. , Rusten Tor Erik , Chauhan Santosh , Chauhan Swati 
Published: October 2020

Abstract

DZIP3/hRUL138 is a poorly characterized RNA-binding RING E3-ubiquitin ligase with functions in embryonic development. Here we demonstrate that DZIP3 is a crucial driver of cancer cell growth, migration, and invasion. In mice and zebrafish cancer models, DZIP3 promoted tumor growth and metastasis. In line with these results, DZIP3 was frequently overexpressed in several cancer types. Depletion of DZIP3 from cells resulted in reduced expression of Cyclin D1 and a subsequent G1 arrest and defect in cell growth. Mechanistically, DZIP3 utilized its two different domains to interact and stabilize Cyclin D1 both at mRNA and protein levels. Using an RNA-binding lysine-rich region, DZIP3 interacted with the AU-rich region in 3′ untranslated region of Cyclin D1 mRNA and stabilized it. Using a RING E3-ligase domain, DZIP3 interacted and increased K63-linked ubiquitination of Cyclin D1 protein to stabilize it. Remarkably, DZIP3 interacted with, ubiquitinated, and stabilized Cyclin D1 predominantly in the G1 phase of the cell cycle, where it is needed for cell-cycle progression. In agreement with this, a strong positive correlation of mRNA expression between DZIP3 and Cyclin D1 in different cancer types was observed. Additionally, DZIP3 regulated several cell cycle proteins by modulating the Cyclin D1–E2F axes. Taken together, this study demonstrates for the first time that DZIP3 uses a unique two-pronged mechanism in its stabilization of Cyclin D1 to drive cell-cycle and cancer progression.

Significance:
These findings show that DZIP3 is a novel driver of cell-cycle and cancer progression via its control of Cyclin D1 mRNA and protein stability in a cell-cycle phase-dependent manner.
A Hyperactive RelA/p65-Hexokinase 2 Signaling Axis Drives Primary Central Nervous System Lymphoma
Authors: Tateishi Kensuke , Miyake Yohei , Kawazu Masahito , Sasaki Nobuyoshi , Nakamura Taishi , Sasame Jo , Yoshii Yukie , Ueno Toshihide , Miyake Akio , Watanabe Jun , Matsushita Yuko , Shiba Norio , Udaka Naoko , Ohki Kentaro , Fink Alexandria L. , Tummala Shilpa S. , Natsumeda Manabu , Ikegaya Naoki , Nishi Mayuko , Ohtake Makoto , Miyazaki Ryohei , Suenaga Jun , Murata Hidetoshi , Aoki Ichio , Miller Julie J. , Fujii Yukihiko , Ryo Akihide , Yamanaka Shoji , Mano Hiroyuki , Cahill Daniel P. , Wakimoto Hiroaki , Chi Andrew S. , Batchelor Tracy T. , Nagane Motoo , Ichimura Koichi , Yamamoto Tetsuya 
Published: October 2020

Abstract

Primary central nervous system lymphoma (PCNSL) is an isolated type of lymphoma of the central nervous system and has a dismal prognosis despite intensive chemotherapy. Recent genomic analyses have identified highly recurrent mutations of MYD88 and CD79B in immunocompetent PCNSL, whereas LMP1 activation is commonly observed in Epstein–Barr virus (EBV)-positive PCNSL. However, a lack of clinically representative preclinical models has hampered our understanding of the pathogenic mechanisms by which genetic aberrations drive PCNSL disease phenotypes. Here, we establish a panel of 12 orthotopic, patient-derived xenograft (PDX) models from both immunocompetent and EBV-positive PCNSL and secondary CNSL biopsy specimens. PDXs faithfully retained their phenotypic, metabolic, and genetic features, with 100% concordance of MYD88 and CD79B mutations present in PCNSL in immunocompetent patients. These models revealed a convergent functional dependency upon a deregulated RelA/p65-hexokinase 2 signaling axis, codriven by either mutated MYD88/CD79B or LMP1 with Pin1 overactivation in immunocompetent PCNSL and EBV-positive PCNSL, respectively. Notably, distinct molecular alterations used by immunocompetent and EBV-positive PCNSL converged to deregulate RelA/p65 expression and to drive glycolysis, which is critical for intracerebral tumor progression and FDG-PET imaging characteristics. Genetic and pharmacologic inhibition of this key signaling axis potently suppressed PCNSL growth in vitro and in vivo. These patient-derived models offer a platform for predicting clinical chemotherapeutics efficacy and provide critical insights into PCNSL pathogenic mechanisms, accelerating therapeutic discovery for this aggressive disease.

Significance:
A set of clinically relevant CNSL xenografts identifies a hyperactive RelA/p65-hexokinase 2 signaling axis as a driver of progression and potential therapeutic target for treatment and provides a foundational preclinical platform.
Circulating Tumor DNA Predicts Outcome from First-, but not Second-line Treatment and Identifies Melanoma Patients Who May Benefit from Combination Immunotherapy
Authors: Marsavela Gabriela , Lee Jenny , Calapre Leslie , Wong Stephen Q. , Pereira Michelle R. , McEvoy Ashleigh C. , Reid Anna L. , Robinson Cleo , Warburton Lydia , Abed Afaf , Khattak Muhammad A. , Meniawy Tarek M. , Dawson Sarah-Jane , Sandhu Shahneen , Carlino Matteo S. , Menzies Alexander M. , Scolyer Richard A. , Long Georgina V. , Amanuel Benhur , Millward Michael , Ziman Melanie R. , Rizos Helen , Gray Elin S. 
Published: October 2020

AbstractPurpose:We evaluated the predictive value of pretreatment ctDNA to inform therapeutic outcomes in patients with metastatic melanoma relative to type and line of treatment.Experimental Design:Plasma circulating tumor DNA (ctDNA) was quantified in 125 samples collected from 110 patients prior to commencing treatment with immune checkpoint inhibitors (ICIs), as first- (n = 32) or second-line (n = 27) regimens, or prior to commencing first-line BRAF/MEK inhibitor therapy (n = 66). An external validation cohort included 128 patients commencing ICI therapies in the first- (N = 77) or second-line (N = 51) settings.Results:In the discovery cohort, low ctDNA (≤20 copies/mL) prior to commencing therapy predicted longer progression-free survival (PFS) in patients treated with first-line ICIs [HR, 0.20; 95% confidence interval (CI) 0.07–0.53; P &lt; 0.0001], but not in the second-line setting. An independent cohort validated that ctDNA is predictive of PFS in the first-line setting (HR, 0.42; 95% CI, 0.22–0.83; P = 0.006), but not in the second-line ICI setting. Moreover, ctDNA prior to commencing ICI treatment was not predictive of PFS for patients pretreated with BRAF/MEK inhibitors in either the discovery or validation cohorts. Reduced PFS and overall survival were observed in patients with high ctDNA receiving anti–PD-1 monotherapy, relative to those treated with combination anti–CTLA-4/anti–PD-1 inhibitors.Conclusions:Pretreatment ctDNA is a reliable indicator of patient outcome in the first-line ICI treatment setting, but not in the second-line ICI setting, especially in patients pretreated with BRAF/MEK inhibitors. Preliminary evidence indicated that treatment-naïve patients with high ctDNA may preferentially benefit from combined ICIs.