bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recent adverse mortality trends in Scotland: comparison with other high-income countries
Authors: Fenton Lynda , Minton Jon , Ramsay Julie , Kaye-Bardgett Maria , Fischbacher Colin , Wyper Grant M A , McCartney Gerry 
Published: November 2019

ObjectiveGains in life expectancy have faltered in several high-income countries in recent years. Scotland has consistently had a lower life expectancy than many other high-income countries over the past 70 years. We aim to compare life expectancy trends in Scotland to those seen internationally and to assess the timing and importance of any recent changes in mortality trends for Scotland.SettingAustria, Croatia, Czech Republic, Denmark, England and Wales, Estonia, France, Germany, Hungary, Iceland, Israel, Japan, Korea, Latvia, Lithuania, Netherlands, Northern Ireland, Poland, Scotland, Slovakia, Spain, Sweden, Switzerland and USA.MethodsWe used life expectancy data from the Human Mortality Database (HMD) to calculate the mean annual life expectancy change for 24 high-income countries over 5-year periods from 1992 to 2016. Linear regression was used to assess the association between life expectancy in 2011 and mean life expectancy change over the subsequent 5 years. One-break and two-break segmented regression models were used to test the timing of mortality rate changes in Scotland between 1990 and 2018.ResultsMean improvements in life expectancy in 2012–2016 were smallest among women (<2 weeks/year) in Northern Ireland, Iceland, England and Wales, and the USA and among men (<5 weeks/year) in Iceland, USA, England and Wales, and Scotland. Japan, Korea and countries of Eastern Europe had substantial gains in life expectancy over the same period. The best estimate of when mortality rates changed to a slower rate of improvement in Scotland was the year to 2012 quarter 4 for men and the year to 2014 quarter 2 for women.ConclusionsLife expectancy improvement has stalled across many, but not all, high-income countries. The recent change in the mortality trend in Scotland occurred within the period 2012–2014. Further research is required to understand these trends, but governments must also take timely action on plausible contributors.
Effects of physical activity and sedentary behaviour on cardiometabolic risk factors and cognitive function in children: protocol for a cohort study
Authors: Lv Yajie , Cai Li , Gui Zhaohuan , Zeng Xia , Tan Minyi , Wan Nianqing , Lai Lijuan , Lu Shaomin , Tan Weiqing , Chen Yajun 
Published: November 2019

IntroductionAlthough studies showed that physical activity (PA) and sedentary behaviour (SB) were associated with cardiometabolic risk factors and cognitive function, both independent and combined associations among them are inconsistent. Cardiometabolic risk factors are also associated with cognitive function, but research of children is limited. Additionally, the brain level mechanisms have not been fully established. The proposed study aims to explore the associations and mechanisms of PA and SB on cognitive function and cardiometabolic risk factors in children.Methods and analysisThis is a school-based prospective cohort study. A total of 8324 participants of this study are primary school students aged 7–12 years old who are followed up every 2 years from January 2017 to December 2026. We used a stratified cluster random sampling to select five primary schools in Guangzhou, China. There are three phases at baseline. At phase I, we collect PA, SB and cognitive function by questionnaires and also conduct anthropometric and biochemical measurements in all participants. At phase II, PA, SB and cognitive function are measured respectively by accelerometers and cognitive tasks among participants randomly selected from four subgroups with different SB and PA levels. At phase III, event-related potentials are recorded using electroencephalogram during a cognitive task among participants randomly selected from phase II. We plan to follow-up all participants until they graduate from high school. The process applied at baseline and follow-up are approximately identical.Ethics and disseminationProcedures described in this manuscript have been approved by the Ethical Review Committee for Biomedical Research, School of Public Health, Sun Yat-sen University (L2016-010). All parents or guardians of participants signed the informed consent form voluntarily before participating in the study. The findings of the study will be published in peer-reviewed journals.Trial registration numberNCT03582709
IntronicSMCHD1variants in FSHD: testing the potential for CRISPR-Cas9 genome editing
Authors: Goossens Remko , van den Boogaard Marlinde L , Lemmers Richard J L F , Balog Judit , van der Vliet Patrick J , Willemsen Iris M , Schouten Julie , Maggio Ignazio , van der Stoep Nienke , Hoeben Rob C , Tapscott Stephen J , Geijsen Niels , Gonçalves Manuel A F V , Sacconi Sabrina , Tawil Rabi , van der Maarel Silvère M 
Published: November 2019

BackgroundFacioscapulohumeral dystrophy (FSHD) is associated with partial chromatin relaxation of theDUX4retrogene containing D4Z4 macrosatellite repeats on chromosome 4, and transcriptional de-repression ofDUX4in skeletal muscle. The common form of FSHD, FSHD1, is caused by a D4Z4 repeat array contraction. The less common form, FSHD2, is generally caused by heterozygous variants inSMCHD1.MethodsWe employed whole exome sequencing combined with Sanger sequencing to screen uncharacterised FSHD2 patients for extra-exonicSMCHD1mutations. We also used CRISPR-Cas9 genome editing to repair a pathogenic intronicSMCHD1variant from patient myoblasts.ResultsWe identified intronicSMCHD1variants in two FSHD families. In the first family, an intronic variant resulted in partial intron retention and inclusion of the distal 14 nucleotides of intron 13 into the transcript. In the second family, a deep intronic variant in intron 34 resulted in exonisation of 53 nucleotides of intron 34. In both families, the aberrant transcripts are predicted to be non-functional. Deleting the pseudo-exon by CRISPR-Cas9 mediated genome editing in primary and immortalised myoblasts from the index case of the second family restored wild-type SMCHD1 expression to a level that resulted in efficient suppression ofDUX4.ConclusionsThe estimated intronic mutation frequency of almost 2% in FSHD2, as exemplified by the two novel intronicSMCHD1variants identified here, emphasises the importance of screening for intronic variants inSMCHD1. Furthermore, the efficient suppression ofDUX4after restoring SMCHD1 levels by genome editing of the mutant allele provides further guidance for therapeutic strategies.
Computational quantification of patient-specific changes in ventricular dynamics associated with pulmonary hypertension
Authors: Finsberg Henrik , Xi Ce , Zhao Xiaodan , Tan Ju Le , Genet Martin , Sundnes Joakim , Lee Lik Chuan , Zhong Liang , Wall Samuel T. 
Published: November 2019

Pulmonary arterial hypertension (PAH) causes an increase in the mechanical loading imposed on the right ventricle (RV) that results in progressive changes to its mechanics and function. Here, we quantify the mechanical changes associated with PAH by assimilating clinical data consisting of reconstructed three-dimensional geometry, pressure, and volume waveforms, as well as regional strains measured in patients with PAH ( n = 12) and controls ( n = 6) within a computational modeling framework of the ventricles. Modeling parameters reflecting regional passive stiffness and load-independent contractility as indexed by the tissue active tension were optimized so that simulation results matched the measurements. The optimized parameters were compared with clinical metrics to find usable indicators associated with the underlying mechanical changes. Peak contractility of the RV free wall (RVFW) γRVFW,max was found to be strongly correlated and had an inverse relationship with the RV and left ventricle (LV) end-diastolic volume ratio (i.e., RVEDV/LVEDV) (RVEDV/LVEDV)+ 0.44, R2 = 0.77). Correlation with RV ejection fraction ( R2 = 0.50) and end-diastolic volume index ( R2 = 0.40) were comparatively weaker. Patients with with RVEDV/LVEDV > 1.5 had 25% lower γRVFW,max ( P < 0.05) than that of the control. On average, RVFW passive stiffness progressively increased with the degree of remodeling as indexed by RVEDV/LVEDV. These results suggest a mechanical basis of using RVEDV/LVEDV as a clinical index for delineating disease severity and estimating RVFW contractility in patients with PAH. NEW & NOTEWORTHY This article presents patient-specific data assimilation of a patient cohort and physical description of clinical observations.
Acute reduction in cerebral blood velocity on supine-to-stand transition increases postural instability in young adults
Authors: Fitzgibbon-Collins Laura K. , Noguchi Mamiko , Heckman George A. , Hughson Richard L. , Robertson Andrew D. 
Published: November 2019

We tested the hypothesis that transient deficits in cerebral blood flow are associated with postural sway. In 19 young, healthy adults, we examined the association between the drop in cerebral blood flow during supine-to-stand transitions, indexed by transcranial Doppler ultrasound [middle cerebral artery blood velocity at diastole (MCAdv)] and near-infrared spectroscopy [tissue saturation index (TSI)] and the center of pressure displacement while standing. Participants performed transitions under three conditions aimed at progressively increasing the drop in MCAdv, in a randomized order: 1) a control transition (Con); 2) a transition that coincided with deflation of bilateral thigh cuffs; and 3) a transition that coincided with both thigh-cuff deflation and 90 s of prior hyperventilation (HTC). The deficit in diastolic blood velocity (MCAdv deficit) was quantified as the difference between MCAdv and its preceding baseline value, summed over 10 s, beginning at the MCAdv nadir. Compared with Con, HTC led to greater drops in MCAdv ( P = 0.003) and TSI ( P < 0.001) at nadir. The MCAdv deficit was positively associated with the center of pressure displacement vector-average using repeated-measures correlation (repeated-measures correlation coefficient = 0.56, P < 0.001). An a posteriori analysis identified a sub-group of participants that showed an exaggerated increase in MCAdv deficit and greater postural instability in both the anterior-posterior ( P = 0.002) and medial-lateral ( P = 0.021) directions in response to the interventions. These findings support the theory that individuals who experience greater initial cerebral hypoperfusion on standing may be at a greater risk for falls. NEW & NOTEWORTHY Dizziness and risk for falls after standing might link directly to reduced delivery of oxygen to the brain. By introducing challenges that increased the drop in brain blood flow in healthy young adults, we have shown for the first time a direct link to greater postural instability. These results point to a need to measure cerebral blood flow and/or oxygenation after postural transitions in populations, such as older adults, to assist in fall risk assessment.
Modeling Tumor Evolutionary Dynamics to Predict Clinical Outcomes for Patients with Metastatic Colorectal Cancer: A Retrospective Analysis
Authors: Zhou Jiawei , Liu Yutong , Zhang Yubo , Li Quefeng , Cao Yanguang 
Published: November 2019

AbstractOver 50% of colorectal cancer patients develop resistance after a transient response to therapy. Understanding tumor resistance from an evolutionary perspective leads to better predictions of treatment outcomes. The objectives of this study were to develop a computational framework to analyze tumor longitudinal measurements and recapitulate the individual evolutionary dynamics in metastatic colorectal cancer (mCRC) patients. A stochastic modeling framework was developed to depict the whole spectrum of tumor evolution prior to diagnosis and during and after therapy. The evolutionary model was optimized using a nonlinear mixed effect (NLME) method based on the longitudinal measurements of liver metastatic lesions from 599 mCRC patients. The deterministic limits in the NLME model were applied to optimize the stochastic model for each patient. Cox proportional hazards models coupled with the least absolute shrinkage and selection operator (LASSO) algorithm were applied to predict patients' progression-free survival (PFS) and overall survival (OS). The stochastic evolutionary model well described the longitudinal profiles of tumor sizes. The evolutionary parameters optimized for each patient indicated substantial interpatient variability. The number of resistant subclones at diagnosis was found to be a significant predictor to survival, and the hazard ratios with 95% CI were 1.09 (0.79–1.49) and 1.54 (1.01–2.34) for patients with three or more resistant subclones. Coupled with several patient characteristics, evolutionary parameters strongly predict patients' PFS and OS. A stochastic computational framework was successfully developed to recapitulate individual patient evolutionary dynamics, which could predict clinical survival outcomes in mCRC patients.Significance:A data analysis framework depicts the individual evolutionary dynamics of mCRC patients and can be generalized to project patient survival outcomes.
Pharmacokinetics of Nilotinib in Pediatric Patients with Philadelphia Chromosome–Positive Chronic Myeloid Leukemia or Acute Lymphoblastic Leukemia
Authors: Hijiya Nobuko , Zwaan C. Michel , Rizzari Carmelo , Foà Robin , Abbink Floor , Lancaster Donna , Landman-Parker Judith , Millot Frédéric , Moppett John , Nelken Brigitte , Caterina Putti Maria , Tian Xianbin , Sinclair Karen , Santanastasio Helene , Buchbinder Aby , Kearns Pamela 
Published: November 2019

Abstract

Purpose:
We investigated nilotinib exposure in pediatric patients with chronic myeloid leukemia (CML) or Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) resistant to, relapsed on, refractory to, or intolerant of previous treatment.

Patients and Methods:
Fifteen patients (aged 1–&lt;18 years) with CML resistant to or intolerant of imatinib and/or dasatinib (n = 11) or Ph+ ALL relapsed on or refractory to standard therapy (n = 4) enrolled in this phase I study. Nilotinib (230 mg/m2 twice daily; equivalent to the adult 400-mg twice-daily dose) was administered orally in 12 or 24 cycles of 28 days. The primary objective was to characterize the pharmacokinetics of nilotinib in pediatric patients.

Results:
The area under the concentration–time curve at steady state was slightly lower in pediatric patients versus adults (14,751.4 vs. 17,102.9 ng/h/mL); the geometric mean ratio (GMR; pediatric:adult) was 0.86 [90% confidence interval (CI), 0.70–1.06]. Body surface area–adjusted systemic clearance was slightly higher in pediatric versus adult patients (GMR, 1.30; 90% CI, 1.04–1.62). Nilotinib was generally well tolerated. The most common adverse events were headache, vomiting, increased blood bilirubin, and rash. Three patients with CML achieved major molecular response, and three with Ph+ ALL achieved complete remission.

Conclusions:
Nilotinib 230 mg/m2 twice daily in pediatric patients provided a pharmacokinetics and safety profile comparable with the adult reference dose; clinical activity was demonstrated in both CML and Ph+ ALL. This dose is recommended for further evaluation in pediatric patients. The safety profile was consistent with that in adults.
Safety and Efficacy of Durvalumab and Tremelimumab Alone or in Combination in Patients with Advanced Gastric and Gastroesophageal Junction Adenocarcinoma
Authors: Kelly Ronan J. , Lee Jeeyun , Bang Yung-Jue , Almhanna Khaldoun , Blum-Murphy Mariela , Catenacci Daniel V.T. , Chung Hyun Cheol , Wainberg Zev A. , Gibson Michael K. , Lee Keun-Wook , Bendell Johanna C. , Denlinger Crystal S. , Chee Cheng Ean , Omori Takeshi , Leidner Rom , Lenz Heinz-Josef , Chao Yee , Rebelatto Marlon C. , Brohawn Philip Z. , He Peng , McDevitt Jennifer , Sheth Siddharth , Englert Judson M. , Ku Geoffrey Y. 
Published: November 2019

AbstractPurpose:This randomized, multicenter, open-label, phase Ib/II study assessed durvalumab and tremelimumab in combination or as monotherapy for chemotherapy-refractory gastric cancer or gastroesophageal junction (GEJ) cancer.Patients and Methods:Second-line patients were randomized 2:2:1 to receive durvalumab plus tremelimumab (arm A), or durvalumab (arm B) or tremelimumab monotherapy (arm C), and third-line patients received durvalumab plus tremelimumab (arm D). A tumor-based IFNγ gene signature was prospectively evaluated as a potential predictive biomarker in second- and third-line patients receiving the combination (arm E). The coprimary endpoints were objective response rate and progression-free survival (PFS) rate at 6 months.Results:A total of 113 patients were treated: 6 in phase Ib and 107 (arm A, 27; arm B, 24; arm C, 12; arm D, 25; arm E, 19) in phase II. Overall response rates were 7.4%, 0%, 8.3%, 4.0%, and 15.8% in the five arms, respectively. PFS rates at 6 months were 6.1%, 0%, 20%, 15%, and 0%, and 12-month overall survival rates were 37.0%, 4.6%, 22.9%, 38.8%, and NA, respectively. Treatment-related grade 3/4 adverse events were reported in 17%, 4%, 42%, 16%, and 11% of patients, respectively.Conclusions:Response rates were low regardless of monotherapy or combination strategies. No new safety signals were identified. Including use of a tumor-based IFNγ signature and change in baseline and on-treatment circulating tumor DNA are clinically feasible and may be novel strategies to improve treatment response in this difficult-to-treat population.
ATM Dysfunction in Pancreatic Adenocarcinoma and Associated Therapeutic Implications
Authors: Armstrong Samantha A. , Schultz Christopher W. , Azimi-Sadjadi Ariana , Brody Jonathan R. , Pishvaian Michael J. 
Published: November 2019

Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal solid malignancies with very few therapeutic options to treat advanced or metastatic disease. The utilization of genomic sequencing has identified therapeutically relevant alterations in approximately 25% of PDAC patients, most notably in the DNA damage response and repair (DDR) genes, rendering cancer cells more sensitive to DNA-damaging agents and to DNA damage response inhibitors, such as PARP inhibitors. ATM is one of the most commonly mutated DDR genes, with somatic mutations identified in 2% to 18% of PDACs and germline mutations identified in 1% to 34% of PDACs. ATM plays a complex role as a cell-cycle checkpoint kinase, regulator of a wide array of downstream proteins, and responder to DNA damage for genome stability. The disruption of ATM signaling leads to downstream reliance on ATR and CHK1, among other DNA-repair mechanisms, which may enable exploiting the inhibition of downstream proteins as therapeutic targets in ATM-mutated PDACs. In this review, we detail the function of ATM, review the current data on ATM deficiency in PDAC, examine the therapeutic implications of ATM alterations, and explore the current clinical trials surrounding the ATM pathway.
An Emerging Regulatory Role for the Tumor Microenvironment in the DNA Damage Response to Double-Strand Breaks
Authors: Lama-Sherpa Tshering D. , Shevde Lalita A. 
Published: November 2019

Abstract

Radiation, alkylating agents, and platinum-based chemotherapy treatments eliminate cancer cells through the induction of excessive DNA damage. The resultant DNA damage challenges the cancer cell's DNA repair capacity. Among the different types of DNA damage induced in cells, double-strand breaks (DSB) are the most lethal if left unrepaired. Unrepaired DSBs in tumor cells exacerbate existing gene deletions, chromosome losses and rearrangements, and aberrant features that characteristically enable tumor progression, metastasis, and drug resistance. Tumor microenvironmental factors like hypoxia, inflammation, cellular metabolism, and the immune system profoundly influence DSB repair mechanisms. Here, we put into context the role of the microenvironment in governing DSB repair mechanisms.
Androgen Receptor Interaction with Mediator Complex Is Enhanced in Castration-Resistant Prostate Cancer by CDK7 Phosphorylation of MED1
Authors: Russo Joshua W. , Nouri Mannan , Balk Steven P. 
Published: November 2019

Abstract

Summary:
In this issue of Cancer Discovery, Rasool and colleagues show that TF11H/CDK7 phosphorylates the MED1 component of the Mediator complex, which enhances its interaction with androgen receptor (AR), and that this phosphorylation is increased in prostate cancer that is resistant to castration and enzalutamide. A covalent CDK7-specific inhibitor (THZ1) impairs AR-mediated MED1 recruitment to chromatin, and can suppress enzalutamide resistance in vitro and induce tumor regression in a castration-resistant prostate cancer xenograft model, suggesting a novel therapeutic approach for advanced prostate cancer.
See related article by Rasool et al., p. 1538.
Harnessing Natural Killer Cell Antitumor Immunity: From the Bench to Bedside
Authors: Woan Karrune V. , Miller Jeffrey S. 
Published: November 2019

AbstractNatural killer (NK) cells are critical effector lymphocytes mediating tumor immune surveillance and clearance. They do so by direct tumor killing using cytolytic granules and death receptors, and by interfacing with and potentiating adaptive immune responses through the production of cytokines. From a therapeutic perspective, NK cells have been shown to exert graft-versus-leukemia activity in the context of hematopoietic stem cell transplantation and are important in the clinical efficacy of antibodies. Advances in basic and translational NK cell biology have led to multiple potential strategies to augment their in vivo activity to improve antitumor responses. Despite their potent effects, NK cells have been shown to be safe for adoptive cell therapy in both the autologous and allogeneic settings, with promising, but so far limited, clinical efficacy. This review will provide an overview of strategies being pursued to improve NK cell activity and efficacy, focusing on cell source, NK cell activation, and in vivo persistence.