bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chemotherapy decision-making in advanced lung cancer: a prospective qualitative study
Authors: Nelson Annmarie , Longo Mirella , Byrne Anthony , Sivell Stephanie , Noble Simon , Lester Jason , Radley Lesley , Jones David , Sampson Catherine , Anagnostou Despina 
Published: August 2020

ObjectiveTo study how treatment decisions are made alongside the lung cancer clinical pathway.MethodsA prospective, multicentre, multimethods, five-stage, qualitative study. Mediated discourse, thematic, framework and narrative analysis were used to analyse the transcripts.Results51 health professionals, 15 patients with advanced lung cancer, 15 family members and 18 expert stakeholders were recruited from three UK NHS trusts. Multidisciplinary team (MDT) members constructed treatment recommendations around patient performance status, pathology, clinical information and imaging. Information around patients’ social context, needs and preferences were limited. The provisional nature of MDTs treatment recommendations was not always linked to future discussions with the patient along the pathway, that is, patients’ interpretation of their prognosis, treatment discussions occurring prior to seeing the oncologist. This together with the rapid disease trajectory placed additional stress on the oncologist, who had to introduce a different treatment option from that recommended by the MDT or patient’s expectations. Palliative treatment was not referred to explicitly as such, due to its potential for confusion. Patients were unaware of the purpose of each consultation and did not fully understand the non-curative intent of treatment pathways. Patients’ priorities were framed around social and family needs, such as being able to attend a family event.ConclusionMissed opportunities for information giving, affect both clinicians and patients; the pathway for patients with non-small cell lung cancer focuses on clinical management at the expense of patient-centred care. Treatment decisions are a complex process and patients draw conclusions from healthcare interactions prior to the oncology clinic, which prioritises aggressive treatment and influences decisions.
Incidence, pattern and severity of abnormal liver blood tests among hospitalised patients with SARS-COV2 (COVID-19) in South Wales
Authors: Yeoman Andrew , Maggs Daniel Raun , Gardezi Syed A A , Haboubi Hasan Nadim , Yahya Muhammad Imran , Yousuf Fidan , Czajkowski Marek Alexander 
Published: August 2020

IntroductionSARS-CoV-2 (COVID-19) is a novel coronavirus that emerged in Wuhan, China in late 2019 and since become a global pandemic. As such, its clinical behaviour is a subject of much interest. Initial reports suggested a significant proportion of patients have abnormal liver blood tests. Gwent has experienced one of the highest incidences of COVID-19 infection in the UK, which itself has among the highest COVID-19 impacts worldwide.MethodWe set out to report the incidence, clinical pattern and severity of liver blood test abnormalities in hospitalised patients with confirmed COVID-19 in our institution over a 3-week period. Data on clinical outcomes such as admission to intensive therapy unit (ITU), hospital discharge and mortality were recorded.Results318 hospitalised COVID-19 positive had liver blood tests available for analysis. Ninety-seven patients (31%) had one or more abnormal liver blood tests and were abnormal admission in 64%. Liver tests were predominantly cholestatic (72%) in contrast to other studies to date. Male gender and abnormal liver blood tests were associated with ITU admission.ConclusionsAlmost one-third of admissions with COVID-19 have abnormal LBTs which are typically mild and are associated with male gender. Importantly, we have identified that cholestatic patterns dominate but were not clearly associated with ITU admission or death.
Increased risk of cardiac ischaemia in a pan-European cohort of 36 205 childhood cancer survivors: a PanCareSurFup study
Authors: Feijen Elizabeth Arnoldina Maria , van Dalen Elvira C , van der Pal Heleen J H , Reulen Raoul C , Winter David L , Kuehni Claudia E , Morsellino Vera , Alessi Daniela , Allodji Rodrigue S , Byrne Julliana , Bardi Edit , Jakab Zsuzsanna , Grabow Desiree , Garwicz Stanislaw , Haddy Nadia , Jankovic Momcilo , Kaatsch Peter , Levitt Gill A , Ronckers Cecile M , Schindera Christina , Skinner Roderick , Zalatel Lorna , Hjorth Lars , Tissing Wim J E , De Vathaire Florent , Hawkins Mike M , Kremer Leontien C M 
Published: August 2020

ObjectiveIn this report, we determine the cumulative incidence of symptomatic cardiac ischaemia and its risk factors among European 5-year childhood cancer survivors (CCS) participating in the PanCareSurFup study.MethodsEight data providers (France, Hungary, Italy (two cohorts), the Netherlands, Slovenia, Switzerland and the UK) participating in PanCareSurFup ascertained and validated symptomatic cardiac events among their 36 205 eligible CCS. Data on symptomatic cardiac ischaemia were graded according to the Criteria for Adverse Events V.3.0 (grade 3–5). We calculated cumulative incidences, both overall and for different subgroups based on treatment and malignancy, and used multivariable Cox regression to analyse risk factors.ResultsOverall, 302 out of the 36 205 CCS developed symptomatic cardiac ischaemia during follow-up (median follow-up time after primary cancer diagnosis: 23.0 years). The cumulative incidence by age 60 was 5.4% (95% CI 4.6% to 6.2%). Men (7.1% (95% CI 5.8 to 8.4)) had higher rates than women (3.4% (95% CI 2.4 to 4.4)) (p<0.0001). Of importance is that a significant number of patients (41/302) were affected as teens or young adults (14–30 years). Treatment with radiotherapy/chemotherapy conferred twofold risk (95% CI 1.5 to 3.0) and cases in these patients appeared earlier than in CCS without treatment/surgery only (15% vs 3% prior to age 30 years, respectively (p=0.04)).ConclusionsIn this very large European childhood cancer cohort, we found that by age 60 years, 1 in 18 CCS will develop a severe, life-threatening or fatal cardiac ischaemia, especially in lymphoma survivors and CCS treated with radiotherapy and chemotherapy increases the risk significantly.
Trends in cardiovascular outcomes after acute coronary syndrome in New Zealand 2006–2016
Authors: Wang Tom Kai Ming , Grey Corina , Jiang Yannan , Selak Vanessa , Bullen Chris , Jackson Rodney T , Kerr Andrew J 
Published: August 2020

ObjectivesCharacterisation of trends in acute coronary syndrome (ACS) outcomes are critical to informing clinical practice and quality improvement, but there are few recent population studies for ACS. We reviewed the recent trends in the outcomes of ACS in New Zealand (NZ).MethodsAll patients with ACS admitted to NZ public hospitals in 2006–2016 were identified from hospital discharge records, and their first ACS hospitalisations per year extracted for analysis. Thirty-day and 1-year death, myocardial infarction, stroke, heart failure and bleeding rates were calculated for each calendar year. Trends in outcome rates were assessed using generalised linear mixed models.ResultsTotal annual ACS hospitalisations decreased from 685 to 424 per 100 000. Using first patient hospitalisations per year (n=1 55 060), we found significant annual declines in all major outcomes except for non-cardiovascular deaths. All-cause mortality fell from 10.5% to 9.1% at 30 days (adjusted OR 0.985 per year change, p<0.001) and from 21.8% to 18.7% at 1 year (OR=0.994, p=0.016). This was related to significant decreases in cardiovascular death at both time points (OR=0.982 and 0.987, respectively, p<0.001), outweighing a slight increase in non-cardiovascular death at 1 year (OR=1.009, p=0.014). One-year rates of myocardial infarction, heart failure, stroke and bleeding rates all decreased significantly over time.ConclusionACS outcomes including all-cause mortality, cardiovascular death, myocardial infarction, stroke, heart failure and bleeding at 30 days and 1 year improved over the last decade in NZ, reflecting successful implementation and advances in prevention, medical and invasive management in ACS over time.
Dose escalation phase 1 study of radiotherapy in combination with anti-cytotoxic-T-lymphocyte-associated antigen 4 monoclonal antibody ipilimumab in patients with metastatic melanoma
Authors: Boutros Celine , Chaput-Gras Nathalie , Lanoy Emilie , Larive Alicia , Mateus Christine , Routier Emilie , Sun Roger , Tao Yun Gan , Massard Christophe , Bahleda Rastilav , Schwob Dominique , Ibrahim Nathalie , Khoury Abboud Rita Maria , Caramella Caroline , Lancia Andrea , Cassard Lydie , Roy Severine , Soria J -C , Robert Caroline , Deutsch Eric 
Published: August 2020

BackgroundA synergy between radiotherapy and anti-cytotoxic-T-lymphocyte-associated antigen 4 (anti-CTLA-4) monoclonal antibody has been demonstrated preclinically. The Mel-Ipi-Rx phase 1 study aimed to determine the maximum tolerated dose (MTD) and safety profile of radiotherapy combined with ipilimumab in patients with metastatic melanoma.Patients and methodsA 3+3 dose escalation design was used with 9, 15, 18 and 24 Gy dose of radiotherapy at week 4 combined with 10 mg/kg ipilimumab every 3 weeks for four doses. Patients with evidence of clinical benefit at week 12 were eligible for maintenance with ipilimumab 10 mg/kg every 12 weeks starting at week 24 until severe toxicity or disease progression. The database lock occurred on April 30, 2019. Tumor growth rate of irradiated lesions and non-irradiated lesions were analyzed to assess the systemic immunologic antitumor response. Blood immune monitoring was performed before and during treatment to determine if radiotherapy could modify ipilimumab pharmacodynamics.Results19 patients received ipilimumab between August 2011 and July 2015. Nine patients received the four doses of ipilimumab. All patients received the combined radiotherapy. Grade 3 adverse events occurred in nine patients, the most common being colitis and hepatitis. No drug-related death occurred. Dose limiting toxicity occurred in two of six patients in the cohort receiving 15 Gy. The MTD was 9 Gy. Two patients had complete response, three had partial response response and seven had stable disease, giving an objective response rate of 31% and a clinical benefit rate of 75% at week 24. The median duration of follow-up was 5.8 years (Q1=4.5; Q3=6.8). The median overall survival (95% CI) was estimated at 0.9 years (0.5–2). The median progression-free survival (PFS) (95% CI) was 0.4 (0.2–1.4). Radiotherapy combined with ipilimumab was associated with increased CD4+ and CD8+ICOS+ T cells. Increased CD8+ was significantly associated with PFS.ConclusionWhen combined with ipilimumab at 10 mg/kg, the MTD of radiotherapy was 9 Gy. This combination of ipilimumab and radiotherapy appears to be associated with antitumor activity. Increased CD8+ was significantly associated with PFS. Thus, immune biomarkers may be useful for early response evaluation.Trial registration numberNCT01557114.
An immune evasion mechanism with IgG4 playing an essential role in cancer and implication for immunotherapy
Authors: Wang Hui , Xu Qian , Zhao Chanyuan , Zhu Ziqi , Zhu Xiaoqing , Zhou Junjie , Zhang Shuming , Yang Tiqun , Zhang Biying , Li Jun , Yan Meiling , Liu Renming , Ma Changchun , Quan Yan , Zhang Yongqu , Zhang Weifeng , Geng Yiqun , Chen Chuangzhen , Chen Shaobin , Liu Ditian , Chen Yuping , Tian Dongping , Su Min , Chen Xueling , Gu Jiang 
Published: August 2020

BackgroundRecent impressive advances in cancer immunotherapy have been largely derived from cellular immunity. The role of humoral immunity in carcinogenesis has been less understood. Based on our previous observations we hypothesize that an immunoglobulin subtype IgG4 plays an essential role in cancer immune evasion.MethodsThe distribution, abundance, actions, properties and possible mechanisms of IgG4 were investigated with human cancer samples and animal tumor models with an extensive array of techniques both in vitro and in vivo.ResultsIn a cohort of patients with esophageal cancer we found that IgG4-containing B lymphocytes and IgG4 concentration were significantly increased in cancer tissue and IgG4 concentrations increased in serum of patients with cancer. Both were positively related to increased cancer malignancy and poor prognoses, that is, more IgG4 appeared to associate with more aggressive cancer growth. We further found that IgG4, regardless of its antigen specificity, inhibited the classic immune reactions of antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis and complement-dependent cytotoxicity against cancer cells in vitro, and these effects were obtained through its Fc fragment reacting to the Fc fragments of cancer-specific IgG1 that has been bound to cancer antigens. We also found that IgG4 competed with IgG1 in reacting to Fc receptors of immune effector cells. Therefore, locally increased IgG4 in cancer microenvironment should inhibit antibody-mediated anticancer responses and help cancer to evade local immune attack and indirectly promote cancer growth. This hypothesis was verified in three different immune potent mouse models. We found that local application of IgG4 significantly accelerated growth of inoculated breast and colorectal cancers and carcinogen-induced skin papilloma. We also tested the antibody drug for cancer immunotherapy nivolumab, which was IgG4 in nature with a stabilizing S228P mutation, and found that it significantly promoted cancer growth in mice. This may provide an explanation to the newly appeared hyperprogressive disease sometimes associated with cancer immunotherapy.ConclusionThere appears to be a previously unrecognized immune evasion mechanism with IgG4 playing an essential role in cancer microenvironment with implications in cancer diagnosis and immunotherapy.
M2-like macrophages dictate clinically relevant immunosuppression in metastatic ovarian cancer
Authors: Hensler Michal , Kasikova Lenka , Fiser Karel , Rakova Jana , Skapa Petr , Laco Jan , Lanickova Tereza , Pecen Ladislav , Truxova Iva , Vosahlikova Sarka , Moserova Irena , Praznovec Ivan , Drochytek Vit , Rehackova Martina , Brtnicky Tomas , Rob Lukas , Benes Vladimir , Pistolic Jelena , Sojka Ludek , Ryska Ales , Sautes-Fridman Catherine , Fridman Wolf Herve , Galluzzi Lorenzo , Spisek Radek , Fucikova Jitka 
Published: August 2020

BackgroundThe immunological microenvironment of primary high-grade serous carcinomas (HGSCs) has a major impact on disease outcome. Conversely, little is known on the microenvironment of metastatic HGSCs and its potential influence on patient survival. Here, we explore the clinical relevance of the immunological configuration of HGSC metastases.MethodsRNA sequencing was employed on 24 paired primary tumor microenvironment (P-TME) and metastatic tumor microenvironment (M-TME) chemotherapy-naive HGSC samples. Immunohistochemistry was used to evaluate infiltration by CD8+ T cells, CD20+ B cells, DC-LAMP+ (lysosomal-associated membrane protein 3) dendritic cells (DCs), NKp46+ (natural killer) cells and CD68+CD163+ M2-like tumor-associated macrophages (TAMs), abundance of PD-1+ (programmed cell death 1), LAG-3+ (lymphocyte-activating gene 3) cells, and PD-L1 (programmed death ligand 1) expression in 80 samples. Flow cytometry was used for functional assessments on freshly resected HGSC samples.Results1468 genes were differentially expressed in the P-TME versus M-TME of HGSCs, the latter displaying signatures of extracellular matrix remodeling and immune infiltration. M-TME infiltration by immune effector cells had little impact on patient survival. Accordingly, M-TME-infiltrating T cells were functionally impaired, but not upon checkpoint activation. Conversely, cytokine signaling in favor of M2-like TAMs activity appeared to underlie inhibited immunity in the M-TME and poor disease outcome.ConclusionsImmunosuppressive M2-like TAM infiltrating metastatic sites limit clinically relevant immune responses against HGSCs.
Nicorandil prevents the nephrotoxic effect of cyclosporine-A in albino rats through modulation of HIF-1α/VEGF/eNOS signaling
Authors: Harb Inas A. , Ashour Hend , Sabry Dina , El-Yasergy Dina Fawzy , Hamza Wael Mostafa , Mostafa Abeer 
Published: August 2020

Despite that cyclosporine-A (CsA) is a widely used immunosuppressive drug, its nephrotoxic effect limits its long-term administration. Herein we tried to investigate its renal effect on endothelial dysfunction targeting the hypoxia-inducible factor (HIF-1α) / vascular endothelial growth factor (VEGF) / endothelial nitric oxide synthase (eNOS) pathway and the possible modulation by nicorandil. Eight groups of adult male Wistar rats were included: (1) control; (2) vehicle group (received oil); (3) glibenclamide 5 mg·kg–1·day–1 administered orally; (4) nicorandil 10 mg·kg–1·day–1 administered orally; (5) CsA 25 mg·kg–1·day–1 administered orally; (6) combined administration of CsA and nicorandil; (7) glibenclamide was added to CsA; and (8) both CsA and nicorandil were combined with glibenclamide. The treatment continued for six weeks. Combined nicorandil with CsA improved renal function deterioration initiated by CsA. CsA decreased the renal expression levels (P < 0.001) of HIF-1α, eNOS, and VEGF, inducing endothelial dysfunction and triggering inflammation, and upregulated the profibrotic marker transforming growth factor (TGF-β). Nicorandil fixed the disturbed HIF-1α/VEGF/eNOS signaling. Nicorandil corrected the renal functions, confirmed by the improved histological glomerular tuft retraction that was obvious in the CsA group, without significant influence by glibenclamide. Proper protection from CsA-induced nephrotoxicity was achieved by nicorandil. Nicorandil reversed the disturbed HIF-1α/VEGF/eNOS pathway created by CsA.
Supplement of biochar and vermicompost amendments in coir and peat growing media improves N management and yields of leafy vegetables
Authors: Messiga Aimé J. , Hao Xiuming , Dorais Martine , Bineng Carine S. , Ziadi Noura 
Published: August 2020

A greenhouse trial assessed the effects of biochar and vermicompost as partial substitutes of conventional growing media on leafy vegetables’ yields and changes of NH4+-N and NO3−-N in growing medium and leachates. Six growing media mixtures [(a) coir, (b) coir + biochar, (c) coir + vermicompost, (d) peat, (e) peat +vermicompost, (f) peat + biochar] combined with three nitrogen (N) rates [0% (0 g N·pot−1), 50% (0.5 g N·pot−1), and 100% (1.0 g N·pot−1) commercial recommendation] were arranged in a split-plot design with three replicates. On average, the yield gap between 100% N and 50% N was improved when biochar and vermicompost were used as substitutes of coir (32% and 28% vs. 49%) and peat (14% and 18% vs. 27%). The concentrations of NH4+-N in the leachates for peat + biochar varied between 17.20 and 1.00 mg·L−1. The concentrations of NO3−-N in the leachates varied between 130.0 and 1.0 mg·L−1for coir + vermicompost, and 60 and 1.0 mg·L−1for peat + vermicompost. The residual NO3−-N in peat + biochar growing media and the leachates did not match the changes observed for NH4+-N, and the much lower residual NH4+-N indicates possible NH4+-N retention by biochar and loss through volatilization in the early growth stages. Our results show that partial substitution of peat with biochar and coir with vermicompost maintained acceptable crop yield at 50% N due probably to N supply by vermicompost and decreased residual mineral N and loss by biochar in the leachates which could be beneficial for the environment.
CaMKIIδC Drives Early Adaptive Ca
2+
Change and Late Eccentric Cardiac Hypertrophy
Authors: Ljubojevic-Holzer Senka , Herren Anthony W. , Djalinac Natasa , Voglhuber Julia , Morotti Stefano , Holzer Michael , Wood Brent M. , Abdellatif Mahmoud , Matzer Ingrid , Sacherer Michael , Radulovic Snjezana , Wallner Markus , Ivanov Milan , Wagner Stefan , Sossalla Samuel , von Lewinski Dirk , Pieske Burkert , Brown Joan Heller , Sedej Simon , Bossuyt Julie , Bers Donald M. 
Published: August 2020

Rationale:

CaMKII (Ca
2+
-Calmodulin dependent protein kinase) δC activation is implicated in pathological progression of heart failure (HF) and CaMKIIδC transgenic mice rapidly develop HF and arrhythmias. However, little is known about early spatio-temporal Ca
2+
handling and CaMKII activation in hypertrophy and HF.

Objective:
To measure time- and location-dependent activation of CaMKIIδC signaling in adult ventricular cardiomyocytes, during transaortic constriction (TAC) and in CaMKIIδC transgenic mice.

Methods and Results:

We used human tissue from nonfailing and HF hearts, 4 mouse lines: wild-type, KO (CaMKIIδ-knockout), CaMKIIδC transgenic in wild-type (TG), or KO background, and wild-type mice exposed to TAC. Confocal imaging and biochemistry revealed disproportional CaMKIIδC activation and accumulation in nuclear and perinuclear versus cytosolic regions at 5 days post-TAC. This CaMKIIδ activation caused a compensatory increase in sarcoplasmic reticulum Ca
2+
content, Ca
2+
transient amplitude, and [Ca
2+
] decline rates, with reduced phospholamban expression, all of which were most prominent near and in the nucleus. These early adaptive effects in TAC were entirely mimicked in young CaMKIIδ TG mice (6–8 weeks) where no overt cardiac dysfunction was present. The (peri)nuclear CaMKII accumulation also correlated with enhanced HDAC4 (histone deacetylase) nuclear export, creating a microdomain for transcriptional regulation. At longer times both TAC and TG mice progressed to overt HF (at 45 days and 11–13 weeks, respectively), during which time the compensatory Ca
2+
transient effects reversed, but further increases in nuclear and time-averaged [Ca
2+
] and CaMKII activation occurred. CaMKIIδ TG mice lacking δB exhibited more severe HF, eccentric myocyte growth, and nuclear changes. Patient HF samples also showed greatly increased CaMKIIδ expression, especially for CaMKIIδC in nuclear fractions.

Conclusions:

We conclude that in early TAC perinuclear CaMKIIδC activation promotes adaptive increases in myocyte Ca
2+
transients and nuclear transcriptional responses but that chronic progression of this nuclear Ca
2+
-CaMKIIδC axis contributes to eccentric hypertrophy and HF.