bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immune Cell–Poor Melanomas Benefit from PD-1 Blockade after Targeted Type I IFN Activation
Authors: Bald Tobias , Landsberg Jennifer , Lopez-Ramos Dorys , Renn Marcel , Glodde Nicole , Jansen Philipp , Gaffal Evelyn , Steitz Julia , Tolba Rene , Kalinke Ulrich , Limmer Andreas , Jönsson Göran , Hölzel Michael , Tüting Thomas 
Published: March 2014

Abstract
Infiltration of human melanomas with cytotoxic immune cells correlates with spontaneous type I IFN activation and a favorable prognosis. Therapeutic blockade of immune-inhibitory receptors in patients with preexisting lymphocytic infiltrates prolongs survival, but new complementary strategies are needed to activate cellular antitumor immunity in immune cell–poor melanomas. Here, we show that primary melanomas in Hgf-Cdk4R24C mice, which imitate human immune cell–poor melanomas with a poor outcome, escape IFN-induced immune surveillance and editing. Peritumoral injections of immunostimulatory RNA initiated a cytotoxic inflammatory response in the tumor microenvironment and significantly impaired tumor growth. This critically required the coordinated induction of type I IFN responses by dendritic, myeloid, natural killer, and T cells. Importantly, antibody-mediated blockade of the IFN-induced immune-inhibitory interaction between PD-L1 and PD-1 receptors further prolonged the survival. These results highlight important interconnections between type I IFNs and immune-inhibitory receptors in melanoma pathogenesis, which serve as targets for combination immunotherapies.
Significance: Using a genetically engineered mouse melanoma model, we demonstrate that targeted activation of the type I IFN system with immunostimulatory RNA in combination with blockade of immune-inhibitory receptors is a rational strategy to expose immune cell–poor tumors to cellular immune surveillance. Cancer Discov; 4(6); 674–87. ©2014 AACR.
This article is highlighted in the In This Issue feature, p. 621
Efficacy of Intermittent Combined RAF and MEK Inhibition in a Patient with Concurrent BRAF- and NRAS-Mutant Malignancies
Authors: Abdel-Wahab Omar , Klimek Virginia M. , Gaskell Alisa A. , Viale Agnes , Cheng Donavan , Kim Eunhee , Rampal Raajit , Bluth Mark , Harding James J. , Callahan Margaret K. , Merghoub Taha , Berger Michael F. , Solit David B. , Rosen Neal , Levine Ross L. , Chapman Paul B. 
Published: March 2014

Abstract
Vemurafenib, a RAF inhibitor, extends survival in patients with BRAFV600-mutant melanoma but activates extracellular signal–regulated kinase (ERK) signaling in RAS-mutant cells. In a patient with a BRAFV600K-mutant melanoma responding to vemurafenib, we observed accelerated progression of a previously unrecognized NRAS-mutant leukemia. We hypothesized that combining vemurafenib with a MAP–ERK kinase (MEK) inhibitor would inhibit ERK activation in the melanoma and prevent ERK activation by vemurafenib in the leukemia, and thus suppress both malignancies. We demonstrate that intermittent administration of vemurafenib led to a near-complete remission of the melanoma, and the addition of the MEK inhibitor cobimetinib (GDC-0973) caused suppression of vemurafenib-induced leukemic proliferation and ERK activation. Antimelanoma and antileukemia responses have been maintained for nearly 20 months, as documented by serial measurements of tumor-derived DNA in plasma in addition to conventional radiographic and clinical assessments of response. These data support testing of intermittent ERK pathway inhibition in the therapy for both RAS-mutant leukemia and BRAF-mutant melanoma.
Significance: We show that in a patient with simultaneous RAS-mutant leukemia and BRAF-mutant melanoma, intermittent RAF inhibitor therapy induced a near-complete melanoma response, and addition of a MEK inhibitor prevented RAF inhibitor-induced activation of the RAS-mutant leukemia. Intermittent therapy may permit greater pathway inhibition with less toxicity, avoid chronic relief of pathway feedback, and have enhanced effectiveness compared with chronic administration. Cancer Discov; 4(5); 538–45. ©2014 AACR.
See related commentary by Davies, p. 510
This article is highlighted in the In This Issue feature, p. 495
Physical activity among older people living alone in Shanghai, China
Authors: Chen Yu , While Alison E , Hicks Allan 
Published: March 2014

Objective: To investigate physical activity among older people living alone in Shanghai, People’s Republic of China, and key factors contributing to their physical activity. Methods: A cross-sectional questionnaire survey was administered in nine communities in Shanghai, using a stratified random cluster sample: 521 community-dwelling older people living alone (aged 60 years and above) completed a structured questionnaire through face-to-face interviews. Their physical activity was measured using their self-reported frequency of engaging in different types of activities. Other data collected included self-rated health, number of chronic diseases, depression, functional ability, loneliness, social support and socio-demographic variables. Results: Only 16.7% of participants reported adequate physical activity, defined as performing at least 30 minutes of moderate/strenuous exercise on at least 5 days per week. A younger age, a lower level of education, better functional ability and walking outside the home 5 – 7 days per week increased the likelihood of adequate physical activity. Gender, self-rated health, number of chronic diseases, depression and social support also had relationships with physical activity levels. Conclusion: The prevalence of adequate physical activity in older people living alone in Shanghai was low. In this population, appropriate health education interventions to promote physical activity levels are needed.
Increased Slope of the Lateral Tibial Plateau Subchondral Bone Is Associated With Greater Risk of Noncontact ACL Injury in Females but Not in Males
Authors: Beynnon Bruce D. , Hall John S. , Sturnick Daniel R. , DeSarno Mike J. , Gardner-Morse Mack , Tourville Timothy W. , Smith Helen C. , Slauterbeck James R. , Shultz Sandra J. , Johnson Robert J. , Vacek Pamela M. 
Published: March 2014

Background: There is an emerging consensus that increased posterior-inferior directed slope of the subchondral bone portion of the tibial plateau is associated with increased risk of suffering an anterior cruciate ligament (ACL) injury; however, most of what is known about this relationship has come from unmatched case-control studies. These observations need to be confirmed in more rigorously designed investigations. Hypothesis: Increased posterior-inferior directed slope of the medial and lateral tibial plateaus are associated with increased risk of suffering a noncontact ACL injury. Study Design: Case-control study; Level of evidence, 3. Methods: In sum, 176 athletes competing in organized sports at the college and high school levels participated in the study: 88 suffering their first noncontact ACL injury and 88 matched controls. Magnetic resonance images were acquired, and geometry of the subchondral bone portion of the tibial plateau was characterized on each athlete bilaterally by measuring the medial and lateral tibial plateau slopes, coronal tibial slope, and the depth of the medial tibial plateau. Comparisons between knees of the same person were made with paired t tests, and associations with injury risk were assessed by conditional logistic regression analysis of ACL-injured and control participants. Results: Controls exhibited side-to-side symmetry of subchondral bone geometry, while the ACL-injured athletes did not, suggesting that the ACL injury may have changed the subchondral bone geometry. Therefore, the uninjured knees of the ACL-injured athletes and the corresponding limbs of their matched controls were used to assess associations with injury risk. Analyses of males and females as a combined group and females as a separate group showed a significant association between ACL injury risk and increased posterior-inferior directed slope of the lateral tibial plateau slope. This relationship was not apparent when males were analyzed as a group. Multivariate analyses indicated that these results were independent of the medial tibial plateau slope, coronal tibial slope, and depth of the medial tibial plateau, which were not associated with ACL injury. Conclusion: There is a 21.7% increased risk of noncontact ACL injury with each degree increase of the lateral tibial plateau slope among females but not among males. The medial tibial plateau slope, coronal tibial slope, and depth of the medial tibial plateau were not associated with risk of injury for females or males.
Inhibition of cellular transdifferentiation by losartan minimizes but does not reverse type 2 diabetes-induced renal fibrosis
Authors: Arnoni Carine P , Maquigussa Edgar , Passos Clévia S , Pereira Luciana G , Boim Mirian A 
Published: March 2014

Hypothesis/Introduction: Transformer Growth Factor (TGF-β1) and angiotensin II (AngII) induce epithelial mesenchymal transition (EMT) and myofibroblastic transdifferentiation (MFT) contributing to renal fibrosis. The present study evaluated the capacity of an AT1 receptor blocker (losartan) to induce the regression of pre-existing fibrosis via interference with MFT and EMT in a rat model of type 2 diabetes, and in cultured mesangial cells (MCs) stimulated with high glucose and AngII. Materials and methods: After 12 weeks of diabetes induction (D12 group), animals showing evidence of nephropathy, were divided in groups untreated for additional 8 weeks (D20 group) and treated for additional 8 weeks with losartan (D20+los group). Results: D12 animals presented hyperglycemia, insulin resistance, hypertension, proteinuria, increased levels of TGF-β1 and MFT/EMT markers. Losartan stabilized all of these parameters and hindered the progression of fibrosis, but it did not reverse the pre-existing fibrotic manifestations. Losartan reduced TGF-β1 in the tubules, but not in the glomeruli. Stimulated MC exhibited myofibroblast phenotype and capacity for migration, which were completely reversed by losartan. Conclusions: Cellular transition may play a role in diabetes-inducing renal fibrogenesis in both AngII-TGF-β1 axis-dependent and independent manners. Losartan was efficient in preventing cells from undergoing further transdifferentiation, but this strategy was not sufficient to induce regression of the pre-existing tissue fibrosis.
Implementing the ban on smoking in Israeli pubs: measuring airborne nicotine and enforcement by local authorities
Authors: Satran Carmit , Drach-Zahavy Anat , Hammond S. Katharine , Baron-Epel Orna 
Published: March 2014

Background: In 2007 an amendment to the law restricting smoking in pubs and bars (P&Bs) was enacted in Israel. However, a year after the ban only slight decreases in airborne smoke in P&Bs in one city have been reported. Purpose: We aimed to assess levels of airborne nicotine in Israeli P&Bs and to measure ifself-reported enforcement of the law by local officials was associated with levels of airborne nicotine in P&Bs. Methods: Airborne nicotine levels were measured in 72 P&Bs in 29 towns in Israel; this consisted of 90% of eligible towns. In addition, 73 local authority officials were interviewed in 25 of these towns. The officials were asked to assess the local authority’s level of enforcement of the law banning smoking in P&Bs. The association of levels of airborne nicotine with the levels of enforcement of the law was calculated. Data were collected during 2009–2010 and analyzed in 2010–2011. Results: Levels of airborne nicotine were comparatively high in P&Bs. No association was detected between levels of nicotine and the P&Bs’ characteristics. In the larger towns, levels of airborne nicotine were higher. In 16% of towns the local authority officials reported high levels of law enforcement. Generally, levels of reported enforcement by local authorities were low and did not predict levels of airborne nicotine in the P&Bs. Conclusions: Self-reported local authorities’ law enforcement was not associated with levels of airborne nicotine in P&Bs in these towns. There is a need to develop ways to increase law enforcement by the local authorities or other agencies.
Differences in Glycemic Variability Between Normoglycemic and Prediabetic Subjects
Authors: Hanefeld Markolf , Sulk Stefan , Helbig Matthias , Thomas Andreas , Köhler Carsta 
Published: March 2014

Objective: So far the criteria for NGT and abnormal glucose tolerance (AGT) are based on HbA1c and 75 g oGTT. We present data on GV and diurnal profiles in stratified cohorts with AGT versus controls. Research designs and methods: 28 NGT, 42 AGT (15 IGT, 11 IFG, 16 CGI) matched for age and BMI classified by 75 g oGTT underwent a CGM with test meal (TM). Diurnal profiles, glucose excursion after TM, and GV (SD, MAGE) were calculated for day 2 and 3. Results: HbA1c, with its values of 5.5 ± 0.37% versus 5.65 ± 0.36%, was within normal range. Average interstitial glucose (AiG) was 5.84 ± 0.52 mmol/l) in NGT and 6.35 ± 0.65 mmol/l in AGT ( P = .002). The 2 h incremental area under curve (iAUC) from TM until 2 h after TM was 1.94 ± 1.31 mmol/l*h versus 2.89 ( ± 1.75) mmol/l*h ( P = .012), AiG 2 hours after TM was 5.99 ± 1.14 mmol/l*d versus 6.64 ± 1.30 mmol/l ( P = .035). Peaks of AiG after TM were 7.69 ± 1.48 mmol/l*d versus 9.18 ± 1.67 mmol/l*d ( P = .001). SD was significantly higher for AGT (1.12 ± 0.37 vs. 0.85 ± 0.32 mmol/l, P = .01) and MAGE 2.26 ± 0.84 vs. 1.60 ± 0.69 mmol/l, P = .005). Conclusions: In this comparative analysis NGT and AGT well matched for age, BMI, and comorbidities, CGM revealed significant differences in daytime AiG, pp glucose excursion and postprandial peaks. SD and MAGE was significantly higher for subjects with AGT. I Impaired glucose homeostasis a better characterizes degree of AGTe than HbA1c and 75 g OGTT.
“Glucose-at-a-Glance”
Authors: Henriques Teresa , Munshi Medha N. , Segal Alissa R. , Costa Madalena D. , Goldberger Ary L. 
Published: March 2014

Background: The standard continuous glucose monitoring (CGM) output provides multiple graphical and numerical summaries. A useful adjunct would be a visualization tool that facilitates immediate assessment of both long- and short-term variability. Methods: We developed an algorithm based on the mathematical method of delay maps to display CGM signals in which the glucose value at time ti is plotted against its value at time ti+1. The data points are then color-coded based on their frequency of occurrence (density). Results: Examples of this new visualization tool, along with the accompanying time series, are presented for selected patients with type 2 diabetes and non-diabetic controls over the age of 70 years. The method reveals differences in the structure of the glucose variability between subjects with a similar range of glucose values. We also observe that patients with comparable hemoglobin A1c (HbA1c) values may have very different delay maps, consistent with marked differences in the dynamics of glucose control. These differences are not accounted by the amplitude of the fluctuations. Furthermore, the delay maps allow for rapid recognition of hypo- and hyperglycemic periods over the full duration of monitoring or any subinterval. Conclusion: The glucose-at-a-glance visualization tool, based on colorized delay maps, provides a way to quickly assess the complex data acquired by CGM systems. This method yields dynamical information not contained in single summary statistics, such as HbA1c values, and may also serve as the basis for developing novel metrics of glycemic control.
Assessment of Patient Perceptions About Web Telemonitoring Applied to Artificial Pancreas Use at Home
Authors: Place Jérôme , Farret Anne , Del Favero Simone , Bruttomesso Daniela , Renard Eric 
Published: March 2014

Background: Patients with chronic diseases as well as health care systems could benefit from telemedicine applications such as remote monitoring (RM). RM relies on a device that sends patients’ health data to a remote server accessible by care teams. Recent smartphone-based artificial pancreas (AP) systems collect comprehensive set of information and could therefore support the development of RM applied to diabetes. To better understand how RM could be integrated in future AP systems, we wanted to get patients’ opinion on this concept, as they are the final users of these systems. Method: An online questionnaire with 11 items was sent to 20 experienced patients who tested AP and RM during our recent outpatient studies in France and Italy. Results: We received 17 answers. All patients considered that during their participation in trials, RM was useful, reassuring, and essential. One-third wouldn’t have participated without it. When AP is commercialized, 88% of respondents think that AP should go with a RM tool, but it should be activated only at certain times, at first use or in case of difficulties (82%). Participants ask for technical support when a device fails (88%) and for medical help in case of prolonged hyperglycemia (65%) or severe or repeated hypoglycemia (53%), but not after each case of hypoglycemia (6%). More than 75% think that RM could help them to improve their blood glucose control. Conclusions: This preliminary work indicates that patients expect RM to be part of future AP development. Larger studies remain to be performed to investigate its usefulness and potential economic effectiveness.
Updating the evidence for the effect of radiofrequency catheter ablation on left atrial volume and function in patients with atrial fibrillation: a meta-analysis
Authors: Zhuang Yan , Yong Yong-hong , Chen Ming-long 
Published: March 2014

Summary Objectives To systematically review the effects of radiofrequency catheter ablation (RFCA) on left atrial (LA) size, volumes and function in patients with atrial fibrillation (AF). Methods We searched MEDLINE, EMBASE, ScienceDirect, Highwire, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and the reference lists of retrieved reports in July 2012. Setting China Participants Twenty-six studies (enrolling 1821 patients) were included in the final analysis. Main outcome measures Changes of LA size or volumes and/or function in patients with AF after RFCA. Results Compared to pre-ablation values, there were significant decreases in LA diameter and LA volumes at post-ablation follow-up. However, compared to pre-ablation values, there were no significant differences in LA ejection fraction/LA active emptying fraction and LA strain at post-ablation follow-up. Decreases in LA diameter and LA volumes remained significant in those without AF recurrence but not in those with AF recurrence. LA ejection fraction/LA active emptying fraction did not decrease in patients without AF recurrence, whereas they decreased in patients with AF recurrence. As for LA strain, it seems that LA strain increases in patients without AF recurrence, with less fibrosis and with more LA volumes decrease, but the differences were not significant. Conclusions Successful RFCA in patients with AF significantly decreases LA size and volumes and does not seem to adversely affect LA function.
‘Back Door Sentencing’ in Italy: Common Reasons and Main Consequences for the Recall of Prisoners
Authors: Gualazzi Alessandra , Mancuso Chiara , Mangiaracina Annalisa 
Published: March 2014

Italian law only provides the general conditions for the institution of recall. It follows that significant discretionary powers are enjoyed by the surveillance judges (and in particular by the Surveillance Tribunal) who evaluate on a case-by-case basis whether the commission of another offence or the infringement of parole conditions demonstrate the offenders' negative attitude to reintegrate into society. However, especially with reference to the commission of serious crimes, the judges' discretionary assessment can result in a restrictive application of the law on recall with the consequence that parolees are returned to prison even when they commit minor violations. The Italian penitentiary system is currently undergoing a serious crisis mainly caused by prison overcrowding. This article argues that reform of the system is thus urgently needed. Such reform should be aimed, among other objectives, at strengthening the role of the bodies which are involved in the different phases of recall (e.g. social services, prison staff, etc.), in order to assist and support judges in their difficult task of decision making in an area — such that of recall — full of social implication.
Donor hematopoiesis in mice following total lymphoid irradiation requires host T-regulatory cells for durable engraftment
Authors: Müller Antonia M. S. , Poyser Jessica , Küpper Natascha J. , Burnett Cassandra , Ko Rose M. , Kohrt Holbrook E.K. , Florek Mareike , Zhang Pei , Negrin Robert S. , Shizuru Judith A. 
Published: March 2014

Key PointsAfter TLI, donor blood stem cells first engraft in irradiated marrow and gradually redistribute into unexposed sites. Long-term donor cell engraftment requires the presence of regulatory host cells that promote host stem-cell cycling.
Asthma in pregnancy: a hit for two
Authors: Murphy Vanessa E. , Schatz Michael 
Published: March 2014

Asthma commonly occurs in pregnant females, and recent data have outlined the risks of adverse perinatal outcomes among this population. There is an increased risk of low birth weight and small for gestational age, particularly among females with moderate-to-severe asthma and exacerbations during pregnancy. There is also an increased risk of preterm birth, especially with oral steroid use, a small but statistically significant increased risk of congenital malformations, particularly of cleft lip with or without cleft palate, and an increased risk of neonatal hospitalisation and death. Active management may reduce these risks, possibly through reductions in exacerbations.Additional reassuring data have been presented for asthma medication use, which support the benefits outweighing the risks of indicated asthma medication use in pregnancy. Viral infections are an important trigger of asthma exacerbations in pregnancy, and recent data provides possible immunological changes that may explain this. Poor medication adherence despite worsening asthma symptoms in pregnancy is a problem which continues to be demonstrated in the literature. Improving asthma control in pregnancy has the potential to improve not only the mother’s health but also that of her child.
Pirfenidone: an update on clinical trial data and insights from everyday practice
Authors: Kreuter Michael 
Published: March 2014

Pirfenidone is an orally active, small molecule that inhibits synthesis of profibrotic and inflammatory mediators. It was approved for the treatment of adults with mild-to-moderate idiopathic pulmonary fibrosis in the European Union based on the results of two pivotal phase III, double-blind, randomised, placebo-controlled clinical trials (CAPACITY) demonstrating efficacy and safety, and supported by two Japanese clinical trials (SP2 and SP3). Currently, there is increasing interest in experience with pirfenidone in patients relating to the real-world setting.Following the publication of the CAPACITY clinical studies, additional analyses have been conducted to provide further support for pirfenidone in clinical practice, including a modified per-protocol analysis of the CAPACITY study population. New data from the RECAP extension study also provided longer term data for pirfenidone and promising continuation rates with treatment. Pirfenidone is also being evaluated in specialist centre cohorts providing important information on real-world efficacy and safety. Increasing experience with pirfenidone in everyday clinical practice is helping to establish \expert guidance on the management of known adverse events, together with practical recommendations, to ensure adherence to treatment so that the possible longer term benefits of pirfenidone treatment in reducing lung function decline can be maximised.