bluuebunny/crossref_metadata_2025 huggingface dataset:
Complete Genome Sequence of Riemerella anatipestifer Serotype 1 Strain CH3
Authors: Wang Xiaolan , Ding Chan , Han Xiangan , Wang Shaohui , Yue Jiaping , Hou Wanwan , Cao Shoulin , Zou Jiechi , Yu Shengqing
Published: February 2015

Riemerella anatipestifer
is a well-described pathogenic bacterium, which is reported worldwide as the cause of epizootic infectious polyserositis of waterfowl and other avian species. Here, we present the complete genome sequence of
R. anatipestifer
strain CH3, the serotype 1 prevalent in China.
Closed Genome Sequence of Clostridium pasteurianum ATCC 6013
Authors: Rotta Carlo , Poehlein Anja , Schwarz Katrin , McClure Peter , Daniel Rolf , Minton Nigel P.
Published: February 2015

We report here the closed genome of
Clostridium pasteurianum
ATCC 6013, a saccharolytic, nitrogen-fixing, and spore-forming Gram-positive obligate anaerobe. The organism is of biotechnological interest due to the production of solvents (butanol and 1,3-propanediol) but can be associated with food spoilage. The genome comprises a total of 4,351,223 bp.
Draft Genomes of Two Strains of Flavobacterium Isolated from Lake Washington Sediment
Authors: McTaggart Tami L. , Shapiro Nicole , Woyke Tanja , Chistoserdova Ludmila
Published: February 2015

We report sequencing the genomes of two new Flavobacterium strains isolated from Lake Washington sediment. From genomic contents, versatile lifestyles were predicted but not
bona fide
methylotrophy. With the availability of their genomic sequences, the new Flavobacterium strains present prospective models for studying microbial communities in lake sediments.
Transmission of Ebola Viruses: What We Know and What We Do Not Know
Authors: Osterholm Michael T. , Moore Kristine A. , Kelley Nicholas S. , Brosseau Lisa M. , Wong Gary , Murphy Frederick A. , Peters Clarence J. , LeDuc James W. , Russell Phillip K. , Van Herp Michel , Kapetshi Jimmy , Muyembe Jean-Jacques T. , Ilunga Benoit Kebela , Strong James E. , Grolla Allen , Wolz Anja , Kargbo Brima , Kargbo David K. , Formenty Pierre , Sanders David Avram , Kobinger Gary P.
Published: February 2015

Available evidence demonstrates that direct patient contact and contact with infectious body fluids are the primary modes for Ebola virus transmission, but this is based on a limited number of studies. Key areas requiring further study include (i) the role of aerosol transmission (either via large droplets or small particles in the vicinity of source patients), (ii) the role of environmental contamination and fomite transmission, (iii) the degree to which minimally or mildly ill persons transmit infection, (iv) how long clinically relevant infectiousness persists, (v) the role that “superspreading events” may play in driving transmission dynamics, (vi) whether strain differences or repeated serial passage in outbreak settings can impact virus transmission, and (vii) what role sylvatic or domestic animals could play in outbreak propagation, particularly during major epidemics such as the 2013–2015 West Africa situation. In this review, we address what we know and what we do not know about Ebola virus transmission. We also hypothesize that Ebola viruses have the potential to be respiratory pathogens with primary respiratory spread.
Sudden unexpected death in infancy: aetiology, pathophysiology, epidemiology and prevention in 2015
Authors: Fleming Peter J , Blair Peter S , Pease Anna
Published: February 2015

Despite the fall in numbers of unexpected infant deaths that followed the ‘Back to Sleep’ campaigns in the early 1990s in the UK and many other countries, such deaths remain one of the largest single groups of deaths in the postneonatal period in many Western countries. Changes in the ways in which unexpected infant deaths are categorised by pathologists and coroners, and increasing reluctance to use the term ‘sudden infant death syndrome’, make assessment of nationally and internationally collected data on incidence potentially inaccurate and confusing. In this paper, we review current understanding of the epidemiology and aetiology of unexpected deaths in infancy, and current hypotheses on the pathophysiology of the processes that may lead to death. We also review interventions that have been adopted, with variable degrees of effectiveness in efforts to reduce the numbers of deaths, and new approaches that offer the possibility of prevention in the future.
Metastatic hepatocellular carcinoma to the pelvis and vertebrae in a patient with chronic hepatitis ‘C’ with unknown primary
Authors: Abbas Syed Hussain , Khan Muhammad Zia Ul Islam , Ijaz Muhammad , Hussain Syed Jawad Akhtar
Published: February 2015

A 54-year-old man infected with hepatitis C virus presented to us with pain in the right iliac fossa radiating to the back and right thigh for the past 2 months. Imaging of the abdomen and pelvis was performed, which revealed a soft tissue mass adherent to right iliac blade and right ala of sacrum. Trucut biopsy of the mass was performed and immunohistochemical stains Glypican-3 and Hep-par 1 were used for histopathological analysis, which diagnosed the mass as hepatocellular carcinoma. This is a unique case of metastasis of hepatocellular carcinoma to the bone in which imaging of the liver did not show any primary lesion. Liver function tests showed that aspartate transaminase and alanine transaminase were twice the normal range with a high viral load and significantly raised serum α-fetoprotein. The patient was treated with intravenous 5-flourouracil and radiotherapy as a palliative measure with only moderate clinical improvement.
Thrombotic thrombocytopenic purpura as an initial presentation of systemic lupus erythematosus with acquired ADAMTS 13 antibody
Authors: Changcharoen Bhisit , Bolger Dennis Thomas
Published: February 2015

We report a female patient presenting with headache, fatigue, ecchymoses and recent, excessive vaginal bleeding. Prompt review of the peripheral blood smear showed evidence of microangiopathic haemolytic anaemia (MAHA) and thrombocytopenia. Thrombotic thrombocytopenic purpura (TTP) was suspected. Plasma exchange and corticosteroids were started urgently. The patient responded favourably to the treatment. Subsequently, positive serological markers returned and were compatible with systemic lupus erythematosus (SLE). A disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13 (ADAMTS 13) activity was remarkably low with a positive inhibitory ADAMTS 13 antibody. Mycophenolate and hydroxychloroquine were started along with a prolonged course and taper of corticosteroids. These medications have been maintained with an excellent response in 14 months of follow-up.
Elevated inflammatory biomarkers during unemployment: modification by age and country in the UK
Authors: Hughes Amanda , McMunn Anne , Bartley Mel , Kumari Meena
Published: February 2015

Background

There is raised risk of mortality following unemployment, and reviews have consistently found worse psychological health among the unemployed. Inflammation is increasingly implicated as a mediating factor relating stress to physical disease and is strongly linked to depression. Inflammation may, therefore, be implicated in processes associated with excess mortality and morbidity during unemployment. This study examined associations of unemployment with inflammatory markers among working-age men and women from England and Scotland.

Methods

Cross-sectional analyses using data from the Health Survey for England and the Scottish Health Survey collected between 1998 and 2010. Systemic inflammation was indexed by serum concentrations of C reactive protein (CRP) and fibrinogen, and compared between participants currently employed/self-employed, currently unemployed and other groups.

Results

CRP, fibrinogen and odds of CRP >3 mg/L were all significantly raised for the unemployed, as compared to the employed participants (eg, OR for CRP >3 mg/L=1.43, CI 1.15 to 1.78 N=23 025), following adjustment for age, gender, occupational social class, housing tenure, smoking, alcohol consumption, body mass index, long-term illness and depressive/anxiety symptoms. Strengths of associations varied considerably by both age and country/region, with effects mainly driven by participants aged ≥48 and participants from Scotland, which had comparatively high unemployment during this time.

Conclusions

Current unemployment is associated with elevated inflammatory markers using data from two large-scale, nationally representative UK studies. Effect modification by age suggests inflammation may be particularly involved in processes leading to ill-health among the older unemployed. Country/regional effects may suggest the relationship of unemployment with inflammation is strongly influenced by contextual factors, and/or reflect life course accumulation processes.
Male involvement and maternal health outcomes: systematic review and meta-analysis
Authors: Yargawa Judith , Leonardi-Bee Jo
Published: February 2015

Background

The developing world accounts for 99% of global maternal deaths. Men in developing countries are the chief decision-makers, determining women's access to maternal health services and influencing their health outcomes. At present, it is unclear whether involving men in maternal health can improve maternal outcomes. This systematic review and meta-analysis aimed to investigate the impact of male involvement on maternal health outcomes of women in developing countries.

Methods

Four electronic databases and grey literature sources were searched (up to May 2013), together with reference lists of included studies. Two reviewers independently screened and assessed the quality of studies based on prespecified criteria. Measures of effects were pooled and random effect meta-analysis was conducted, where possible.

Results

Fourteen studies met the inclusion criteria. Male involvement was significantly associated with reduced odds of postpartum depression (OR=0.36, 95% CI 0.19 to 0.68 for male involvement during pregnancy; OR=0.34, 95% CI 0.19 to 0.62 for male involvement post partum), and also with improved utilisation of maternal health services (skilled birth attendance and postnatal care). Male involvement during pregnancy and at post partum appeared to have greater benefits than male involvement during delivery.

Conclusions

Male involvement is associated with improved maternal health outcomes in developing countries. Contrary to reports from developed countries, there was little evidence of positive impacts of husbands’ presence in delivery rooms. However, more rigorous studies are needed to improve this area's evidence base.
Incarceration and perinatal smoking: a missed public health opportunity
Authors: Dumont Dora M , Parker Donna R , Viner-Brown Samara , Clarke Jennifer G
Published: February 2015

Background

Incarceration is simultaneously a public health opportunity and a public health concern. We examined the association between maternal/partner incarceration in the year prior to birth and perinatal smoking.

Methods

We pooled 2006–2010 data from the Centers for Disease Control and Prevention's Pregnancy Risk Assessment and Monitoring System. Controlling for age, race/ethnicity, education, marital status and other stressors, we assessed prevalence and heaviness of perinatal smoking.

Findings

Women who reported incarceration of themselves or their partners in the year prior to delivery were more likely to smoke during the last trimester of pregnancy (adjusted OR (AOR) 1.51 (95% CI 1.36 to 1.67)), and they were more likely to smoke more than 10 cigarettes a day compared to smokers who did not report incarceration (AOR 1.35 (95% CI 1.10 to 1.65)). Patterns were similar for the 3 months prior to pregnancy and postbirth smoking.

Conclusions

Incarceration of a parent in the 12 months before birth is associated with increased risk of fetal and newborn exposure to smoking. The criminal justice system can be utilised by public health practitioners to target perinatal smoking reduction interventions.
Relative deprivation in income and mortality by leading causes among older Japanese men and women: AGES cohort study
Authors: Kondo Naoki , Saito Masashige , Hikichi Hiroyuki , Aida Jun , Ojima Toshiyuki , Kondo Katsunori , Kawachi Ichiro
Published: February 2015

Background

Relative deprivation of income is hypothesised to generate frustration and stress through upward social comparison with one's peers. If psychosocial stress is the mechanism, relative deprivation should be more strongly associated with specific health outcomes, such as cardiovascular disease (compared with other health outcomes, eg, non-tobacco-related cancer).

Methods

We evaluated the association between relative income deprivation and mortality by leading causes, using a cohort of 21 031 community-dwelling adults aged 65 years or older. A baseline mail-in survey was conducted in 2003. Information on cause-specific mortality was obtained from death certificates. Our relative deprivation measure was the Yitzhaki Index, derived from the aggregate income shortfall for each person, relative to individuals with higher incomes in that person's reference group. Reference groups were defined according to gender, age group and same municipality of residence.

Results

We identified 1682 deaths during the 4.5 years of follow-up. A Cox regression demonstrated that, after controlling for demographic, health and socioeconomic factors including income, the HR for death from cardiovascular diseases per SD increase in relative deprivation was 1.50 (95% CI 1.09 to 2.08) in men, whereas HRs for mortality by cancer and other diseases were close to the null value. Additional adjustment for depressive symptoms and health behaviours (eg, smoking and preventive care utilisation) attenuated the excess risks for mortality from cardiovascular disease by 9%. Relative deprivation was not associated with mortality for women.

Conclusions

The results partially support our hypothesised mechanism: relative deprivation increases health risks via psychosocial stress among men.
Mondor's disease: a unique cause of penile pain
Authors: Dalal Adam , Erlich Y
Published: February 2015

Superficial dorsal penile vein thrombosis (penile Mondor's disease (MD)) is a unique and reportedly uncommon condition. Many cases of penile MD are idiopathic, but it is often precipitated by trauma, sexually transmitted infections and different sexual practices, such as vigorous sexual activity and the use of sexual devices. We describe the case of a young active duty man diagnosed with a penile MD, preceded by an intense sexual activity. Once diagnosed, a supportive care was instituted, consisting of administration of non-steroidal anti-inflammatory drug, temporary sexual abstinence and proper patient reassurance with complete recovery. We believe that military physicians, who care for a majority of young and sexually active adults, must be familiar with the diagnosis of penile MD and its treatment. To the best of our knowledge, this is the first case of penile MD to be reported in a military setting.
Enrollment bias: frequency and impact on patient selection in endovascular stroke trials
Authors: Sheth Sunil A , Saver Jeffrey L , Starkman Sidney , Grunberg Ileana D , Guzy Judy , Ali Latisha K , Kim Doojin , Gonzalez Nestor R , Jahan Reza , Tateshima Satoshi , Duckwiler Gary , Liebeskind David S
Published: February 2015

Background

Selection bias may have affected enrollment in first generation endovascular stroke trials. We investigate, evaluate, and quantify such bias for these trials at our institution.

Methods

Demographic, clinical, imaging, and angiographic data were prospectively collected on a consecutive cohort of patients with acute ischemic stroke who were enrolled in formal trials of endovascular stroke therapy (EST) or received EST in clinical practice outside of a randomized trial for acute cerebral ischemia at a single tertiary referral center from September 2004 to December 2012.

Results

Among patients considered appropriate for EST in practice, 47% were eligible for trials, with rates for individual trials ranging from 17% to 70%. Compared with trial ineligible patients treated with EST, trial eligible patients were younger (67 vs 74 years; p<0.05), more often treated with intravenous tissue plasminogen activator (53% vs 34%; p<0.01), and had shorter last known well to puncture times (328 vs 367 min; p<0.05). Focusing on the largest trial with a non-interventional control arm, compared with trial eligible patients treated with EST outside the trial, enrolled patients presented later (274 vs 163 min; p<0.001), had higher National Institutes of Health Stroke Scale scores (20 vs 17; p<0.05), and larger strokes (diffusion weighted imaging volumes 49 vs 18; p<0.001).

Conclusions

The majority of patients felt suitable for EST at our institution were excluded from recent trials. Formal entry criteria succeeded in selecting patients with better prognostic features, although many of these patients were treated outside of trials. Acknowledging and mitigating these biases will be crucial to ongoing investigations.
Implementation of NICE Clinical Guideline 95 for assessment of stable chest pain in a rapid access chest pain clinic reduces the mean number of investigations and cost per patient
Authors: Lee Alvin J X , Michail Michael , Quaderi Shumonta A , Richardson James A , Aggarwal Suneil K , Speechly-Dick M Elsya
Published: February 2015

Objective

In 2010, the National Institute for Health and Care Excellence (NICE) in the UK published Clinical Guideline 95 (CG95) advocating risk stratification of patients using ‘CADScore’ to guide appropriate cardiac investigations for chest pain of recent onset. Implementation of the guideline in the University College London Hospitals NHS Foundation Trust was evaluated to see if it led to a reduction in the average cost of the diagnostic journey per patient and fewer investigations per patient in order to confirm a diagnosis.

Methods

This was a single centre study at a Tertiary Centre in Central London. The investigative journey for each patient presenting to the Rapid Access Chest Pain Clinic (RACPC) at University College London Hospitals NHS Foundation Trust was recorded. Retrospective analysis on this data was performed.

Results

Data for 4968 patients presenting to the RACPC from 2004 to 2012 was analysed and a size-matched cohort of 1503 patients preimplementation and postimplementation of the guidelines was compared. The mean cost of investigations postimplementation was £291.83 as compared to £319.54 preimplementation of the guidelines despite higher costs associated with some of the recommended initial investigations. The mean number of tests per patient postguidelines was 0.78 compared to 0.97 for preguidelines. An approximate twofold increase in patients not requiring tests was seen post-CG95 implementation (245 pre-CG95 vs 476 post-CG95).

Conclusions

The implementation of the NICE guidelines in our trust has reduced the average cost of the investigative journey and the number of investigations required per patient.
Online-List Scheduling on a Single Bounded Parallel-Batch Machine to Minimize Makespan
Authors: Li Wenhua , Gao Jie , Yuan Jinjiang
Published: February 2015

In this paper, we consider the online-list scheduling on a single bounded parallel-batch machine to minimize makespan. In the problem, the jobs arrive online over list. The first unassigned job in the list should be assigned to a batch before the next job is released. Each batch can accommodate up to b jobs. For b = 2, we establish a lower bound 1 + γ of competitive ratio and provide an online algorithm with a competitive ratio of [Formula: see text], where γ is the positive root of γ(γ + 1)2 = 1. For b = 3, we establish a lower bound 1 + α of competitive ratio and provide an online algorithm with a competitive ratio of 2, where α is the positive root of the equation (1 + α)(1 + α2) = 2.
The real software crisis
Authors: Krishnamurthi Shriram , Vitek Jan
Published: February 2015

Sharing experiences running artifact evaluation committees for five major conferences.
HTTP/2.0
Authors: Kamp Poul-Henning
Published: February 2015

Bad protocol, bad politics.
Inflammasomes in pancreatic physiology and disease
Authors: Hoque Rafaz , Mehal Wajahat Z.
Published: February 2015

In this review we summarize the role of inflammasomes in pancreatic physiology and disease with a focus on acute pancreatitis where much recent progress has been made. New findings have identified inducers of and cell specificity of inflammasome component expression in the pancreas, the contribution of inflammasome-regulated effectors to pancreatitis, and metabolic regulation of inflammasome activation, which are strong determinants of injury in pancreatitis. New areas of pancreatic biology will be highlighted in the context of our evolving understanding of gut microbiome- and injury-induced inflammasome priming, pyroptosis, and innate immune-mediated regulation of cell metabolism.
Impaired exercise training-induced muscle fiber hypertrophy and Akt/mTOR pathway activation in hypoxemic patients with COPD
Authors: Costes Frédéric , Gosker Harry , Feasson Léonard , Desgeorges Marine , Kelders Marco , Castells Josiane , Schols Annemie , Freyssenet Damien
Published: February 2015

Exercise training (ExTr) is largely used to improve functional capacity in patients with chronic obstructive pulmonary disease (COPD). However, ExTr only partially restores muscle function in patients with COPD, suggesting that confounding factors may limit the efficiency of ExTr. In the present study, we hypothesized that skeletal muscle adaptations triggered by ExTr could be compromised in hypoxemic patients with COPD. Vastus lateralis muscle biopsies were obtained from patients with COPD who were either normoxemic ( n = 15, resting arterial Po2 = 68.5 ± 1.5 mmHg) or hypoxemic ( n = 8, resting arterial Po2 = 57.0 ± 1.0 mmHg) before and after a 2-mo ExTr program. ExTr induced a significant increase in exercise capacity both in normoxemic and hypoxemic patients with COPD. However, ExTr increased citrate synthase and lactate dehydrogenase enzyme activities only in skeletal muscle of normoxemic patients. Similarly, muscle fiber cross-sectional area and capillary-to-fiber ratio were increased only in patients who were normoxemic. Expression of atrogenes (MuRF1, MAFbx/Atrogin-1) and autophagy-related genes (Beclin, LC3, Bnip, Gabarapl) remained unchanged in both groups. Phosphorylation of Akt (Ser473), GSK-3β (Ser9), and p70S6k (Thr389) was nonsignificantly increased in normoxemic patients in response to ExTr, but it was significantly decreased in hypoxemic patients. We further showed on C2C12 myotubes that hypoxia completely prevented insulin-like growth factor-1-induced phosphorylation of Akt, GSK-3β, and p70S6K. Together, our observations suggest a role for hypoxemia in the adaptive response of skeletal muscle of patients with COPD in an ExTr program.
Sarcolipin overexpression improves muscle energetics and reduces fatigue
Authors: Sopariwala Danesh H. , Pant Meghna , Shaikh Sana A. , Goonasekera Sanjeewa A. , Molkentin Jeffery D. , Weisleder Noah , Ma Jianjie , Pan Zui , Periasamy Muthu
Published: February 2015

Sarcolipin (SLN) is a regulator of sarcoendoplasmic reticulum calcium ATPase in skeletal muscle. Recent studies using SLN-null mice have identified SLN as a key player in muscle thermogenesis and metabolism. In this study, we exploited a SLN overexpression ( SlnOE) mouse model to determine whether increased SLN level affected muscle contractile properties, exercise capacity/fatigue, and metabolic rate in whole animals and isolated muscle. We found that SlnOEmice are more resistant to fatigue and can run significantly longer distances than wild-type (WT). Studies with isolated extensor digitorum longus (EDL) muscles showed that SlnOEEDL produced higher twitch force than WT. The force-frequency curves were not different between WT and SlnOEEDLs, but at lower frequencies the pyruvate-induced potentiation of force was significantly higher in SlnOEEDL. SLN overexpression did not alter the twitch and force-frequency curve in isolated soleus muscle. However, during a 10-min fatigue protocol, both EDL and soleus from SlnOEmice fatigued significantly less than WT muscles. Interestingly, SlnOEmuscles showed higher carnitine palmitoyl transferase-1 protein expression, which could enhance fatty acid metabolism. In addition, lactate dehydrogenase expression was higher in SlnOEEDL, suggesting increased glycolytic capacity. We also found an increase in store-operated calcium entry (SOCE) in isolated flexor digitorum brevis fibers of SlnOEcompared with WT mice. These data allow us to conclude that increased SLN expression improves skeletal muscle performance during prolonged muscle activity by increasing SOCE and muscle energetics.
Effect of skin temperature on cutaneous vasodilator response to the β-adrenergic agonist isoproterenol
Authors: Hodges Gary J. , Kellogg Dean L. , Johnson John M.
Published: February 2015

The vascular response to local skin cooling is dependent in part on a cold-induced translocation of α2C-receptors and an increased α-adrenoreceptor function. To discover whether β-adrenergic function might contribute, we examined whether β-receptor sensitivity to the β-agonist isoproterenol was affected by local skin temperature. In seven healthy volunteers, skin blood flow was measured from the forearm by laser-Doppler flowmetry and blood pressure was measured by finger photoplethysmography. Data were expressed as cutaneous vascular conductance (CVC; laser-Doppler flux/mean arterial blood pressure). Pharmacological agents were administered via intradermal microdialysis. We prepared four skin sites: one site was maintained at a thermoneutral temperature of 34°C (32 ± 10%CVCmax) one site was heated to 39°C (38 ± 11%CVCmax); and two sites were cooled, one to 29°C (22 ± 7%CVCmax) and the other 24°C (16 ± 4%CVCmax). After 20 min at these temperatures to allow stabilization of skin blood flow, isoproterenol was perfused in concentrations of 10, 30, 100, and 300 μM. Each concentration was perfused for 15 min. Relative to the CVC responses to isoproterenol at the thermoneutral skin temperature (34°C) (+21 ± 10%max), low skin temperatures reduced (at 29°C) (+17 ± 6%max) or abolished (at 24°C) (+1 ± 5%max) the vasodilator response, and warm (39°C) skin temperatures enhanced the vasodilator response (+40 ± 9%max) to isoproterenol. These data indicate that β-adrenergic function was influenced by local skin temperature. This finding raises the possibility that a part of the vasoconstrictor response to direct skin cooling could include reduced background β-receptor mediated vasodilation.
The Effects of Uric Acid, Serum Vitamin D3, and Their Interaction on Parkinson’s Disease Severity
Authors: Meamar Rokhsareh , Shaabani Pooria , Tabibian Seyed Reza , Aghaye Ghazvini Mohammad Reza , Feizi Awat
Published: February 2015

Objectives. In current study, the relationships between serum vitamin D3 levels and serum UA concentrations as well as their interaction with severity of PD were evaluated in a sample of Iranian PD patients.Method. In a cross sectional study at the one of the main referral hospitals in central region of Iran, during September to November 2011, 112 patients were recruited. Severity of PD was evaluated sing H&R stages and UPDRS.Results. The Spearman rank correlation coefficient suggests the negative significant association between serum vitamin D3 and UPDRS in patients aged >62 (r=-0.34,P<0.05). No statistically significant association was observed between the UA levels and severity of PD (represented by H&Y categories) in different levels of serum vitamin D3 not only in total sample but also in separate age and sex groups. The linear regression coefficients suggested positive association between UA and serum vitamin D3 with UPDRSIII scores while negative relationship between UA and serum vitamin D3 interaction with UPDRSIII; however it was only statistically significant in age group ≤62 (P<0.05).Conclusion. Our study revealed a negative correlation between interaction of serum vitamin D3 and UA with severity of PD; other studies are required to confirm our findings.
Beneficial Effects ofTeucrium poliumand Metformin on Diabetes-Induced Memory Impairments and Brain Tissue Oxidative Damage in Rats
Authors: Mousavi S. Mojtaba , Niazmand Saeed , Hosseini Mahmoud , Hassanzadeh Zarha , Sadeghnia Hamid Reza , Vafaee Farzaneh , Keshavarzi Zakieh
Published: February 2015

Objective.The effects of hydroalcoholic extract ofTeucrium poliumand metformin on diabetes-induced memory impairment and brain tissues oxidative damage were investigated.Methods.The rats were divided into: (1) Control, (2) Diabetic, (3) Diabetic-Extract 100 (Dia-Ext 100), (4) Diabetic-Extract 200 (Dia-Ext 200), (5) Diabetic-Extract 400 (Dia-Ext 400), and (6) Diabetic-Metformin (Dia-Met). Groups 3–6 were treated by 100, 200, and 400 mg/kg of the extract or metformin, respectively, for 6 weeks (orally).Results. In passive avoidance test, the latency to enter the dark compartment in Diabetic group was lower than that of Control group (P<0.01). In Dia-Ext 100, Dia-Ext 200, and Dia-Ext 400 and Metformin groups, the latencies were higher than those of Diabetic group (P<0.01). Lipid peroxides levels (reported as malondialdehyde, MDA, concentration) in the brain of Diabetic group were higher than Control (P<0.001). Treatment by all doses of the extract and metformin decreased the MDA concentration (P<0.01).Conclusions.The results of present study showed that metformin and the hydroalcoholic extract ofTeucrium poliumprevent diabetes-induced memory deficits in rats. Protection against brain tissues oxidative damage might have a role in the beneficial effects of the extract and metformin.
The Surgical Treatment of Pelvic Bone Metastases
Authors: Müller Daniel A. , Capanna Rodolfo
Published: February 2015

Pelvic bone metastases are a growing concern in the field of orthopedic surgery. Patients with pelvic metastasis are individually different with different needs of treatment in order to attain the best possible quality of life despite the advanced stage of disease. A holistic collaboration among the oncologist, radiation therapist, and orthopedic surgeon is mandatory. Special attention has to be directed to osteolytic lesions in the periacetabular region as they can provoke pathological fractures and subsequent functional impairment. Different reconstruction techniques for the pelvis are available; the choice depends on the patient’s prognosis, size of the bone defect, and response of the tumor to adjuvant treatment. If all the conservative treatments are exhausted and the patient is not eligible for surgery, one of the various percutaneous ablation procedures can be considered. We propose a pelvic analogue to the treatment algorithm in long bone metastasis and a scoring system in pelvic metastasis. This algorithm aims to simplify the teamwork and to avoid under- or overtreatment of pelvic bone metastases.
Combined Cognitive-Psychological-Physical Intervention Induces Reorganization of Intrinsic Functional Brain Architecture in Older Adults
Authors: Zheng Zhiwei , Zhu Xinyi , Yin Shufei , Wang Baoxi , Niu Yanan , Huang Xin , Li Rui , Li Juan
Published: February 2015

Mounting evidence suggests that enriched mental, physical, and socially stimulating activities are beneficial for counteracting age-related decreases in brain function and cognition in older adults. Here, we used functional magnetic resonance imaging (fMRI) to demonstrate the functional plasticity of brain activity in response to a combined cognitive-psychological-physical intervention and investigated the contribution of the intervention-related brain changes to individual performance in healthy older adults. The intervention was composed of a 6-week program of combined activities including cognitive training, Tai Chi exercise, and group counseling. The results showed improved cognitive performance and reorganized regional homogeneity of spontaneous fluctuations in the blood oxygen level-dependent (BOLD) signals in the superior and middle temporal gyri, and the posterior lobe of the cerebellum, in the participants who attended the intervention. Intriguingly, the intervention-induced changes in the coherence of local spontaneous activity correlated with the improvements in individual cognitive performance. Taken together with our previous findings of enhanced resting-state functional connectivity between the medial prefrontal cortex and medial temporal lobe regions following a combined intervention program in older adults, we conclude that the functional plasticity of the aging brain is a rather complex process, and an effective cognitive-psychological-physical intervention is helpful for maintaining a healthy brain and comprehensive cognition during old age.
Bevacizumab Preconditioning Followed by Etoposide and Cisplatin Is Highly Effective in Treating Brain Metastases of Breast Cancer Progressing from Whole-Brain Radiotherapy
Authors: Lu Yen-Shen , Chen Tom Wei-Wu , Lin Ching-Hung , Yeh Dah-Cherng , Tseng Ling-Ming , Wu Pei-Fang , Rau Kun-Ming , Chen Bang-Bin , Chao Ta-Chung , Huang Shu-Min , Huang Chiun-Sheng , Shih Tiffany Ting-Fang , Cheng Ann-Lii
Published: February 2015

Purpose: We hypothesized that a window period between bevacizumab and cytotoxic agents may enhance drug delivery into tumor tissue through bevacizumab-induced vascular normalization in patients with brain metastases of breast cancer (BMBC).

Experimental Design: A single-arm phase II study was conducted in which BMBC patients refractory to whole-brain radiotherapy (WBRT) were enrolled. In a 21-day cycle, patients received bevacizumab (15 mg/kg) on day 1, which, with a 1-day window period, was followed by etoposide (70 mg/m2/day; days 2–4) and cisplatin (70 mg/m2; day 2; BEEP regimen). The BEEP regimen was administered for a maximum of 6 cycles. The primary endpoint was the central nervous system (CNS)–objective response rate according to volumetric response criteria.

Results: A total of 35 patients were enrolled between January 2011 and January 2013. The median age was 54.3 years (range, 33–75); 19 patients (54.3%) had an Eastern Cooperative Oncology Group performance status of 2 or 3. Twenty-seven patients [77.1%; 95% confidence interval (CI), 59.9–89.6] achieved a CNS-objective response, including 13 patients (37.1%) with a ≥80% volumetric reduction of CNS lesions. With a median follow-up of 16.1 months, the median CNS progression-free survival and overall survival times were 7.3 months (95% CI, 6.5–8.1) and 10.5 months (95% CI, 7.8–13.2), respectively. Common grade 3 or 4 toxicities included neutropenia (30.8%) and infection (21.3%).

Conclusions: By administering bevacizumab 1 day before etoposide and cisplatin, the BEEP regimen appeared highly effective in BMBC refractory to WBRT. Further study of vascular normalization window concept is warranted. Clin Cancer Res; 21(8); 1851–8. ©2015 AACR.
Obesity and Fatty Pancreatic Infiltration Are Risk Factors for Pancreatic Precancerous Lesions (PanIN)
Authors: Rebours Vinciane , Gaujoux Sébastien , d'Assignies Gaspard , Sauvanet Alain , Ruszniewski Philippe , Lévy Philippe , Paradis Valérie , Bedossa Pierre , Couvelard Anne
Published: February 2015

Purpose: The roles of intravisceral and subcutaneous fat are unknown, and the prevalence of precancerous lesions in obese patients was never evaluated. This study aims to assess the frequency and severity of pancreatic intraepithelial neoplasia (PanIN) and to correlate pathologic findings with metabolic abnormalities, type of fat, and fatty pancreatic infiltration.

Experimental Design: Normal pancreatic tissue from surgical specimens was analyzed. Fatty infiltration and fibrosis in intra- and extralobular locations and PanIN lesions were assessed. General characteristics were collected: body mass index (BMI), diabetes, and tobacco intake. Liver steatosis and subcutaneous and intravisceral fat were assessed by CT scan (ImageJ software).

Results: Of note, 110 patients were included [median age, 53.8 (17–85) years]. Arterial hypertension, diabetes, and tobacco intake were found in 19%, 9%, and 23%, respectively. Median BMI was 24 (16–37; BMI < 25: 45%, 25 ≤ 30: 24%, ≥30: 11%). Overall, PanIN lesions were found in 65% (type I, II, and III PanIN in 62%, 38%, and 1%, respectively). Fibrosis and fatty pancreas (intra- and extralobular locations) were found in 1% and 24% and in 30% and 51%, respectively. A correlation was observed between PanIN lesions and fatty pancreas [extralobular (0.01) and intralobular (<0.0001)], intralobular fibrosis (0.003), high BMI (P = 0.02), and subcutaneous (P = 0.02) and intravisceral fat (P = 0.02). The number of PanIN lesions was correlated with intravisceral fat (r = 0.22, P = 0.04), but not with subcutaneous fat (r = 0.14, P = 0.22). In multivariate analysis, PanIN lesions were associated with intralobular fibrosis [OR, 5.61; 95% confidence interval (CI), 1.18–42.99] and intralobular fat (OR, 17.86; 95% CI, 4.935–88.12).

Conclusions: Obesity (especially android obesity) and pancreatic fatty infiltration are risk factors for pancreatic precancerous lesions. Clin Cancer Res; 21(15); 3522–8. ©2015 AACR.

See related commentary by Wang et al., p. 3369
Trifluridine Induces p53-Dependent Sustained G2 Phase Arrest with Its Massive Misincorporation into DNA and Few DNA Strand Breaks
Authors: Matsuoka Kazuaki , Iimori Makoto , Niimi Shinichiro , Tsukihara Hiroshi , Watanabe Sugiko , Kiyonari Shinichi , Kiniwa Mamoru , Ando Koji , Tokunaga Eriko , Saeki Hiroshi , Oki Eiji , Maehara Yoshihiko , Kitao Hiroyuki
Published: February 2015

Trifluridine (FTD) is a key component of the novel oral antitumor drug TAS-102, which consists of FTD and a thymidine phosphorylase inhibitor. Like 5-fluoro-2′-deoxyuridine (FdUrd), a deoxynucleoside form of 5-fluorouracil metabolite, FTD is sequentially phosphorylated and not only inhibits thymidylate synthase activity, but is also incorporated into DNA. Although TAS-102 was effective for the treatment of refractory metastatic colorectal cancer in clinical trials, the mechanism of FTD-induced cytotoxicity is not completely understood. Here, we show that FTD as well as FdUrd induce transient phosphorylation of Chk1 at Ser345, and that this is followed by accumulation of p53 and p21 proteins in p53-proficient human cancer cell lines. In particular, FTD induced p53-dependent sustained arrest at G2 phase, which was associated with a proteasome-dependent decrease in the Cyclin B1 protein level and the suppression of CCNB1 and CDK1 gene expression. In addition, a p53-dependent increase in p21 protein was associated with an FTD-induced decrease in Cyclin B1 protein. Although numerous ssDNA and dsDNA breaks were induced by FdUrd, few DNA strand breaks were detected in FTD-treated HCT-116 cells despite massive FTD misincorporation into genomic DNA, suggesting that the antiproliferative effect of FTD is not due to the induction of DNA strand breaks. These distinctive effects of FTD provide insights into the cellular mechanism underlying its antitumor effect and may explain the clinical efficacy of TAS-102. Mol Cancer Ther; 14(4); 1004–13. ©2015 AACR.
P7170: A Novel Molecule with Unique Profile of mTORC1/C2 and Activin Receptor-like Kinase 1 Inhibition Leading to Antitumor and Antiangiogenic Activity
Authors: Jalota-Badhwar Archana , Bhatia Dimple R. , Boreddy Srinivas , Joshi Asavari , Venkatraman Magesh , Desai Nikesh , Chaudhari Sarika , Bose Julie , Kolla Lakshmi S. , Deore Vijaykumar , Yewalkar Nilambari , Kumar Sanjay , Sharma Rajiv , Damre Anagha , More Avinash , Sharma Somesh , Agarwal Veena R.
Published: February 2015

The mTOR pathway is often upregulated in cancer and thus intensively pursued as a target to design novel anticancer therapies. Approved and emerging drugs targeting the mTOR pathway have positively affected the clinical landscape. Recently, activin receptor-like kinase 1 (ALK1), belonging to the TGFβ receptor family, has been reported as an emerging target for antiangiogenic cancer therapy. Here, we describe a novel orally efficacious compound, P7170, that inhibits mTORC1/mTORC2/ALK1 activity with a potent cell growth inhibition. In cell-based assays, P7170 strongly inhibited (IC50 < 10 nmol/L) the phosphorylation of p70S6K (T389) and pAKT (S473). In many cancer cell lines, such as prostate, ovarian, colon, and renal, P7170 treatment resulted in marked cell growth inhibition. Furthermore, it induced G1–S cell-cycle arrest and autophagy. In vitro HUVEC tube formation, in vivo Matrigel plug, and rat aorta ring assays demonstrated that P7170 exhibited significant antiangiogenic activity. In addition, ALK1 knockdown studies in HUVEC confirmed that the antiangiogenic activity of P7170 was primarily due to ALK1 inhibition. Strong inhibition of ALK1 in addition to mTORC1/mTORC2 differentiates P7170 in its mechanism of action in comparison with existing inhibitors. In vivo mouse xenograft studies revealed P7170 to exhibit a significant dose-dependent tumor growth inhibition in a broad range of human tumor types when administered orally at 10 to 20 mg/kg doses. The distinctive pharmacological profile with favorable pharmacokinetic parameters and in vivo efficacy makes P7170 an attractive candidate for clinical development. It is currently being tested in phase I clinical studies. Mol Cancer Ther; 14(5); 1095–106. ©2015 AACR.
p53 and ΔNp63α Coregulate the Transcriptional and Cellular Response to TGFβ and BMP Signals
Authors: Balboni Amanda L. , Cherukuri Pratima , Ung Matthew , DeCastro Andrew J. , Cheng Chao , DiRenzo James
Published: February 2015

The TGFβ superfamily regulates a broad range of cellular processes, including proliferation, cell-fate specification, differentiation, and migration. Molecular mechanisms underlying this high degree of pleiotropy and cell-type specificity are not well understood. The TGFβ family is composed of two branches: (i) TGFβs, activins, and nodals, which signal through SMAD2/3, and (ii) bone morphogenetic proteins (BMP), which signal through SMAD1/5/8. SMADs have weak DNA-binding affinity and rely on coactivators and corepressors to specify their transcriptional outputs. This report reveals that p53 and ΔNp63α act as transcriptional partners for SMAD proteins and thereby influence cellular responses to TGFβ and BMPs. Suppression of p53 or overexpression of ΔNp63α synergistically enhance BMP-induced transcription. Mechanistically, p53 and ΔNp63α physically interact with SMAD1/5/8 proteins and co-occupy the promoter region of inhibitor of differentiation (ID2), a prosurvival BMP target gene. Demonstrating further convergence of these pathways, TGFβ-induced canonical BMP regulated transcription in a ΔNp63α- and p53-dependent manner. Furthermore, bioinformatic analyses revealed that SMAD2/3 and ΔNp63α coregulate a significant number of transcripts involved in the regulation of epithelial-to-mesenchymal transition. Thus, p53 and ΔNp63α are transcriptional partners for a subset of TGFβ- and BMP-regulated SMAD target genes in the mammary epithelium. Collectively, these results establish an integrated gene network of SMADs, p53, and ΔNp63α that contribute to EMT and metastasis.

Implications: This study identifies aberrant BMP activation as a result of p53 mutation or ΔNp63α expression. Mol Cancer Res; 13(4); 732–42. ©2015 AACR.
PD-1 Restrains Radiotherapy-Induced Abscopal Effect
Authors: Park Sean S. , Dong Haidong , Liu Xin , Harrington Susan M. , Krco Christopher J. , Grams Michael P. , Mansfield Aaron S. , Furutani Keith M. , Olivier Kenneth R. , Kwon Eugene D.
Published: February 2015

We investigated the influence of PD-1 expression on the systemic antitumor response (abscopal effect) induced by stereotactic ablative radiotherapy (SABR) in preclinical melanoma and renal cell carcinoma models. We compared the SABR-induced antitumor response in PD-1–expressing wild-type (WT) and PD-1–deficient knockout (KO) mice and found that PD-1 expression compromises the survival of tumor-bearing mice treated with SABR. None of the PD-1 WT mice survived beyond 25 days, whereas 20% of the PD-1 KO mice survived beyond 40 days. Similarly, PD-1–blocking antibody in WT mice was able to recapitulate SABR-induced antitumor responses observed in PD-1 KO mice and led to increased survival. The combination of SABR plus PD-1 blockade induced near complete regression of the irradiated primary tumor (synergistic effect), as opposed to SABR alone or SABR plus control antibody. The combination of SABR plus PD-1 blockade therapy elicited a 66% reduction in size of nonirradiated, secondary tumors outside the SABR radiation field (abscopal effect). The observed abscopal effect was tumor specific and was not dependent on tumor histology or host genetic background. The CD11ahigh CD8+ T-cell phenotype identifies a tumor-reactive population, which was associated in frequency and function with a SABR-induced antitumor immune response in PD-1 KO mice. We conclude that SABR induces an abscopal tumor-specific immune response in both the irradiated and nonirradiated tumors, which is potentiated by PD-1 blockade. The combination of SABR and PD-1 blockade has the potential to translate into a potent immunotherapy strategy in the management of patients with metastatic cancer. Cancer Immunol Res; 3(6); 610–9. ©2015 AACR.
PD-1+Tim-3+ CD8+ T Lymphocytes Display Varied Degrees of Functional Exhaustion in Patients with Regionally Metastatic Differentiated Thyroid Cancer
Authors: Severson Jill J. , Serracino Hilary S. , Mateescu Valerica , Raeburn Christopher D. , McIntyre Robert C. , Sams Sharon B. , Haugen Bryan R. , French Jena D.
Published: February 2015

Regional metastatic differentiated thyroid cancer (mDTC) provides a unique model in which to study the tumor–immune interface. These lymph node metastases persist for years, generally without progression to distant metastases. Although the immune system likely impedes disease progression, it is unsuccessful in eliminating disease. Our previous studies revealed that programmed death-1 (PD-1)+ T cells were enriched in tumor-involved lymph nodes (TILN). Tumor-associated leukocytes and tumor cells were collected from grossly involved lymph nodes from 12 patients to further characterize the phenotype and functional potential of mDTC-associated PD-1+ T cells. PD-1+CD4+ and PD-1+CD8+ T cells were enriched in 8 of 12 TILN samples. PD-1+ T cells coexpressed Tim-3 and CD69 and failed to downregulate CD27. CD8+ T cells, but not CD4+ T cells, from these samples were variably deficient in their ability to produce effector cytokines when compared with control TILNs that lacked resident PD-1+ T cells. PD-1+CD8+ T cells were capable of exocytosis but lacked intracellular perforin. Surprisingly, T-cell proliferative capacity was largely maintained in all samples. Thus, although PD-1 expression by mDTC-associated CD8+ T cells was associated with dysfunction, exhaustion was not complete. Notably, molecular markers of exhaustion did not translate to dysfunction in all samples or in CD4+ T cells. Regulatory T cells (Treg), PD-L1, and galectin-9 were commonly found in mDTC and likely contributed to the initiation of T-cell exhaustion and disease progression. Therapies that release the effects of PD-1 and Tim-3 and reduce the suppressive effects of Tregs may encourage tumor elimination in patients with mDTC. Cancer Immunol Res; 3(6); 620–30. ©2015 AACR.