bluuebunny/crossref_metadata_2025_split huggingface dataset:
On-target Resistance to the Mutant-Selective EGFR Inhibitor Osimertinib Can Develop in an Allele-Specific Manner Dependent on the Original EGFR-Activating Mutation
Authors: Brown Benjamin P. , Zhang Yun-Kai , Westover David , Yan Yingjun , Qiao Huan , Huang Vincent , Du Zhenfang , Smith Jarrod A. , Ross Jeffrey S. , Miller Vincent A. , Ali Siraj , Bazhenova Lyudmila , Schrock Alexa B. , Meiler Jens , Lovly Christine M. 
Published: February 2019

Abstract

Purpose:
The third-generation EGFR inhibitor, osimertinib, is the first mutant-selective inhibitor that has received regulatory approval for the treatment of patients with EGFR-mutant lung cancer. Despite the development of highly selective third-generation inhibitors, acquired resistance remains a significant clinical challenge. Recently, we and others have identified a novel osimertinib resistance mutation, G724S, which was not predicted in in vitro screens. Here, we investigate how G724S confers resistance to osimertinib.
Experimental Design: We combine structure-based predictive modeling of G724S in combination with the 2 most common EGFR-activating mutations, exon 19 deletion (Ex19Del) and L858R, with in vitro drug-response models and patient genomic profiling.

Results:
Our simulations suggest that the G724S mutation selectively reduces osimertinib-binding affinity in the context of Ex19Del. Consistent with our simulations, cell lines transduced with Ex19Del/G724S demonstrate resistance to osimertinib, whereas cells transduced with L858R/G724S are sensitive to osimertinib. Subsequent clinical genomic profiling data further suggest G724S occurs with Ex19Del but not L858R. Furthermore, we demonstrate that Ex19Del/G724S retains sensitivity to afatinib, but not to erlotinib, suggesting a possible therapy for patients at the time of disease relapse.

Conclusions:
Altogether, these data suggest that G724S is an allele-specific resistance mutation emerging in the context of Ex19Del but not L858R. Our results fundamentally reframe the problem of targeted therapy resistance from one focused on the “drug–resistance mutation” pair to one focused on the “activating mutation–drug–resistance mutation” trio. This has broad implications across clinical oncology.
MST1 Suppresses Pancreatic Cancer Progression via ROS-Induced Pyroptosis
Authors: Cui Jiujie , Zhou Zhuqing , Yang Haiyan , Jiao Feng , Li Ning , Gao Yong , Wang Liwei , Chen Jingde , Quan Ming 
Published: February 2019

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease, and its incidence is increasing annually. It is critical to reveal and delineate the molecular mechanism promoting PDAC development and progression. Mammalian STE20-like kinase 1 (MST1) is a proapoptotic cytoplasmic kinase and also one of the core components of the Hippo pathway. Here, we showed that MST1 expression was decreased in PDAC, and restored expression of MST1 promoted PDAC cell death and suppressed the proliferation, migration, invasion, and cell spheroid formation of PDAC via caspase-1–induced pyroptosis. Further studies demonstrated that pyroptosis induced by MST1 was independent of the Hippo pathway, but mediated by reactive oxygen species (ROS). And ROS scavenger N-acetyl-cysteine attenuated the activation of caspase-1 induced by MST1 and the effect of MST1 in PDAC cell death, proliferation, migration, and invasion. Collectively, our study demonstrated that MST1 suppressed the progression of PDAC cells at least partly through ROS-induced pyroptosis.

Implications:
In this study, we identified a new mechanism of MST1 in inhibiting PDAC development and progression and revealed that MST1 would be a potential prognostic and therapeutic target for PDAC.
The SIAH1–HIPK2–p53ser46 Damage Response Pathway is Involved in Temozolomide-Induced Glioblastoma Cell Death
Authors: He Yang , Roos Wynand P. , Wu Qianchao , Hofmann Thomas G. , Kaina Bernd 
Published: February 2019

Abstract

Patients suffering from glioblastoma have a dismal prognosis, indicating the need for new therapeutic targets. Here we provide evidence that the DNA damage kinase HIPK2 and its negative regulatory E3-ubiquitin ligase SIAH1 are critical factors controlling temozolomide-induced cell death. We show that HIPK2 downregulation (HIPK2kd) significantly reduces the level of apoptosis. This was not the case in glioblastoma cells expressing the repair protein MGMT, suggesting that the primary DNA lesion responsible for triggering HIPK2-mediated apoptosis is O6-methylguanine. Upon temozolomide treatment, p53 becomes phosphorylated whereby HIPK2kd had impact exclusively on ser46, but not ser15. Searching for the transcriptional target of p-p53ser46, we identified the death receptor FAS (CD95, APO-1) being involved. Thus, the expression of FAS was attenuated following HIPK2kd, supporting the conclusion that HIPK2 regulates temozolomide-induced apoptosis via p-p53ser46-driven FAS expression. This was substantiated in chromatin-immunoprecipitation experiments, in which p-p53ser46 binding to the Fas promotor was regulated by HIPK2. Other pro-apoptotic proteins such as PUMA, NOXA, BAX, and PTEN were not affected in HIPK2kd, and also double-strand breaks following temozolomide remained unaffected. We further show that downregulation of the HIPK2 inactivator SIAH1 significantly ameliorates temozolomide-induced apoptosis, suggesting that the ATM/ATR target SIAH1 together with HIPK2 plays a proapoptotic role in glioma cells exhibiting p53wt status. A database analysis revealed that SIAH1, but not SIAH2, is significantly overexpressed in glioblastomas.

Implications:
The identification of a novel apoptotic pathway triggered by the temozolomide-induced DNA damage O6-methylguanine supports the role of p53 in the decision between survival and death and suggests SIAH1 and HIPK2 as new therapeutic targets.
Screening Migrants in the Early Cold War: The Geopolitics of U.S. Immigration Policy
Authors: Verovšek Peter J. 
Published: February 2019

Abstract
The main elements of U.S. immigration policy date back to the early Cold War. One such element is a screening process initially designed to prevent infiltration by Communist agents posing as migrants from East-Central Europe. The development of these measures was driven by geopolitical concerns, resulting in vetting criteria that favored the admission of hardline nationalists and anti-Communists. The argument proceeds in two steps. First, the article demonstrates that geopolitics influenced immigration policy, resulting in the admission of extremist individuals. Second, it documents how geopolitical concerns and the openness of U.S. institutions provided exiles with the opportunity to mobilize politically. Although there is little evidence that the vetting system succeeded in preventing the entry of Communist subversives into the United States, it did help to create a highly mobilized anti-Communist ethnic lobby that supported extremist policies vis-à-vis the Soviet Union during the early Cold War.
Impacts of the North Atlantic Warming Hole in Future Climate Projections: Mean Atmospheric Circulation and the North Atlantic Jet
Authors: Gervais Melissa , Shaman Jeffrey , Kushnir Yochanan 
Published: February 2019

AbstractIn future climate simulations there is a pronounced region of reduced warming in the subpolar gyre of the North Atlantic Ocean known as the North Atlantic warming hole (NAWH). This study investigates the impact of the North Atlantic warming hole on atmospheric circulation and midlatitude jets within the Community Earth System Model (CESM). A series of large-ensemble atmospheric model experiments with prescribed sea surface temperature (SST) and sea ice are conducted, in which the warming hole is either filled or deepened. Two mechanisms through which the NAWH impacts the atmosphere are identified: a linear response characterized by a shallow atmospheric cooling and increase in sea level pressure shifted slightly downstream of the SST changes, and a transient eddy forced response whereby the enhanced SST gradient produced by the NAWH leads to increased transient eddy activity that propagates vertically and enhances the midlatitude jet. The relative contributions of these two mechanisms and the details of the response are strongly dependent on the season, time period, and warming hole strength. Our results indicate that the NAWH plays an important role in midlatitude atmospheric circulation changes in CESM future climate simulations.
A Climatology of Extratropical Cyclones Leading to Extreme Weather Events over Central and Eastern North America
Authors: Bentley Alicia M. , Bosart Lance F. , Keyser Daniel 
Published: February 2019

Abstract
Cool-season extreme weather events (EWEs) (i.e., high-impact weather events that are societally disruptive, geographically widespread, exceptionally prolonged, and climatologically infrequent) are typically associated with strong extratropical cyclones (ECs). The opportunity to investigate the genesis locations, tracks, and frequencies of ECs leading to EWEs over central and eastern North America and compare them to those of ordinary ECs forming over and traversing the same region motivates this study. ECs leading to EWEs are separated from ordinary ECs according to the magnitude, areal extent, and duration of their 925-hPa standardized wind speed anomalies in the 0.5° NCEP CFSR dataset. This separation allows for the construction of an October–March 1979–2016 climatology of ECs leading to EWEs over central and eastern North America. The climatology of ECs leading to EWEs over central and eastern North America reveals that these ECs typically form in the lee of the Rocky Mountains, over the south-central United States, and along the east coast of North America at latitudes equatorward of the typical genesis locations of ordinary ECs. ECs leading to EWEs exhibit equatorward-shifted tracks relative to ordinary ECs, likely associated with an equatorward shift in the position of the subtropical or polar-front jet. ECs leading to EWEs form most frequently in November and March, when the seasonal alignment of baroclinic and diabatic forcings is maximized. Similar to ordinary ECs, the genesis locations, tracks, and frequencies of ECs leading to EWEs are partially determined by the states of the Pacific–North American pattern and North Atlantic Oscillation.
Commercially Available Friction-Reducing Patient-Transfer Devices Reduce Biomechanical Stresses on Caregivers’ Upper Extremities and Low Back
Authors: Hwang Jaejin , Kuppam Veera Aneesh , Chodraju Subhramanya Suryanarayana Raju , Chen Jie , Kim Jeong Ho 
Published: February 2019

Objective: The aim of this study was to evaluate the efficacy of commercially available friction-reducing patient-transfer devices in reducing biomechanical stresses on caregivers and patients. Background: Caregivers suffer from high prevalence of work-related musculoskeletal disorders, which is associated with manual patient handling. However, there is not enough information available on the efficacy of various friction-reducing devices in reducing biomechanical stresses in the upper extremities and low back. Method: During patient-transfer tasks performed by 20 caregivers, we measured hand force; shoulder and trunk posture; shoulder moment; muscle activity in the flexor digitorum superficialis, extensor digitorum communis, biceps, triceps, trapezius, and erector spinae; and usability ratings from four devices: a draw sheet, a repositioning sheet, a slide board, and an air-assisted device. In addition, triaxial head acceleration of mock patients was measured to evaluate patients’ head acceleration. Results: The slide board and air-assisted device significantly reduced hand force ( p < .001), shoulder flexion ( p < .001), shoulder moment ( p < .001), muscle activities of caregivers ( p < .004), and patients’ head acceleration ( p < .023) compared with the draw sheet. However, no significant differences in biomechanical measures were found between the repositioning and draw sheets. The air-assisted device consistently showed the lowest biomechanical stresses and was most preferred by participants. Conclusion: Reduction in caregivers’ biomechanical stresses and mock patients’ head acceleration indicates that a slide board and an air-assisted device can be effective engineering controls to reduce risk of injury. Application: The study results can provide a recommendation for engineering controls to reduce biomechanical stresses for both caregivers and patients.
The Incomplete Medicalization of Obesity: Physician Office Visits, Diagnoses, and Treatments, 1996-2014
Authors: Ciciurkaite Gabriele , Moloney Mairead Eastin , Brown Robyn Lewis 
Published: February 2019

Objectives: Despite increased awareness of obesity-related health risks and myriad treatment options, obesity still affects more than one-third of persons in the United States and is a substantial public health problem. Studies show that physicians play a key role in obesity prevention and treatment. The objective of this study was to examine the extent to which obesity is diagnosed and treated at the level of patient-physician interaction. Methods: We used data from the National Ambulatory Medical Care Survey (NAMCS), a nationally representative data set of US physician office visits. We estimated the number of obesity diagnoses and prescriptions of weight-loss management solutions (exercise counseling, diet counseling, or weight-loss drugs) in clinical practice from 1996 through 2014. We also calculated rates of obesity diagnosis and compared these rates with national rates of obesity based on body mass index data from the Behavioral Risk Factor Surveillance System (BRFSS) for the same period. Results: The estimated number of weight gain–related physician office visits increased from 2.3 million in 1996 to a peak of 7.6 million in 2012, and then fell to 4.5 million in 2014. National estimates of obesity diagnoses resulting from physician office visits ranged from 7.1 million in 1996 to 12.7 million in 2014 and substantially outnumbered the estimates for weight gain–related physician office visits throughout the study period. Estimates of exercise counseling and diet counseling and weight-loss medication prescriptions resulting from physician office visits fluctuated over time but never exceeded obesity diagnoses. When compared with national rates of obesity from the BRFSS, rates of obesity diagnoses resulting from physician office visits were substantially lower in the NAMCS (17%-30% vs 1%). National trends for weight-loss medication prescriptions closely mirrored those of weight gain–related physician office visits, even though fluctuations were substantial. Conclusions: Our results suggest that obesity is largely underdiagnosed and undertreated in clinical encounters. Future studies should investigate the structural changes needed to better engage physicians in obesity prevention and care. Practitioners should also reflect on their biases in treating obesity as a chronic disease.
A therapeutic songwriting intervention to promote reconstruction of self-concept and enhance well-being following brain or spinal cord injury: pilot randomized controlled trial
Authors: Baker Felicity A , Tamplin Jeanette , Rickard Nikki , Ponsford Jennie , New Peter W , Lee Young-Eun C 
Published: February 2019

Objective: To determine the size of the effects and feasibility (recruitment and retention rates) of a therapeutic songwriting protocol for in-patients and community-dwelling people with acquired brain injury or spinal cord injury. Design: Randomized controlled trial with songwriting intervention and care-as-usual control groups, in a mixed measures design assessed at three time points. Participants: A total of 47 participants (3 in-patients with acquired brain injury, 20 community participants with acquired brain injury, 12 in-patients with spinal cord injury, and 12 community participants with spinal cord injury: 23 1208 days post injury). Interventions: The intervention group received a 12-session identity-targeted songwriting programme, where participants created three songs reflecting on perceptions of past, present, and future self. Control participants received care as usual. Measures: Baseline, postintervention, and follow-up measures comprised the Head Injury Semantic Differential Scale (primary outcome measure), Patient Health Questionnaire-9, Emotion Regulation Questionnaire, and Satisfaction with Life Scale. Results: No significant between group pre–post intervention differences were found on the primary self-concept measure, the Head Injury Semantic Differential Scale ( p = 0.38, d = 0.44). Significant and large effect sizes from baseline to post between groups in favour of the songwriting group for Satisfaction with Life ( p = 0.04, n2 p = 0.14). There were no significant between group pre-post interaction effects for the Emotion Regulation Suppression subscale ( p = 0.12, n2 p = –0.08) although scores decreased in the songwriting group over time while increasing for the standard care group. There were no significant differences in baseline to follow-up between groups in any other outcome measures. Recruitment was challenging due to the small number of people eligible to participate combined with poor uptake by eligible participants, particularly the in-patient group. Retention rates were higher for the community-dwelling cohorts. Conclusion: This study demonstrates the challenges in recruitment and retention of participants invited to participate in a music therapy study. Findings suggest this identity-focused therapeutic songwriting protocols may be more beneficial for people who have transitioned from in-patient to community-contexts given the greater proportion of participants who consent and complete the intervention. Preliminary effects in favour of the intervention group were detected in a range of well-being measures suggesting that a larger study is warranted.
Definitive radiotherapy for recurrent vulvar carcinoma after primary surgery: a two-institutional Italian experience
Authors: Laliscia Concetta , Gadducci Angiolo , Fabrini Maria Grazia , Barcellini Amelia , Parietti Emanuela , Pasqualetti Francesco , Morganti Riccardo , Mazzotti Valentina , Cafaro Ines , Paiar Fabiola 
Published: February 2019

Objective: To assess the clinical outcome of patients treated with radiotherapy (RT) for recurrent squamous cell carcinoma of the vulva after primary surgery. Methods: Fifty-six patients developed recurrent disease after surgery, consisting of deep total vulvectomy with inguino-femoral lymphadenectomy in 44 (78.6%) and deep partial vulvectomy with inguino-femoral lymphadenectomy in 12 (21.4%). All patients underwent RT at the Divisions of Radiotherapy, University of Pisa and ASST Cremona, between 1992 and 2016. Forty-three patients (76.8%) underwent external beam RT and 13 (23.2%) were treated with exclusive high-dose rate brachytherapy. Results: Five-year progression-free survival (PFS) and overall survival (OS) were 19% and 43%, respectively. Primary tumor size ⩽4 cm, early FIGO stage, and negative lymph node status were significantly associated with better PFS ( p = .005, p = .020 and p = .036, respectively) and OS ( p < .0001, p = .023 and p = .008, respectively). Patients with more than 1 positive lymph node at primary surgery had significantly worse PFS ( p = .028) and OS ( p = .001). Patients with local recurrence had significantly better PFS and OS ( p = .022, p = .002, respectively). RT total dose >54 Gy was associated with a lower risk of recurrence. Conclusions: Primary tumor size, FIGO stage, nodal status, and site of recurrent disease were significant predictors of clinical outcome in patients treated with RT for recurrent squamous cell carcinoma of the vulva.
La négociation identitaire des personnes âgées dans un contexte de mobilité. Le cas des voyages en train
Authors: Welté Jean-Baptiste 
Published: February 2019

Résumé Cette recherche vise à comprendre le processus de négociation identitaire vécue par les personnes âgées. Le vieillissement s’accompagne des limites croissantes. Les personnes âgées doivent également négocier avec l’image sociale du vieillissement. Elles éprouvent cette négociation identitaire de manière emblématique en situation de mobilité. La recherche menée à partir d’une méthodologie ethnographique des voyages en train identifie quatre stratégies de négociation identitaire pour les personnes âgées : celle du fatalisme stoïque, de l’acceptation opportuniste, de l’appropriation valorisante, et de l’adéquation similaire. Ces quatre stratégies peuvent se retrouver chez une même personne au cours d’un même voyage. Elles sont ensuite discutées avec le concept de bien vieillir.
Hemostatic wound dressings: Predicting their effects by in vitro tests
Authors: Wiegand Cornelia , Abel Martin , Hipler Uta-Christina , Elsner Peter , Zieger Michael , Kurz Julia , Wendel Hans P , Stoppelkamp Sandra 
Published: February 2019

Background Application of controlled in vitro techniques can be used as a screening tool for the development of new hemostatic agents allowing quantitative assessment of overall hemostatic potential. Materials and methods Several tests were selected to evaluate the efficacy of cotton gauze, collagen, and oxidized regenerated cellulose for enhancing blood clotting, coagulation, and platelet activation. Results Visual inspection of dressings after blood contact proved the formation of blood clots. Scanning electron microscopy demonstrated the adsorption of blood cells and plasma proteins. Significantly enhanced blood clot formation was observed for collagen together with β-thromboglobulin increase and platelet count reduction. Oxidized regenerated cellulose demonstrated slower clotting rates not yielding any thrombin generation; yet, led to significantly increased thrombin-anti-thrombin-III complex levels compared to the other dressings. As hemostyptica ought to function without triggering any adverse events, induction of hemolysis, instigation of inflammatory reactions, and initiation of the innate complement system were also tested. Here, cotton gauze provoked high PMN elastase and elevated SC5b-9 concentrations. Conclusions A range of tests for desired and undesired effects of materials need to be combined to gain some degree of predictability of the in vivo situation. Collagen-based dressings demonstrated the highest hemostyptic properties with lowest adverse reactions whereas gauze did not induce high coagulation activation but rather activated leukocytes and complement.
Prevalence of multiple sclerosis in Sardinia: A systematic cross-sectional multi-source survey
Authors: Urru Silvana AM , Antonelli Antonello , Sechi Giuseppe M ,   MS Working Group
Published: February 2019

Background: Partial surveys in sub-regions of Sardinia have suggested a high prevalence of multiple sclerosis (MS) on the island, relative to other Mediterranean populations. We assessed the island-wide prevalence of MS and its detailed distribution in Sardinia. Methods: The study population consisted of 5677 MS patients, 1735 men and 3942 women, living in Sardinia. Neurologists retrospectively examined electronic and paper-based records of patients with a diagnosis of MS. The data were then linked to the administrative health information systems. Crude, age-, and sex-specific prevalence estimates of disease were calculated. Results: The overall age-adjusted MS prevalence was 330 per 100,000 (95% confidence interval (CI) 321–338) in individuals older than 15 years, 447 in women (95% CI 433–461), and 205 in men (95% CI 195–214). The prevalence was highest in the Ogliastra and Nuoro districts, respectively, 425 (95% CI 372–478) and 419 (95% CI 387–451), and lowest in the Olbia-Tempio district, 217 (95% CI 195–239). Most cases had relapsing–remitting MS (79.3%), 16.3% had secondary-progressive MS, and 4.4% had primary-progressive MS. Conclusion: These prevalence are among the highest reported so far worldwide. They provide estimates for comparative analyses in other populations and are essential for public health interventions.