bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intestinal current measurement and nasal potential difference to make a diagnosis of cases with inconclusiveCFTRgenetics and sweat test
Authors: Minso Rebecca , Schulz Angela , Dopfer Christian , Alfeis Nadine , Barneveld Andrea van , Makartian-Gyulumyan Lena , Hansen Gesine , Junge Sibylle , Müller Carsten , Ringshausen Felix C C , Sauer-Heilborn Annette , Stanke Frauke , Stolpe Cornelia , Tamm Stephanie , Welte Tobias , Dittrich Anna-Maria , Tümmler Burkhard 
Published: October 2020

BackgroundNasal potential difference (NPD) and intestinal current measurements (ICM) are cystic fibrosis transmembrane conductance regulator (CFTR) biomarkers recommended to make a diagnosis in individuals with inconclusive sweat test andCFTRgenetics and a clinical suspicion for cystic fibrosis (CF) or CFTR-related disorder (CFTR-RD).MethodsNPD and ICM were measured according to standard operating procedures of the European Cystic Fibrosis Society Diagnostic Network Working Group.ResultsWe assessed 219 individuals by NPD or ICM who had been referred to our laboratory due to clinical symptoms suggestive of CF, but inconclusive sweat test andCFTRgenetics (median age: 16.3 years, range 0.4 to 76 years). CF or CFTR-related disorder was diagnosed in 22 of 29 patients (76%) with aCFTRgenotype of unknown or variable clinical significance and in 51 of 190 carriers (27%) of one (35/42) or no (16/148) identifiedCFTRmutation. If twoCFTRsequence variants had been identified, the outcome of NPD and ICM was consistent with the classification of the CFTR2 database. Moreover, a suspected false-positive diagnosis of CF was confirmed in seven and withdrawn in eight patients. Of 26 individuals assessed by both NPD and ICM, eleven individuals exhibited discordant tracings of ICM and NPD, with one measurement being in the CF range and the other in the normal range.ConclusionThe majority of patients whom we diagnosed with CF or CFTR-RD by extended electrophysiology are carriers of the wild-typeCFTRcoding sequence on at least one of their CF alleles. The disease-causing genetic lesions should reside in the non-coding region ofCFTRor elsewhere in the genome, affecting the regulation of CFTR expression in a tissue-depending fashion which may explain the large within-group variability of CFTR activity in the respiratory and intestinal epithelium seen in this group.
Expression of YAP1 and pSTAT3-S727 and their prognostic value in glioma
Authors: Sang Wei , Xue Jing , Su Li-Ping , Gulinar Abulajiang , Wang Qian , Zhai Yang-Yang , Hu Yan-Ran , Gao Hai-Xia , Li Xinxia , Li Qiao-Xing , Zhang Wei 
Published: October 2020

AimsA growing research demonstrated that YAP1 played important roles in gliomagenesis. We explored the expression of YAP1 and STAT3, the relationship between them and the effect of YAP1, STAT3 on prognosis in glioma.MethodsExpression of YAP1, p-YAP1, STAT3, pSTAT3-S727 and pSTAT3-Y705 in 141 cases of low-grade gliomas (LGG) and 74 cases of high-grade gliomas (HGG) of surgical specimens were measured by immunohistochemistry. Pearson’s X2test was used to determine the correlation between immunohistochemical expressions and clinicopathological parameters. Pearson’s or Spearman correlation test was used to determine the association between these proteins expression. Survival analysis was used to investigate the effect of these proteins on prognosis.ResultsHigh expressions of YAP1, STAT3, pSTAT3-S727 and pSTAT3-Y705 were found in HGG compared with LGG (p=0.000). High expressions of YAP1, STAT3, pSTAT3-S727 and pSTAT3-Y705 were found in 63.5%, 59.5%, 66.2% and 31.1% cases of HGG, respectively. YAP1 expression was associated to tumour location, Ki-67 and P53, STAT3 expression was related with Ki-67 and P53, and the expression of pSTAT3-S727 was associated with Ki-67. There was a significantly positive correlation between YAP1 and pSTAT3-S727 (p<0.0001; r=0.5663). Survival analysis revealed that patients with YAP1 and pSTAT3-S727 coexpression had worse overall survival (OS) and progression-free survival (PFS) (p<0.0001). Tumour grade, age, Ki-67 and YAP1 expression were independent prognostic factors for OS. In LGG group, both YAP1 and pSTAT3-S727 expressions were negative correlation with IDH1 mutation, YAP1 and pSTAT3-S727 coexpression showed worse OS and PFS of glioma patients.ConclusionOur research showed that YAP1 and STAT3 were significantly activated in HGG compared with LGG. YAP1 significantly correlated with pSTAT3-S727 in glioma, YAP1 and pSTAT3-S727 coexpression may serve as a reliable prognostic biomarker and therapeutic target for glioma.
Effect of cyclo-oxygenase inhibitor use during checkpoint blockade immunotherapy in patients with metastatic melanoma and non-small cell lung cancer
Authors: Wang Shang-Jui , Khullar Karishma , Kim Sinae , Yegya-Raman Nikhil , Malhotra Jyoti , Groisberg Roman , Crayton Samuel H , Silk Ann W , Nosher John L , Gentile Michael A , Mehnert Janice M , Jabbour Salma K 
Published: October 2020

BackgroundImmune checkpoint inhibitors (ICIs) improve survival outcomes in metastatic melanoma and non-small cell lung cancer (NSCLC). Preclinical evidence suggests that overexpression of cyclo-oxygenase-2 (COX2) in tumors facilitates immune evasion through prostaglandin E2 production and that COX inhibition synergizes with ICIs to promote antitumor T-cell activation. This study investigates whether concurrent COX inhibitor (COXi) use during ICI treatment compared with ICI alone is associated with improved time-to-progression (TTP), objective response rate (ORR) and overall survival (OS) in patients with metastatic melanoma and NSCLC.MethodsWe retrospectively reviewed 90 metastatic melanoma and 37 metastatic NSCLC patients, treated with ICI between 2011 and 2019. Differences in TTP and OS by ICI+COXi versus ICI alone were compared using Kaplan-Meier and Cox regression. Interaction between ICI+COXi versus ICI alone and pretreatment neutrophil–lymphocyte ratio (NLR) was examined. Independent radiology review per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 was performed.ResultsFor patients with melanoma, median TTP was significantly prolonged in ICI+COXi versus ICI alone (245 vs 100.5 days, p=0.002). On multivariate analysis, ICI+COXi associated with increased TTP (HR 0.36, 95% CI 0.2 to 0.66, p=0.001), adjusted for age, pretreatment NLR, and gender. For NSCLC patients, ICI+COXi also associated with increased TTP compared with ICI alone on multivariate analysis (HR 0.45; 95% CI 0.21 to 0.97; p=0.042) adjusted for age. ORR at 6 months was significantly higher in patients who received ICI+COXi compared with ICI alone in both melanoma (58.6% vs 19.2%, p=0.0005) and NSCLC (73.7% vs 33.3%, p=0.036) cohorts. In the melanoma cohort, high pretreatment NLR (>5) associated with decreased TTP (HR 3.21, 95% CI 1.64 to 6.3; p=0.0007); however, ICI+COXi significantly associated with increased TTP in high NLR (>5) patients (HR 0.08, 95% CI 0.03 to 0.25), but not in low NLR (≤5) patients (HR 0.65, 95% CI 0.32 to 1.32). Similar outcomes were found in an adjusted melanoma cohort after RECIST review.ConclusionsOur study suggests that COXi use concurrently with ICI significantly associated with longer TTP and improved ORR at 6 months in patients with metastatic melanoma and NSCLC compared with ICI alone. Furthermore, COXi use appears to reverse the negative prognostic effect of a high NLR by prolonging TTP in patients with melanoma.
89Zr-pembrolizumab biodistribution is influenced by PD-1-mediated uptake in lymphoid organs
Authors: van der Veen Elly L , Giesen Danique , Pot-de Jong Linda , Jorritsma-Smit Annelies , De Vries Elisabeth G E , Lub-de Hooge Marjolijn N 
Published: October 2020

BackgroundTo better predict response to immune checkpoint therapy and toxicity in healthy tissues, insight in the in vivo behavior of immune checkpoint targeting monoclonal antibodies is essential. Therefore, we aimed to study in vivo pharmacokinetics and whole-body distribution of zirconium-89 (89Zr) labeled programmed cell death protein-1 (PD-1) targeting pembrolizumab with positron-emission tomography (PET) in humanized mice.MethodsHumanized (huNOG) and non-humanized NOG mice were xenografted with human A375M melanoma cells. PET imaging was performed on day 7 post 89Zr-pembrolizumab (10 µg, 2.5 MBq) administration, followed by ex vivo biodistribution studies. Other huNOG mice bearing A375M tumors received a co-injection of excess (90 µg) unlabeled pembrolizumab or 89Zr-IgG4 control (10 µg, 2.5 MBq). Tumor and spleen tissue were studied with autoradiography and immunohistochemically including PD-1.ResultsPET imaging and biodistribution studies showed high 89Zr-pembrolizumab uptake in tissues containing human immune cells, including spleen, lymph nodes and bone marrow. Tumor uptake of 89Zr-pembrolizumab was lower than uptake in lymphoid tissues, but higher than uptake in other organs. High uptake in lymphoid tissues could be reduced by excess unlabeled pembrolizumab. Tracer activity in blood pool was increased by addition of unlabeled pembrolizumab, but tumor uptake was not affected. Autoradiography supported PET findings and immunohistochemical staining on spleen and lymph node tissue showed PD-1 positive cells, whereas tumor tissue was PD-1 negative.Conclusion89Zr-pembrolizumab whole-body biodistribution showed high PD-1-mediated uptake in lymphoid tissues, such as spleen, lymph nodes and bone marrow, and modest tumor uptake. Our data may enable evaluation of 89Zr-pembrolizumab whole-body distribution in patients.
Real-world treatment switching to sacubitril/valsartan in patients with heart failure with reduced ejection fraction: A cohort study
Authors: Ganesananthan Sashiananthan , Shah Nisar , Shah Parin , Elsayed Hossam , Phillips Julie , Parkes Ann , Morgan Angharad , Yousef Zaheer 
Published: October 2020

BackgroundSacubitril/valsartan is an effective treatment for heart failure with reduced ejection fraction (HFrEF) based on clinical trial data. However, little is known about its use or impact in real-world practice. The aim of this study was to describe our routine clinical experience of switching otherwise optimally treated patients with HFrEF to sacubitril/valsartan with respect to patient outcomes such as quality of life (QoL) and echocardiographic variables.Methods and resultsFrom June 2017 to May 2019, 80 consecutive stable patients with HFrEF on established and maximally tolerated guideline-directed HF therapies were initiated on sacubitril/valsartan with bimonthly uptitration. Clinical assessment, biochemistry, echocardiography and QoL were compared pretreatment and post-treatment switching. We were able to successfully switch 89% of patients from renin–angiotensin axis inhibitors to sacubitril/valsartan (71 of 80 patients). After 3 months of switch therapy, we observed clinically significant and incremental improvements in blood pressure (systolic blood pressure 123 vs 112 mm Hg, p<0.001; diastolic blood pressure 72 vs 68 mm Hg, p=0.004), New York Heart Association functional classification score (2.3 vs 1.9, p<0.001), Minnesota Living with Heart Failure Questionnaire score (46 vs 38, p=0.016), left ventricular ejection fraction (26% vs 33%, p<0.001) and left ventricular end systolic diameter (5.2 vs 4.9 cm, p=0.013) compared with baseline. There were no significant changes in renal function or serum potassium.ConclusionThis study provides real-world clinical practice data demonstrating incremental improvements in functional and echocardiographic outcomes in optimally treated patients with HFrEF switched to sacubitril/valsartan. The data provide evidence beyond that observed in clinical trial settings of the potential benefits of sacubitril/valsartan when used as part of a multidisciplinary heart failure programme.
An integrated organic–inorganic geochemical characterization of Paleogene sediments in No.1 Structural Belt of the Nanpu Sag, Bohai Bay Basin, eastern China: implications for the origin of organic matter
Authors: Guo Yu , Gang Wenzhe , Gao Gang , Yang Shangru , Jiang Chong , Chen Guo , Zhu Chuanzhen , Li Xiaofeng , Wang Yifan , Dong Yuexia , Goldberg Karin 
Published: October 2020

Paleogene sediments, especially the third member of the Dongying Formation (Ed
3
) and the first and third members of the Shahejie Formation (Es
1
and Es
3
), have been regarded as the most important source rocks in the Nanpu Sag. Organic and inorganic analyses, including Rock-Eval pyrolysis, gas chromatography-mass spectrometry, and element geochemistry, in 91 mudstone samples, were used to reconstruct the palaeoenvironmental conditions, such as palaeoclimate, palaeo-salinity and palaeo-redox conditions, and to recognize the origin of organic matter. The results show that Es
3
has a higher TOC content than Es
1
and Ed
3
. Hydrocarbon genetic potential (S
1
+ S
2
) of the samples indicate fair to good hydrocarbon potential. The kerogen type of Ed
3
and Es
1
source rocks are Type II
1
–II
2
, while Es
3
source rocks are dominated by Type II
2
–III kerogens. Biomarkers and inorganic geochemical indicatives of source rocks, such as Pr/Ph, V/(V + Ni) and Cu/Zn, indicate a lacustrine environment with fresh to brackish water under suboxic to anoxic conditions during deposition. Ed
3
source rocks are characterized by low G/C
30
H (gamacerane/C
30
hopane) (<0.1), TT/C
30
H (tricyclic terpane/C
30
hopane) and S/H (serane/hopane), high Pr/Ph (pristane/phytane) and C
24
TeT/C
23
TT (C
24
tetracyclic terpane/C
23
tricyclic terpane), indicating mixed input of both algae and terrestrial higher plants, dominated by terrestrial higher plants. Es
1
source rocks display medium G/C
30
H, TT/C
30
H, S/H, Pr/Ph and C
24
TeT/C
23
TT, indicative of a mixed input of both algae and terrestrial higher plants. Es
3
source rocks are characterized by high G/C
30
H (>0.1), TT/C
30
H and S/H, low Pr/Ph and C
24
TeT/C
23
TT, typical of a mixed input of algae and terrestrial higher plants, with algal dominance. Ed
3
, Es
1
and Es
3
source rocks were mostly deposited in semi-arid to humid-warm climate conditions, with an average temperature higher than 15°C. This study suggests that suitable temperatures, a fresh to brackish lacustrine environment and suboxic to anoxic conditions could result in a high organic matter concentration and preservation, thus providing prerequisites for the formation of high-quality source rocks.

Supplementary material
: Tables S1–S3 are available at
https://doi.org/10.6084/m9.figshare.c.5227684
Genome and Transcriptome Biomarkers of Response to Immune Checkpoint Inhibitors in Advanced Solid Tumors
Authors: Pender Alexandra , Titmuss Emma , Pleasance Erin D. , Fan Kevin Y. , Pearson Hillary , Brown Scott D. , Grisdale Cameron J. , Topham James T. , Shen Yaoqing , Bonakdar Melika , Taylor Gregory A. , Williamson Laura M. , Mungall Karen L. , Chuah Eric , Mungall Andrew J. , Moore Richard A. , Lavoie Jean-Michel , Yip Stephen , Lim Howard , Renouf Daniel J. , Sun Sophie , Holt Robert A. , Jones Steven J.M. , Marra Marco A. , Laskin Janessa 
Published: October 2020

Abstract

Purpose:
Immune checkpoint inhibitors (ICI) have revolutionized the treatment of solid tumors with dramatic and durable responses seen across multiple tumor types. However, identifying patients who will respond to these drugs remains challenging, particularly in the context of advanced and previously treated cancers.

Experimental Design:
We characterized fresh tumor biopsies from a heterogeneous pan-cancer cohort of 98 patients with metastatic predominantly pretreated disease through the Personalized OncoGenomics program at BC Cancer (Vancouver, Canada) using whole genome and transcriptome analysis (WGTA). Baseline characteristics and follow-up data were collected retrospectively.

Results:
We found that tumor mutation burden, independent of mismatch repair status, was the most predictive marker of time to progression (P = 0.007), but immune-related CD8+ T-cell and M1-M2 macrophage ratio scores were more predictive for overall survival (OS; P = 0.0014 and 0.0012, respectively). While CD274 [programmed death-ligand 1 (PD-L1)] gene expression is comparable with protein levels detected by IHC, we did not observe a clinical benefit for patients with this marker. We demonstrate that a combination of markers based on WGTA provides the best stratification of patients (P = 0.00071, OS), and also present a case study of possible acquired resistance to pembrolizumab in a patient with non–small cell lung cancer.

Conclusions:
Interpreting the tumor-immune interface to predict ICI efficacy remains challenging. WGTA allows for identification of multiple biomarkers simultaneously that in combination may help to identify responders, particularly in the context of a heterogeneous population of advanced and previously treated cancers, thus precluding tumor type–specific testing.
Tamoxifen Accelerates Endothelial Healing by Targeting ERα in Smooth Muscle Cells
Authors: Zahreddine Rana , Davezac Morgane , Smirnova Natalia , Buscato Melissa , Lhuillier Emeline , Lupieri Adrien , Solinhac Romain , Vinel Alexia , Vessieres Emilie , Henrion Daniel , Renault Marie-Ange , Gadeau Alain-Pierre , Flouriot Gilles , Lenfant Françoise , Laffargue Muriel , Métivier Raphaël , Arnal Jean-François , Fontaine Coralie 
Published: October 2020

Rationale:
Tamoxifen prevents the recurrence of breast cancer and is also beneficial against bone demineralization and arterial diseases. It acts as an ER (estrogen receptor) α antagonist in ER-positive breast cancers, whereas it mimics the protective action of 17β-estradiol in other tissues such as arteries. However, the mechanisms of these tissue-specific actions remain unclear.

Objective:
Here, we tested whether tamoxifen is able to accelerate endothelial healing and analyzed the underlying mechanisms.

Methods and Results:
Using 3 complementary mouse models of carotid artery injury, we demonstrated that both tamoxifen and estradiol accelerated endothelial healing, but only tamoxifen required the presence of the underlying medial smooth muscle cells. Chronic treatment with 17β-estradiol and tamoxifen elicited differential gene expression profiles in the carotid artery. The use of transgenic mouse models targeting either whole ERα in a cell-specific manner or ERα subfunctions (membrane/extranuclear versus genomic/transcriptional) demonstrated that 17β-estradiol-induced acceleration of endothelial healing is mediated by membrane ERα in endothelial cells, while the effect of tamoxifen is mediated by the nuclear actions of ERα in smooth muscle cells.

Conclusions:
Whereas tamoxifen acts as an antiestrogen and ERα antagonist in breast cancer but also on the membrane ERα of endothelial cells, it accelerates endothelial healing through activation of nuclear ERα in smooth muscle cells, inviting to revisit the mechanisms of action of selective modulation of ERα.
Long-Term Results of the RAPCO Trials
Authors: Buxton Brian F. , Hayward Philip A. , Raman Jai , Moten Simon C. , Rosalion Alexander , Gordon Ian , Seevanayagam Siven , Matalanis George , Benedetto Umberto , Gaudino Mario , Hare David L. , Gaer Jullien , Negri Justin , Komeda Masashi , Bellomo Rinaldo , Doolan Laurie , McNicol Larry , Brennan John , Chan Robert , Clark David , Dick Ronald , Dortimer Anthony , Ecclestone David , Farouque Omar , Fernando Dharsh , Horrigan Mark , Jackson Anthony , Oliver Leslie , Mehta Nilesh , Nadurata Voltaire , Nadarajah Nim , Proimos George , Rowe Michael , Sia Ben , Webb Christopher , Anaveker Nagesh , Barlis Peter , Calafiore Paul , Chan Boniface , Cotroneo John , Johns Jennifer , Jones Elizabeth , Kertes Paul , O’Donnell David , Sylviris Stephen , Tonkin Anew , Fabini Robert , Kearney Leighton , Lim Ruth , Molan Maurice , Smith Gerard , Wellman Chris , Eng John , Hameed Irbaz , Shaw Margaret , Gerbo Sana 
Published: October 2020

Background:
An internal thoracic artery graft to the left anterior descending artery is standard in coronary bypass surgery, but controversy exists on the best second conduit. The RAPCO trials (Radial Artery Patency and Clinical Outcomes) were designed to compare the long-term patency of the radial artery (RA) with that of the right internal thoracic artery (RITA) and the saphenous vein (SV).

Methods:
In RAPCO-RITA (the RITA versus RA arm of the RAPCO trial), 394 patients <70 years of age (or <60 years of age if they had diabetes mellitus) were randomized to receive RA or free RITA graft on the second most important coronary target. In RAPCO-SV (the SV versus RA arm of the RAPCO trial), 225 patients ≥70 years of age (or ≥60 years of age if they had diabetes mellitus) were randomized to receive RA or SV graft. The primary outcome was 10-year graft failure. Long-term mortality was a nonpowered coprimary end point. The main analysis was by intention to treat.

Results:
In the RA versus RITA comparison, the estimated 10-year patency was 89% for RA versus 80% for free RITA (hazard ratio for graft failure, 0.45 [95% CI, 0.23–0.88]). Ten-year patient survival estimate was 90.9% in the RA arm versus 83.7% in the RITA arm (hazard ratio for mortality, 0.53 [95% CI, 0.30–0.95]). In the RA versus SV comparison, the estimated 10-year patency was 85% for the RA versus 71% for the SV (hazard ratio for graft failure, 0.40 [95% CI, 0.15–1.00]), and 10-year patient survival estimate was 72.6% for the RA group versus 65.2% for the SV group (hazard ratio for mortality, 0.76 [95% CI, 0.47–1.22]).

Conclusions:
The 10-year patency rate of the RA is significantly higher than that of the free RITA and better than that of the SV.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT00475488.