bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dynamic and Thermodynamic Predictors of Vertical Structure in Radar-Observed Regional Precipitation
Authors: Rudolph James V. , Friedrich Katja 
Published: December 2013

Abstract
Radar-observed vertical structure of precipitation as defined by contoured frequency by altitude diagrams (CFADs) is related to dynamic and thermodynamic environmental parameters. CFADs from 559 storms occurring over the years 2004–11 in the vicinity of Locarno, Switzerland, combined with Interim ECMWF Re-Analysis (ERA-Interim) data show that the radar-observed vertical structure of precipitation correlates with synoptic pattern (as defined by 1000- and 500-hPa geopotential heights), integrated water vapor flux, atmospheric stability, and vertical profiles of temperature, moisture, and wind. Following the analysis of vertical structure and environmental parameters, a generalized linear model (GLM) is developed for radar-observed vertical structure as a function of data from ERA-Interim. The GLM provides expected values for the vertical extent and magnitude of radar reflectivity and predicts storm vertical structure type with 79% overall accuracy. The relationships found between environmental parameters and storm vertical structure underscore the importance of including both dynamic and thermodynamic variables when evaluating climate change effects on precipitation. In addition, the ability of the GLM to reproduce storm types shows the potential for using GLMs as a link between lower-resolution global model data and high-resolution precipitation observations.
Structure and agency in the Malaysian government’s policies for economic development
Authors: Akhir Md Nasrudin Md , Kim Keum Hyun , Suh Chung-Sok 
Published: December 2013

AbstractThis article examines the role of government in Malaysia’s history of economic development. In addressing two key challenges – inter-ethnic inequalities, conflicts and tensions, and exposure to global trade and economic relations – the Malaysian government has become directly involved in the economy. Strong government has played a role in Malaysia’s economic success in a range of ways, from 5-year plans to specific industry promotion and the creation of organisations for particular economic development purposes. Government has also been aware of environmental changes and in response has modified its strategies, established new organisations and invested in innovative ventures. Thus, while the drivers of economic development in Malaysia have been deeply embedded structural phenomena, the actual economic development path taken has been determined by the actions of the Malaysian government in concert with other stakeholders.
Human herpesvirus-8: Kaposi sarcoma, multicentric Castleman disease, and primary effusion lymphoma
Authors: Kaplan Lawrence D. 
Published: December 2013

Abstract
Human herpesvirus 8 (HHV8) is a gamma herpesvirus associated with Kaposi sarcoma, multicentric Castleman disease, and primary effusion lymphoma, lymphoproliferative diseases that are most commonly observed in immunocompromised individuals. The viral genome expresses genes responsible for inhibition of apoptosis, cell cycle entry, and angiogenesis. Viral homologs of human regulatory genes are expressed, providing stimuli for angiogenesis, B-cell proliferation, and immune evasion. Variations in expression of these factors give rise to the 3 known HHV8-associated malignancies. Identification of these pathogenetic mechanisms has led to exploration of targeted treatment approaches for all 3 of these disorders with success in Kaposi sarcoma and multicentric Castleman disease; primary effusion lymphoma remains a clinical challenge.
Targeting signaling pathways in acute lymphoblastic leukemia: new insights
Authors: Harrison Christine J. 
Published: December 2013

Abstract
The genetics of acute lymphoblastic leukemia are becoming well understood and the incidence of individual chromosomal abnormalities varies considerably with age. Cytogenetics provide reliable risk stratification for treatment: high hyperdiploidy and ETV6-RUNX1 are good risk, whereas BCR-ABL1, MLL rearrangements, and hypodiploidy are poor risk. Nevertheless, some patients within the good- and intermediate-risk groups will unpredictably relapse. With advancing technologies in array-based approaches (single nucleotide polymorphism arrays) and next-generation sequencing to study the genome, increasing numbers of new genetic changes are being discovered. These include deletions of B-cell differentiation and cell cycle control genes, as well as mutations of genes in key signaling pathways. Their associations and interactions with established cytogenetic subgroups and with each other are becoming elucidated. Whether they have a link to outcome is the most important factor for refinement of risk factors in relation to clinical trials. For several newly identified abnormalities, including intrachromosomal amplification of chromosome 21 (iAMP21), that are associated with a poor prognosis with standard therapy, appropriately modified treatment has significantly improved outcome. After the successful use of tyrosine kinase inhibitors in the treatment of BCR-ABL1–positive acute lymphoblastic leukemia, patients with alternative ABL1 translocations and rearrangements involving PDGFRB may benefit from treatment with tyrosine kinase inhibitors. Other aberrations, for example, CRLF2 overexpression and JAK2 mutations, are also providing potential novel therapeutic targets with the prospect of reduced toxicity.
Phase 4 research: what happens when the rubber meets the road?
Authors: Crowther Mark 
Published: December 2013

AbstractApproval of a novel drug is oftentimes seen as the end of the development pathway. However, the appearance of rare but serious side effects in patients taking approved drugs has led to increased attention to phase 4, or postmarketing, research. Traditionally, postmarketing research relied on reports from clinicians to monitor for unexpected toxicity. However, such reporting will produce a biased assessment of risk due to underreporting of toxic effects in older medications. The availability of large, representative databases and more flexible analysis tools has led to comprehensive and near “real-time” surveillance programs. These programs have been used by the US Food and Drug Administration to explore toxicities of approved medications. The need for effective tools with which to monitor clinically relevant outcome events has been further increased by the development of accelerated pathways to drug approval. In areas without effective treatments, such pathways lead to licensure without rigorous clinical efficacy data. Continued approval is frequently made contingent on the availability of postmarketing surveillance data demonstrating improvements in clinical end points and these data can also be used to monitor for unexpected toxicity.
Which TKI? An embarrassment of riches for chronic myeloid leukemia patients
Authors: Hughes Timothy , White Deborah 
Published: December 2013

Abstract
With the approval in many countries of nilotinib and dasatinib for frontline therapy in chronic myeloid leukemia, clinicians now have to make a difficult choice. Because none of the 3 available tyrosine kinase inhibitors (TKIs) have shown a clear survival advantage, they all represent reasonable choices. However, in individual patients, the case may be stronger for a particular TKI. In the younger patient, in whom the prospect of eventually achieving treatment-free remission is likely to be of great importance, dasatinib or nilotinib may be preferred, although their advantage over imatinib in this setting remains to be proven. In patients with a higher risk of transformation (which is currently based on prognostic scoring), the more potent TKIs may be preferred because they appear to be more effective at reducing the risk of transformation to BC. However, imatinib still represents an excellent choice for many chronic myeloid leukemia patients. All of these considerations need to be made in the context of the patient's comorbidities, which may lead to one or more TKIs being ruled out of contention. Whatever first choice of TKI is made, treatment failure or intolerance must be recognized early because a prompt switch to another TKI likely provides the best chance of achieving optimal response.
Current management of immune thrombocytopenia
Authors: Neunert Cindy E. 
Published: December 2013

Abstract
Immune thrombocytopenia (ITP) is an autoimmune-mediated condition that results from antibody-mediated destruction of platelets and impaired megakaryocyte platelet production. ITP patients exhibit severe thrombocytopenia and are at risk for significant hemorrhage. Few randomized trials exist to guide management of patients with ITP. Ultimately, each patient requires an individualized treatment plan that takes into consideration the platelet count, bleeding symptoms, health-related quality of life, and medication side effects. This article provides an up-to-date review of management strategies drawing on links between the expanding amounts of clinical trial data and associated biology studies to enhance understanding of the disease heterogeneity with regard to the complex pathogenesis and response to treatment.
Genomic applications in the clinic: use in treatment paradigm of acute myeloid leukemia
Authors: Schlenk Richard F. , Döhner Hartmut 
Published: December 2013

Abstract
In recent years, research in genomics has resulted in the rapid uncovering of the molecular pathogenesis of acute myeloid leukemia (AML). The identification of the genetic determinants of response to standard—but also to experimental—treatment is increasingly used for patient counseling, to guide clinical decision making, and for resource-efficient care provision at diagnosis, during consolidation treatment and follow-up, and after relapse. Gene mutations now allow us to explore the enormous diversity among cytogenetically defined subsets of AML, in particular the large subset of cytogenetically normal AML. Nonetheless, there are several challenges in evaluating the prognostic value of a specific mutation in the concert of the various concurrent mutations and determining the relative prognostic value of the genetic profile during the disease course. In particular, changes in the genetic profile in relapse compared with that at diagnosis will increasingly affect the treatment strategy at relapse, but also will give us the possibility of learning which treatment strategy during frontline therapy is best to prevent them.
Multidrug-resistant bacteria: what is the threat?
Authors: Bassetti Matteo , Righi Elda 
Published: December 2013

Abstract
Despite big advances in antimicrobial therapies and infection strategies, the emergence of antibiotic resistance represents an emergency situation, especially in immunocompromised hosts. Specifically, infections due to multidrug resistant, gram-negative pathogens are responsible for high mortality rates and may leave few effective antimicrobial options. Furthermore, although new compounds are available for severe methicillin-resistant staphylococcal infections, there is a paucity of novel classes of antimicrobials to target resistant gram-negatives. A careful assessment of the clinical conditions and underlying comorbidities, along with knowledge about the previous history of colonization or infections due to multidrug-resistant bacteria, represent key points in approaching the hematological patient with signs of infection. A de-escalation therapy with initial use of wide-spectrum antimicrobials followed by a reassessment after 72 hours of treatment may represent a good option in severe infections if a resistant pathogen is suspected. Prompt empiric or targeted therapy using combination regimens (ie, antipseudomonal beta-lactam plus an aminoglycoside or a quinolone) with the addition of colistin, along with increased dosage and therapeutic drug monitoring, represent options for these life-threatening infections. Continuous epidemiological surveillance of local bacteremias is necessary, along with stringent enforcement of antibiotic stewardship programs in cancer patients.
Targeting the epigenome and other new strategies in diffuse large B-cell lymphoma: beyond R-CHOP
Authors: Cerchietti Leandro , Leonard John P. 
Published: December 2013

AbstractDiffuse large B-cell lymphoma, the most common lymphoma subtype, is curable in the majority of patients. However, one of the greatest unmet needs in lymphoma treatment remains novel approaches to prevent relapsed or refractory disease. Genomic profiling has provided important prognostic information that is being used in the development of novel therapeutic strategies currently in clinical trials. It is clear, however, that epigenetic alterations provide an additional series of targets that can be pharmacologically modified and offer great potential to improving patient outcomes. Greater understanding of this area is providing important new insights that are now being explored in the clinical setting. Demethylating agents and drugs that disrupt histone modifiers are in early clinical trials with promising results, and other approaches targeting epigenetic pathways are in active preclinical and early clinical development.
Does hematopoietic stem cell transplantation benefit infants with acute leukemia?
Authors: Sison Edward Allan R. , Brown Patrick 
Published: December 2013

Abstract
A 6-month-old girl was diagnosed with acute lymphoblastic leukemia (ALL). She has completed induction therapy and is currently in first complete remission (CR1). You are asked by your resident if hematopoietic stem cell transplantation (HSCT) would benefit infants with acute leukemia.
Hemochromatosis: the new blood donor
Authors: Leitman Susan F. 
Published: December 2013

Abstract
Hereditary hemochromatosis (HH) due to homozygosity for the C282Y mutation in the HFE gene is a common inherited iron overload disorder in whites of northern European descent. Hepcidin deficiency, the hallmark of the disorder, leads to dysregulated intestinal iron absorption and progressive iron deposition in the liver, heart, skin, endocrine glands, and joints. Survival is normal if organ damage is prevented by early institution of phlebotomy therapy. HH arthropathy is the symptom most affecting quality of life and can be debilitating. Genotype screening in large population studies has shown that the clinical penetrance of C282Y homozygosity is highly variable and can be very low, with up to 50% of women and 20% of men showing a silent phenotype. Targeted population screening for the HFE C282Y mutation is not recommended at present, but might be reconsidered as a cost-effective approach to management if counseling and care were better organized and standardized. Referral of patients to the blood center for phlebotomy therapy and use of HH donor blood for transfusion standardizes treatment, minimizes treatment costs, and may benefit society as a whole. Physician practices should be amended such that HH subjects are more frequently referred to the blood center for therapy.
Junctional adhesion molecule-A suppresses platelet integrin αIIbβ3 signaling by recruiting Csk to the integrin-c–Src complex
Authors: Naik Meghna U. , Caplan Jeffrey L. , Naik Ulhas P. 
Published: December 2013

Key PointsPhosphorylated JAM-A associates with resting integrin αIIbβ3. JAM-A suppresses outside-in signaling by recruiting Csk to the integrin-c–Src complex.
Telomere length in circulating leukocytes is associated with lung function and disease
Authors: Albrecht Eva , Sillanpää Elina , Karrasch Stefan , Alves Alexessander Couto , Codd Veryan , Hovatta Iiris , Buxton Jessica L. , Nelson Christopher P. , Broer Linda , Hägg Sara , Mangino Massimo , Willemsen Gonneke , Surakka Ida , Ferreira Manuel A.R. , Amin Najaf , Oostra Ben A. , Bäckmand Heli M. , Peltonen Markku , Sarna Seppo , Rantanen Taina , Sipilä Sarianna , Korhonen Tellervo , Madden Pamela A.F. , Gieger Christian , Jörres Rudolf A. , Heinrich Joachim , Behr Jürgen , Huber Rudolf M. , Peters Annette , Strauch Konstantin , Wichmann H. Erich , Waldenberger Melanie , Blakemore Alexandra I.F. , de Geus Eco J.C. , Nyholt Dale R. , Henders Anjali K. , Piirilä Päivi L. , Rissanen Aila , Magnusson Patrik K.E. , Viñuela Ana , Pietiläinen Kirsi H. , Martin Nicholas G. , Pedersen Nancy L. , Boomsma Dorret I. , Spector Tim D. , van Duijn Cornelia M. , Kaprio Jaakko , Samani Nilesh J. , Jarvelin Marjo-Riitta , Schulz Holger 
Published: December 2013

Several clinical studies suggest the involvement of premature ageing processes in chronic obstructive pulmonary disease (COPD). Using an epidemiological approach, we studied whether accelerated ageing indicated by telomere length, a marker of biological age, is associated with COPD and asthma, and whether intrinsic age-related processes contribute to the interindividual variability of lung function.Our meta-analysis of 14 studies included 934 COPD cases with 15 846 controls defined according to the Global Lungs Initiative (GLI) criteria (or 1189 COPD cases according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria), 2834 asthma cases with 28 195 controls, and spirometric parameters (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC) of 12 595 individuals. Associations with telomere length were tested by linear regression, adjusting for age, sex and smoking status.We observed negative associations between telomere length and asthma (β= −0.0452, p=0.024) as well as COPD (β= −0.0982, p=0.001), with associations being stronger and more significant when using GLI criteria than those of GOLD. In both diseases, effects were stronger in females than males. The investigation of spirometric indices showed positive associations between telomere length and FEV1(p=1.07×10−7), FVC (p=2.07×10−5), and FEV1/FVC (p=5.27×10−3). The effect was somewhat weaker in apparently healthy subjects than in COPD or asthma patients.Our results provide indirect evidence for the hypothesis that cellular senescence may contribute to the pathogenesis of COPD and asthma, and that lung function may reflect biological ageing primarily due to intrinsic processes, which are likely to be aggravated in lung diseases.
Pulmonary matrix metalloproteinase-9 activity in mechanically ventilated children with respiratory syncytial virus
Authors: Kong Michele Y.F. , Clancy John P. , Peng Ning , Li Yao , Szul Tomasz J. , Xu Xin , Oster Robert , Sullender Wayne , Ambalavanan Namasivayam , Blalock J. Edwin , Gaggar Amit 
Published: December 2013

Respiratory syncytial virus (RSV) infection is a potent stimulus for airway epithelial expression of matrix metalloproteinase (MMP)-9. MMP-9 activityin vivois a predictor of disease severity in children with RSV-induced respiratory failure.Human airway epithelial cells were infected with RSV A2 strain and analysed for MMP-9 and tissue inhibitor of metalloproteinase (TIMP)-1 (a natural inhibitor of MMP-9) release. In addition, endotracheal samples from children with RSV-RF and controls (non-RSV pneumonia and nonlung disease controls) were analysed for MMP-9, TIMP-1, human neutrophil elastase and myeloperoxidase activity.RSV infection of airway epithelia was sufficient to rapidly induce MMP-9 transcription and protein release. Pulmonary MMP-9 activity peaked at 48 h in infants with RSV-induced respiratory failure. In the RSV group, MMP-9 activity and MMP-9/TIMP-1 ratio imbalance predicted higher oxygen requirement and worse paediatric risk of mortality scores. The highest levels of human neutrophil elastase and myeloperoxidase activity were measured in the RSV cohort; however, unlike MMP-9, these neutrophil markers failed to predict disease severity.These results support the hypothesis that RSV is a potent stimulus for MMP-9 expression and release from human airway epithelium, and that MMP-9 is an important biomarker of disease severity in mechanically ventilated children with RSV lung infection.
Does exercise test modality influence dyspnoea perception in obese patients with COPD?
Authors: Ciavaglia Casey E. , Guenette Jordan A. , Ora Josuel , Webb Katherine A. , Neder J. Alberto , O’Donnell Denis E. 
Published: December 2013

The purpose of this study was to investigate whether differences in physiological responses to weight-bearing (walking) and weight-supported (cycle) exercise influence dyspnoea perception in obese chronic obstructive pulmonary disease (COPD) patients, where such discrepancies are probably exaggerated.We compared metabolic, ventilatory and perceptual responses during incremental treadmill and cycle exercise using a matched linearised rise in work rate in 18 (10 males and eight females) obese (mean±sdbody mass index 36.4±5.0 kg·m−2) patients with COPD (forced expiratory volume in 1 s 60±11% predicted).Compared with cycle testing, treadmill testing was associated with a significantly higher oxygen uptake, lower ventilatory equivalent for oxygen and greater oxyhaemoglobin desaturation at a given work rate (p<0.01). Cycle testing was associated with a higher respiratory exchange ratio (p<0.01), earlier ventilatory threshold (p<0.01) and greater peak leg discomfort ratings (p=0.01). Ventilation, breathing pattern and operating lung volumes were similar between tests, as were dyspnoea/work rate and dyspnoea/ventilation relationships.Despite significant between-test differences in physiological responses, ventilation, operating lung volumes and dyspnoea intensity were similar at any given external power output during incremental walking and cycling exercise in obese COPD patients. These data provide evidence that either exercise modality can be selected for reliable evaluation of exertional dyspnoea in this population in research and clinical settings.
The anti-tumor effect of shikonin on osteosarcoma by inducing RIP1 and RIP3 dependent necroptosis
Authors: Fu Zeze , Deng Biyong , Liao Yuxin , Shan Liancheng , Yin Fei , Wang Zhuoying , Zeng Hui , Zuo Dongqing , Hua Yingqi , Cai Zhengdong 
Published: December 2013

Abstract

Background
Osteosarcoma is the most frequent primary malignant bone tumor, notorious for its lung metastasis. Shikonin, an effective constituent extracted from Chinese medicinal herb, was demonstrated to induce necroptosis in some cancers.

Methods
MTT assay was performed to detect cell survival rate in vitro. Flow cytometry was used to analyze cell cycle and cell death. Western blot was performed to determine the expression levels of RIP1, RIP3, caspase-3, caspase-6 and PARP. The tibial primary and lung metastatic osteosarcoma models were used to evaluate the anti-tumor effect of shikonin in vivo.

Results
The cell survival rate was decreased in a dose and time dependent manner when treated with shikonin. No major change in cell cycle was observed after shikonin treatment. The cell death induced by shikonin could be mostly rescued by specific necroptosis inhibitor necrostatin-1, but not by general caspase inhibitor Z-VAD-FMK. The number of necrotic cells caused by shikonin was decreased after being pretreated with Nec-1 detected by flow cytometry in K7 cells. After 8-hour treatment of shikonin, the expression levels of RIP1 and RIP3 were increased while caspase-3, caspase-6 and PARP were not activated in K7 and U2OS cells determined by Western blot. Size of primary tumor and lung metastasis in shikonin treated group were significantly reduced. The protein levels of RIP1 and RIP3 in primary tumor tissues were increased by shikonin. The overall survival of lung metastatic models was longer compared with control group (p < 0.001).

Conclusions
Shikonin had prompt but profound anti-tumor effect on both primary and metastatic osteosarcoma, probably by inducing RIP1 and RIP3 dependent necroptosis. Shikonin would be a potential anti-tumor agent on the treatment of primary and metastatic osteosarcoma.