bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influence of room heating on ambulatory blood pressure in winter: a randomised controlled study
Authors: Saeki Keigo , Obayashi Kenji , Iwamoto Junko , Tanaka Yuu , Tanaka Noriyuki , Takata Shota , Kubo Hiroko , Okamoto Nozomi , Tomioka Kimiko , Nezu Satoko , Kurumatani Norio 
Published: February 2013

BackgroundPrevious studies have proposed that higher blood pressure (BP) in winter is an important cause of increased mortality from cardiovascular disease during the winter. Some observational and physiological studies have shown that cold exposure increases BP, but evidence from a randomised controlled study assessing the effectiveness of intensive room heating for lowering BP was lacking.ObjectivesThe present study aimed to determine whether intensive room heating in winter decreases ambulatory BP as compared with weak room heating resulting in a 10°C lower target room temperature when sufficient clothing and bedclothes are available.MethodsWe conducted a parallel group, assessor blinded, simple randomised controlled study with 1:1 allocation among 146 healthy participants in Japan from November 2009 to March 2010. Ambulatory BP was measured while the participants stayed in single experimental rooms from 21:00 to 8:00. During the session, participants could adjust the amount of clothing and bedclothes as required. Compared with the weak room heating group (mean temperature±SD: 13.9±3.3°C), systolic morning BP (mean BP 2 h after getting out of bed) of the intensive room heating group (24.2±1.7°C) was significantly lower by 5.8 mm Hg (95% CI 2.4 to 9.3). Sleep-trough morning BP surges (morning BP minus lowest night-time BP) in the intensive room heating group were significantly suppressed to about two thirds of the values in the weak room heating group (14.3 vs 21.9 mm Hg; p<0.01).ConclusionsIntensive room heating decreased morning BP and the morning BP surge in winter.
Late Permian (Zechstein) magnetostratigraphy in Western and Central Europe
Authors: Szurlies Michael 
Published: February 2013

Abstract
Owing to the lack of fossils, the subdivision and correlation of the dominantly continental Permian (Rotliegend and Zechstein groups) and the overlying epicontinental Germanic Triassic (Buntsandstein, Muschelkalk and Keuper groups) from Western and Central Europe, traditionally, relies on lithological criteria. From the combination of magnetic polarity records from The Netherlands, Germany and Poland, a well-documented magnetostratigraphical composite for the Zechstein–lowermost Buntsandstein has been constructed. This interval is dominantly of normal polarity with few reversed magnetozones, allowing a reliable correlation throughout the intracontinental Central European Basin. Moreover, together with available biostratigraphical data, this integrated stratigraphical approach facilitates detailed links to the marine realm. The basal Zechstein is most probably equivalent to the uppermost lower–upper Wuchiapingian. The overlying upper Zechstein and the lowermost Buntsandstein are equivalent to the entire Changhsingian. Present bio- and magnetostratigraphical data indicate a possible duration of the Zechstein of only 2.8–3.5 Myr. A distinct climatic change accompanied by a major shift in sediment sources and a palynofloral turnover constitute important proxies for the terrestrial extinction event within the Central European Basin. A transition from a short reversed to a longer normal magnetozone within the uppermost Zechstein, which predates both the end-Permian ecological crisis and the conodont-calibrated biostratigraphical Permian–Triassic boundary (PTB), represents a prime time-marker for global correlation. Above this reverse to normal (R/N) reversal, the continental PTB is located within the lowermost Buntsandstein. The integration of magnetostratigraphy with other stratigraphical data is a prerequisite to establishing causal links between Late Permian climatic events in the sea and on land.
Activation of HIF2α in Kidney Proximal Tubule Cells Causes Abnormal Glycogen Deposition but not Tumorigenesis
Authors: Fu Leiping , Wang Gang , Shevchuk Maria M. , Nanus David M. , Gudas Lorraine J. 
Published: February 2013

Abstract
Renal cell carcinoma (RCC) is the most common primary cancer arising from the kidney in adults, with clear cell renal cell carcinoma (ccRCC) representing approximately 75% of all RCCs. Increased expression of the hypoxia-induced factors-1α (HIF1α) and HIF2α has been suggested as a pivotal step in ccRCC carcinogenesis, but this has not been thoroughly tested. Here, we report that expression of a constitutively activated form of HIF2α (P405A, P530A, and N851A, named as HIF2αM3) in the proximal tubules of mice is not sufficient to promote ccRCC by itself, nor does it enhance HIF1αM3 oncogenesis when coexpressed with constitutively active HIF1αM3. Neoplastic transformation in kidneys was not detected at up to 33 months of age, nor was increased expression of Ki67 (MKI67), γH2AX (H2AFX), or CD70 observed. Furthermore, the genome-wide transcriptome of the transgenic kidneys does not resemble human ccRCC. We conclude that a constitutively active HIF2α is not sufficient to cause neoplastic transformation of proximal tubules, arguing against the idea that HIF2α activation is critical for ccRCC tumorigenesis. Cancer Res; 73(9); 2916–25. ©2013 AACR.
New Strategies in Hodgkin Lymphoma: Better Risk Profiling and Novel Treatments
Authors: Diefenbach Catherine , Steidl Christian 
Published: February 2013

AbstractRecent advances in Hodgkin lymphoma research are expected to prelude a promising new treatment era for patients and their treating physicians. Scientific investigations over the last few years have provided new insights into risk stratification, and, simultaneously, a plethora of novel targeted therapies are emerging for patients with relapsed and refractory disease. These novel therapies will be tested primarily in high-risk patients because 75% of the patients are cured with conventional therapies. The challenges, as Hodgkin lymphoma therapy moves forward, will be using these biologic insights to identify the patients who may benefit earlier in treatment from these novel agents, and tailoring the therapy to the tumor biology of the patient. These dual aims are intertwined; as our therapeutic arsenal increases, these biologic determinants of risk may themselves inform the design of therapies and the choice of treatments for high-risk patients. Clin Cancer Res; 19(11); 2797–803. ©2013 AACR.
Extracellular Signal–Regulated Kinase 5: A Potential Therapeutic Target for Malignant Mesotheliomas
Authors: Shukla Arti , Miller Jill M. , Cason Christopher , Sayan Mutlay , MacPherson Maximilian B. , Beuschel Stacie L. , Hillegass Jedd , Vacek Pamela M. , Pass Harvey I. , Mossman Brooke T. 
Published: February 2013

Abstract
Purpose: Malignant mesothelioma is a devastating disease with a need for new treatment strategies. In the present study, we showed the importance of extracellular signal–regulated kinase 5 (ERK5) in malignant mesothelioma tumor growth and treatment.
Experimental Design: ERK5 as a target for malignant mesothelioma therapy was verified using mesothelial and mesothelioma cell lines as well as by xenograft severe combined immunodeficient (SCID) mouse models.
Results: We first showed that crocidolite asbestos activated ERK5 in LP9 cells and mesothelioma cell lines exhibit constitutive activation of ERK5. Addition of doxorubicin resulted in further activation of ERK5 in malignant mesothelioma cells. ERK5 silencing increased doxorubicin-induced cell death and doxorubicin retention in malignant mesothelioma cells. In addition, shERK5 malignant mesothelioma lines exhibited both attenuated colony formation on soft agar and invasion of malignant mesothelioma cells in vitro that could be related to modulation of gene expression linked to cell proliferation, apoptosis, migration/invasion, and drug resistance as shown by microarray analysis. Most importantly, injection of shERK5 malignant mesothelioma cell lines into SCID mice showed significant reduction in tumor growth using both subcutaneous and intraperitoneal models. Assessment of selected human cytokine profiles in peritoneal lavage fluid from intraperitoneal shERK5 and control tumor-bearing mice showed that ERK5 was critical in regulation of various proinflammatory (RANTES/CCL5, MCP-1) and angiogenesis-related (interleukin-8, VEGF) cytokines. Finally, use of doxorubicin and cisplatin in combination with ERK5 inhibition showed further reduction in tumor weight and volume in the intraperitoneal model of tumor growth.
Conclusion: ERK5 inhibition in combination with chemotherapeutic drugs is a beneficial strategy for combination therapy in patients with malignant mesothelioma. Clin Cancer Res; 19(8); 2071–83. ©2013 AACR.
Targeting miR-21 InhibitsIn VitroandIn VivoMultiple Myeloma Cell Growth
Authors: Leone Emanuela , Morelli Eugenio , Di Martino Maria T. , Amodio Nicola , Foresta Umberto , Gullà Annamaria , Rossi Marco , Neri Antonino , Giordano Antonio , Munshi Nikhil C. , Anderson Kenneth C. , Tagliaferri Pierosandro , Tassone Pierfrancesco 
Published: February 2013

AbstractPurpose: Deregulated expression of miRNAs plays a role in the pathogenesis and progression of multiple myeloma. Among upregulated miRNAs, miR-21 has oncogenic potential and therefore represents an attractive target for the treatment of multiple myeloma.Experimental Design: Here, we investigated the in vitro and in vivo anti-multiple myeloma activity of miR-21 inhibitors.Results: Either transient-enforced expression or lentivirus-based constitutive expression of miR-21 inhibitors triggered significant growth inhibition of primary patient multiple myeloma cells or interleukin-6–dependent/independent multiple myeloma cell lines and overcame the protective activity of human bone marrow stromal cells. Conversely, transfection of miR-21 mimics significantly increased proliferation of multiple myeloma cells, showing its tumor-promoting potential in multiple myeloma. Importantly, upregulation of miR-21 canonical validated targets (PTEN, Rho-B, and BTG2), together with functional impairment of both AKT and extracellular signal–regulated kinase signaling, were achieved by transfection of miR-21 inhibitors into multiple myeloma cells. In vivo delivery of miR-21 inhibitors in severe combined immunodeficient mice bearing human multiple myeloma xenografts expressing miR-21induced significant antitumor activity. Upregulation of PTEN and downregulation of p-AKT were observed in retrieved xenografts following treatment with miR-21 inhibitors.Conclusion: Our findings show the first evidence that in vivo antagonism of miR-21 exerts anti-multiple myeloma activity, providing the rationale for clinical development of miR-21 inhibitors in this still incurable disease. Clin Cancer Res; 19(8); 2096–106. ©2013 AACR.
Phase Ib Dose-Escalation Study (PX-171-006) of Carfilzomib, Lenalidomide, and Low-Dose Dexamethasone in Relapsed or Progressive Multiple Myeloma
Authors: Niesvizky Ruben , Martin Thomas G. , Bensinger William I. , Alsina Melissa , Siegel David S. , Kunkel Lori A. , Wong Alvin F. , Lee Susan , Orlowski Robert Z. , Wang Michael 
Published: February 2013

Abstract
Purpose: Carfilzomib, a selective proteasome inhibitor, has shown safety and efficacy in relapsed and/or refractory multiple myeloma. This phase I study in patients with relapsed or progressive multiple myeloma assessed the safety and tolerability of escalating doses of carfilzomib in combination with lenalidomide and low-dose dexamethasone (CRd) to identify the dose for a phase II expansion study.
Experimental Design: Patients with multiple myeloma who relapsed after 1 to 3 prior regimens enrolled into dose-escalation cohorts. CRd was administered on 28-day dosing cycles: carfilzomib 15 to 27 mg/m2 on days 1, 2, 8, 9, 15, and 16; lenalidomide 10 to 25 mg on days 1 to 21; and dexamethasone 40 mg weekly.
Results: Forty patients enrolled in six cohorts. Prior treatment included bortezomib (75%) and lenalidomide (70%); 20% and 36% were refractory overall. The maximum tolerated dose was not identified, and the highest dose combination tested was recommended for the phase II study. The most common toxicities of any grade were fatigue (62.5%), neutropenia (55.5%), and diarrhea (52.5%). Grade 3/4 toxicities included neutropenia (42.5%), thrombocytopenia (32.5%), and lymphopenia (27.5%), with no grade 3/4 neuropathy reported. Proteasome inhibition 1-hour after dose was more than 80% in cycles 1 and 2. Among all patients, the overall response rate was 62.5%, the clinical benefit response rate was 75.0%, and the median duration of response and progression-free survival were 11.8 and 10.2 months, respectively.
Conclusion: The maximum planned CRd dose, carfilzomib 27 mg/m2, lenalidomide 25 mg, and dexamethasone 40 mg, was recommended for further study, with promising safety and efficacy. Clin Cancer Res; 19(8); 2248–56. ©2013 AACR.
Dual PI3K/AKT/mTOR Inhibitor BEZ235 Synergistically Enhances the Activity of JAK2 Inhibitor against Cultured and Primary Human Myeloproliferative Neoplasm Cells
Authors: Fiskus Warren , Verstovsek Srdan , Manshouri Taghi , Smith Jacqueline E. , Peth Karissa , Abhyankar Sunil , McGuirk Joseph , Bhalla Kapil N. 
Published: February 2013

Abstract
Hemopoietic progenitor cells (HPC) from myeloproliferative neoplasms (MPN) such as myelofibrosis commonly express mutant JAK2-V617F or other mutations that are associated with increased activities of JAK-STAT5/3, RAS/RAF/MAPK, and PI3K/AKT/mTOR pathways. This confers proliferative and survival advantage on the MPN HPCs. Treatment with JAK tyrosine kinase inhibitor (TKI), for example, TG101209, TG101348 (SAR302503), or INCB018424 (ruxolitinib), inhibits mutant JAK2-mediated signaling. Although effective in reducing constitutional symptoms and splenomegaly, treatment with JAK-TKI does not ameliorate myelofibrosis or significantly improve survival of patients with advanced myelofibrosis. Here, we show that treatment with the dual phosphoinositide-3-kinase (PI3K)/AKT and mTOR inhibitor BEZ235 attenuated PI3K/AKT and mTOR signaling, as well as induced cell-cycle growth arrest and apoptosis of the cultured human JAK2-V617F-expressing HEL92.1.7 (HEL), UKE1 cells, and primary CD34+ myelofibrosis (MF)-MPN cells. Treatment with BEZ235 also induced significant apoptosis of the JAK2-TKI resistant HEL/TGR cells that were selected for resistance against JAK-TKI. Cotreatment with BEZ235 and JAK2-TKI (TG101209 and SAR302503) synergistically induced lethal activity against the cultured and primary CD34+ MPN cells while relatively sparing the normal CD34+ HPCs. These findings create a compelling rationale to determine the in vivo activity of dual PI3K/mTOR inhibitors in combination with JAK inhibitors against myelofibrosis HPCs. Mol Cancer Ther; 12(5); 577–88. ©2013 AACR.
Tumor-Initiating Cells and FZD8 Play a Major Role in Drug Resistance in Triple-Negative Breast Cancer
Authors: Yin Shuping , Xu Liping , Bonfil R. Daniel , Banerjee Sanjeev , Sarkar Fazlul H. , Sethi Seema , Reddy Kaladhar B. 
Published: February 2013

Abstract
Triple-negative breast cancer (TNBC) studies have shown that neoadjuvant chemotherapy before surgery was effective in the minority of women, whereas the majority who had residual tumor had a relatively poor outcome. To identify the mechanism by which residual cancer cells survive chemotherapy, we initially conducted gene expression profiling using the CRL2335 TNBC cell line derived from a squamous breast carcinoma before and after treatment with cisplatin plus TRAIL. We found a significant increase in the expression of FZD8, one of Wnt receptors, and its downstream targets LEF1 and TCF in residual CRL2335 tumor cells after treatment with cisplatin plus TRAIL. Increased FZD8 levels were further confirmed in other TNBC cell lines. Inhibition of FZD8 by siRNA in CRL2335 cells in the presence of cisplatin plus TRAIL reduced β-catenin and survivin levels and increased apoptosis compared with scrambled siRNA–treated cells. In vivo data show that cisplatin plus TRAIL treatment significantly reduces tumor volume in NOD/SCID mice. However, we found that cisplatin plus TRAIL treatment predominantly eliminated non–tumor-initiating cells, as shown by whole-body fluorescent imaging of mice injected with mammosphere-forming CRL2335 cells stably transfected with DsRed. This led to TIC enrichment in residual tumors, as confirmed by immunostaining for TIC markers. Moreover, an increase in FZD8 expression was observed in residual tumors treated with cisplatin and TRAIL. Taken together, our findings suggest that FZD8-mediated Wnt signaling may play a major role in mediating resistance to chemotherapy, making it a potential target to enhance chemotherapeutic efficacy in patients with TNBCs. Mol Cancer Ther; 12(4); 491–8. ©2013 AACR.
Evidence on the pathogenic role of auto-antibodies in acute cardiovascular diseases
Authors: Carbone Federico , Nencioni Alessio , Mach François , Vuilleumier Nicolas , Montecucco Fabrizio 
Published: February 2013

SummaryAtherothrombosis is the major determinant of acute ischaemic cardiovascular events, such as myocardial infarction and stroke. Inflammatory processes have been linked to all phases of atherogenesis In particular, the identification of autoimmunity mediators in the complex microenvironment of chronic inflammation has become the focus of attention in both early and advanced atherogenic processes. Autoantibodies against self-molecules or new epitopes generated by oxidative processes infiltrate atherosclerotic plaques and were shown to modulate the activity of immune cells by binding various types of receptors. However, despite mounting evidence for a pathophysiological role of autoantibodies in atherothrombosis, the clinical relevance for circulating autoantibodies in cardiovascular outcomes is still debated. This review aims at illustrating the mechanisms by which different types of autoantibodies might either promote or repress atherothrombosis and to discuss the clinical studies assessing the role of auto-antibodies as prognostic biomarkers of plaque vulnerability.
Kallikrein-related peptidases (KLKs) in gastrointestinal cancer: Mechanistic and clinical aspects
Authors: Kontos Christos K. , Mavridis Konstantinos , Talieri Maroulio , Scorilas Andreas 
Published: February 2013

SummaryThe human tissue kallikrein (KLK1) and kallikrein-related peptidases (KLKs) are secreted serine proteases with diverse expression patterns and physiological roles in different systems, including the digestive system. The aberrant expression of KLKs in gastrointestinal malignancies as well as their implication in carcinogenesis including cell growth regulation, angiogenesis, invasion, and metastasis, has prompted scientists to investigate their potential as cancer biomarkers. Expression of distinct KLKs is associated with various clinic-pathological parameters of patients with gastric, colorectal, pancreatic, hepatic, and esophageal cancer. Moreover, several KLKs possess significant favourable or unfavourable prognostic value in these human malignancies. Identification of novel diagnostic, prognostic and predictive biomarkers will contribute utmost to clinical decision-making, since early diagnosis of gastrointestinal cancer and early detection of recurrence following surgery are critical for the effective treatment of patients and for a positive clinical outcome. The current review provides a brief overview of the functional role of KLKs in gastric, colorectal, pancreatic, hepatic, and esophageal cancer, and describes the current status of KLKs as potential tumour biomarkers in these human malignancies.
Genetic Determinant for Amino Acid Metabolites and Changes in Body Weight and Insulin Resistance in Response to Weight-Loss Diets
Authors: Xu Min , Qi Qibin , Liang Jun , Bray George A. , Hu Frank B. , Sacks Frank M. , Qi Lu 
Published: February 2013

Background—
Circulating branched-chain amino acids and aromatic amino acids were recently related to insulin resistance and diabetes mellitus in prospective cohorts. We tested the effects of a genetic determinant of branched-chain amino acid/aromatic amino acid ratio on changes in body weight and insulin resistance in a 2-year diet intervention trial.

Methods and Results—

We genotyped the branched-chain amino acid/aromatic amino acid ratio—associated variant rs1440581 near the
PPM1K
gene in 734 overweight or obese adults who were assigned to 1 of 4 diets varying in macronutrient content. At 6 months, dietary fat significantly modified genetic effects on changes in weight, fasting insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) after adjustment for the confounders (all
P
for interaction ≤0.006). Further adjustment for weight change did not appreciably change the interactions for fasting insulin and HOMA-IR. In the high-fat diet group, the C allele was related to less weight loss and smaller decreases in serum insulin and HOMA-IR (all
P
≤ 0.02 in an additive pattern), whereas an opposite genotype effect on changes in insulin and HOMA-IR was observed in the low-fat diet group (
P
=0.02 and
P
=0.04, respectively). At 2 years, the gene-diet interactions remained significant for weight loss (
P
=0.008) but became null for changes in serum insulin and HOMA-IR resulting from weight regain.

Conclusions—
Individuals carrying the C allele of the branched-chain amino acid/aromatic amino acid ratio—associated variant rs1440581 may benefit less in weight loss and improvement of insulin sensitivity than those without this allele when undertaking an energy-restricted high-fat diet.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00072995.
The Neurobiology of Rhyme Judgment by Deaf and Hearing Adults: An ERP Study
Authors: MacSweeney Mairéad , Goswami Usha , Neville Helen 
Published: February 2013

Abstract
We used electrophysiology to determine the time course and distribution of neural activation during an English word rhyme task in hearing and congenitally deaf adults. Behavioral performance by hearing participants was at ceiling and their ERP data replicated two robust effects repeatedly observed in the literature. First, a sustained negativity, termed the contingent negative variation, was elicited following the first stimulus word. This negativity was asymmetric, being more negative over the left than right sites. The second effect we replicated in hearing participants was an enhanced negativity (N450) to nonrhyming second stimulus words. This was largest over medial, parietal regions of the right hemisphere. Accuracy on the rhyme task by the deaf group as a whole was above chance level, yet significantly poorer than hearing participants. We examined only ERP data from deaf participants who performed the task above chance level (n = 9). We observed indications of subtle differences in ERP responses between deaf and hearing groups. However, overall the patterns in the deaf group were very similar to that in the hearing group. Deaf participants, just as hearing participants, showed greater negativity to nonrhyming than rhyming words. Furthermore the onset latency of this effect was the same as that observed in hearing participants. Overall, the neural processes supporting explicit phonological judgments are very similar in deaf and hearing people, despite differences in the modality of spoken language experience. This supports the suggestion that phonological processing is to a large degree amodal or supramodal.