bluuebunny/crossref_metadata_2025 huggingface dataset:
Complete Genome Sequences of Human Respiratory Syncytial Virus Genotype A and B Isolates from South Korea
Authors: Yun Mi-ran , Kim A-Reum , Lee Han Saem , Kim Dae-Won , Lee Wan-Ji , Kim Kisoon , Kim Sung Soon , Kim You-Jin
Published: April 2015

There is a paucity of complete genome sequence information for human respiratory syncytial virus (HRSV). To this end, we sequenced the complete genome sequences of HRSV genotype A (HRSV-A/IC688/12) and genotype B (HRSV-B/GW0047/14 and HRSV-B/IC0027/14). This information will increase the understanding of HRSV genetic diversity, evolution, pathogenicity, antigenicity, and transmissibility.
Genome Sequences of Four Staphylococcus aureus Strains Isolated from Bovine Mastitis
Authors: Kant Ravi , Taponen Suvi , Koort Joanna , Paulin Lars , Åvall-Jääskeläinen Silja , Palva Airi
Published: April 2015

Staphylococcus aureus
is a major causative agent of mastitis in dairy cows. The pathogenicity of
S. aureus
may vary; it is able to cause severe clinical mastitis, but most often it is associated with chronic subclinical mastitis. Here, we present the genome assemblies of four
S. aureus
strains from bovine mastitis.
Draft Genome Sequences of Paenibacillus polymyxa NRRL B-30509 and Paenibacillus terrae NRRL B-30644, Strains from a Poultry Environment That Produce Tridecaptin A and Paenicidins
Authors: van Belkum Marco J. , Lohans Christopher T. , Vederas John C.
Published: April 2015

Paenibacillus polymyxa
NRRL B-30509 and
Paenibacillus terrae
NRRL B-30644 produce tridecaptin A that is inhibitory to
Campylobacter jejuni
, as well as lantibiotics in the paenicidin family. Here, we report the draft genome sequences of
P. polymyxa
NRRL B-30509 and
P. terrae
NRRL B-30644 that contain gene clusters for various nonribosomal lipopeptides.
A rare cause of severe lactic acidosis
Authors: Saeed Saad , Kuravi Aditya , Rowley Matt , Saeed Marwa
Published: April 2015

Sarcoidosis is a multisystem disease of unknown aetiology with a classic histology of non-caseating granulomas. It most often occurs in those below the age of 50 years, and has a female preponderance. The main targets, often symptomless, are the lung and hilar lymph nodes, although liver involvement is not uncommon. Hepatic sarcoidosis encompasses a broad spectrum of presentations, from asymptomatic hepatic granulomas with slight liver function test derangement to severe liver involvement with cholestasis, advanced liver cirrhosis or chronic liver failure. Mortality due to acute liver failure is far less common than lung and heart involvement. We describe a case of fulminant liver failure with multiorgan failure presenting initially with chronic non-specific symptoms, in addition to minimal abnormal investigations such as mild anaemia, neutrophil leucocytosis and mild obstructive liver dysfunction. Presenting features included confusion, hypotension, oliguria and rapidly deteriorating liver function with severe lactic acidosis. Postmortem examination confirmed extensive systemic sarcoidosis.
Severe pelvic abscess formation following caesarean section
Authors: Muin Dana A , Takes Martin Thanh-Long , Hösli Irene , Lapaire Olav
Published: April 2015

We report a case of a 24-year-old woman with severe pelvic abscess formation 2 weeks after secondary caesarean section. The isolated pathogens were a mixture ofGardnerella vaginalis, Mycoplasma hominisandUreaplasma urealyticum. After initial resistance to systemic antibiotic treatment, she underwent radiologically-guided drainage of the abscesses, whereon she had a continuous recovery.
Primary osteosarcoma of the clavicle and the perils of bone biopsy
Authors: Cundy William J , Carter Christopher , Dhatrak Deepak , Clayer Mark
Published: April 2015

We present a rare case of delayed diagnosis of osteosarcoma of the medial clavicle in a young man. He presented following a pathological fracture with a falsely reassuring core and fine-needle aspiration biopsy. The initial biopsy was suggestive of an aneurysmal bone cyst and was therefore treated conservatively without further follow-up. The rapid increase in size over the next 8 months triggered a repeat presentation and subsequent repeat biopsy. The open biopsy confirmed high-grade osteosarcoma and the patient underwent claviculectomy with neoadjuvant chemotherapy.
Detecting and developing youth athlete potential: different strokes for different folks are warranted
Authors: Suppiah Haresh T , Low Chee Yong , Chia Michael
Published: April 2015

Sport talent identification and development (TI and TD) in youth continues to attract strong interest among coaches, sport scientists and sport administrators. TI for sport in youth with the anticipation of future elite level sport achievement is both an art and a science, and is strongly influenced by within athlete and extraneous-to-athlete factors (ecosystem of support or the lack of). The returns from investment on current TI and TD models of sport in youth are subpar in that few continue in the sport to achieve podium positions at the elite sport level in adulthood. Why, where and how one succeeds in sport, and what that success means to the athlete and stakeholders are dependent on the culture and context of the country. We advocate harnessing the power of sport to help in youth development, to be holistic in its nurturance, to allow for individual idiosyncratic expressions of the athletes, to provide for talent transfer across sport, and to facilitate key stakeholders to ‘join’ hands to work for the common interest and understanding for as many youth and adults so as to provide them with opportunities through support and coaching to compete at the different levels of competition in sport. Governments, policy makers and administrators of sport must decide, within their specific circumstances, if TI and TD in sport in youth is serving a meaningful purpose and is a viable return on investment; in short, is it mission possible or is it… a quest for the Holy Grail for a podium finish in elite level sport competition?
Clinical characteristics, precipitating factors, management and outcome of patients with prior stroke hospitalised with heart failure: an observational report from the Middle East
Authors: Khafaji Hadi A R , Sulaiman Kadhim , Singh Rajvir , AlHabib Khalid F , Asaad Nidal , Alsheikh-Ali Alawi , Al-Jarallah Mohammed , Bulbanat Bassam , AlMahmeed Wael , Ridha Mustafa , Bazargani Nooshin , Amin Haitham , Al-Motarreb Ahmed , AlFaleh Hussam , Elasfar Abdelfatah , Panduranga Prashanth , Al Suwaidi Jassim
Published: April 2015

Objectives

The purpose of this study is to report the prevalence, clinical characteristics, precipitating factors, management and outcome of patients with prior stroke hospitalised with acute heart failure (HF).

Design

Retrospective analysis of prospectively collected data.

Setting

Data were derived from Gulf CARE (Gulf aCute heArt failuRe rEgistry), a prospective multicentre study of consecutive patients hospitalised with acute HF in 2012 in seven Middle Eastern countries and analysed according to the presence or absence of prior stroke; demographics, management and outcomes were compared.

Participants

A total of 5005 patients with HF.

Outcome measures

In-hospital and 1-year outcome.

Results

The prevalence of prior stroke in patients with HF was 8.1%. Patients with stroke with HF were more likely to be admitted under the care of internists rather than cardiologists. When compared with patients without stroke, patients with stroke were more likely to be older and to have diabetes mellitus, hypertension, atrial fibrillation, hyperlipidaemia, chronic kidney disease, ischaemic heart disease, peripheral arterial disease and left ventricular dysfunction (p=0.001 for all). Patients with stroke were less likely to be smokers (0.003). There were no significant differences in terms of precipitating risk factors for HF hospitalisation between the two groups. Patients with stroke with HF had a longer hospital stay (mean±SD days; 11±14 vs 9±13, p=0.03), higher risk of recurrent strokes and 1-year mortality rates (32.7% vs 23.2%, p=0.001). Multivariate logistic regression analysis showed that stroke is an independent predictor of in-hospital and 1-year mortality.

Conclusions

This observational study reports high prevalence of prior stroke in patients hospitalised with HF. Internists rather than cardiologists were the predominant caregivers in this high-risk group. Patients with stroke had higher risk of in-hospital recurrent strokes and long-term mortality rates.

Trial registration number

NCT01467973.
The use of simulation to develop advanced communication skills relevant to psychiatry
Authors: Kowalski Christopher , Sathanandan Shivanthi
Published: April 2015

Objective

Using simulation, we developed an advanced communication skill training programme with the objective of improving core psychiatry trainees’ confidence in managing difficult situations at work.

Design

Two simulation courses, comprising six scenarios, were developed for psychiatry core trainees (CTs) on the University College London Partners (UCLP) training scheme. Trainees were divided into small groups. Each trainee undertook two scenarios each. Feedback was delivered by facilitators, peers and the simulated patients. Written feedback was also given.

Setting

The courses were delivered in a local postgraduate medical education centre.

Patients

Actors were used to simulate adult psychiatric patients and their relatives. Other scenarios involved actors portraying colleagues.

Interventions

The simulations offered an opportunity for experiential learning while the debriefs allowed for focused feedback on trainees’ communication styles.

Main outcome measures

Changes in trainees’ perception of their ability to deal with difficult situations at work were measured. Semistructured interviews further explored trainees’ experience of the course and its educational impact.

Results

100% (n=39) of the trainees felt that their communication skills had improved after the training. 97% felt more able to defuse an angry/tense situation at work while 92% felt more able to deal with a difficult situation requiring sophisticated communication skills. 97% felt that regular simulation training would be valuable while 100% (n=24) of facilitators agreed that the experience was valuable to the trainees’ professional development. Qualitative analysis showed that trainees found the scenarios realistic, that the experience had led to an increased awareness of their communication style and that original improvements in confidence had translated to their clinical work.

Conclusions

The programme demonstrates that it is possible to use simulation in a simple, inexpensive and time-effective manner to provide realistic, enjoyable and educationally beneficial advanced communication skill training relevant to psychiatric practice.
Electronic structure and bonding analysis of transition metal sandwich and half-sandwich complexes of the triphenylene ligand
Authors: Saiad Amira , Zouchoune Bachir
Published: April 2015

Full geometry optimization using the BP86 and B3LYP methods has been carried out for all of the low-energy isomers of half-sandwich L3M(Tphn) (Tphn = triphenylene, M = Ti–Ni, and L3= (CO)3, Cp–) and sandwich M(Tphn)2(Tphn = triphenylene and M = Ti, Cr, Fe, Ni) structures. Depending on the electron richness of the molecule and the nature of the metal, a complete rationalization of the bonding in triphenylene complexes has been provided. The triphenylene adopts various hapticities from η2to η6, some of them involving full or partial coordination of the C6ring and shown to be quite flexible with respect to the ground spin state. The triphenylene behavior remains dependent on the electron-withdrawing and electron-donor properties of the (CO)3M and CpM fragments, respectively. For the sandwich complexes, both triphenylene ligands prefer to behave differently depending on the coordination mode to satisfy the metal electron demand.
Relative importance of vessel hull fouling and ballast water as transport vectors of nonindigenous species to the Canadian Arctic
Authors: Chan Farrah T. , MacIsaac Hugh J. , Bailey Sarah A.
Published: April 2015

Ships’ hull fouling and ballast water are leading vectors of marine nonindigenous species globally, yet few studies have examined their magnitude in the Arctic. To determine the relative importance of these vectors in Canada’s Arctic, we collected hull and ballast water samples from 13 and 32 vessels, respectively, at Churchill, Manitoba. We compared total abundance and richness of invertebrates transported on hulls versus those in ballast water. We found that hull fouling was associated with higher total abundance and richness of nonindigenous species when compared with ballast water. Additionally, a significant positive richness–total abundance relationship for nonindigenous species for hull fouling but not for ballast water assemblages suggests that the likelihood of a high-risk (i.e., species-rich and high abundance) introduction event is greater for the former than the latter vector. The discovery of viable, widespread nonindigenous barnacles in hull samples further underscores the prominence of hull fouling over ballast water as a vector of nonindigenous species. Our study demonstrates that hull fouling is a more important vector for transfer of nonindigenous species to the Canadian Arctic than ballast water based on abundance and richness of nonindigenous species transported by the two vectors.
Na+–H+ exchanger inhibitor prevents early death in hereditary cardiomyopathy
Authors: Bkaily Ghassan , Chahine Mirna , Al-Khoury Johny , Avedanian Levon , Beier Norbert , Scholz Wolfgang , Jacques Danielle
Published: April 2015

Using the UM-X7.1 hereditary cardiomyopathic and muscular dystrophy hamsters (HCMH), we tested the effects of lifelong preventive or curative treatments during the heart failure phase with the NHE-1 inhibitor EMD 87580 (EMD) or with the angiotensin-converting enzyme inhibitor cilazapril on the intracellular Na+ and Ca2+ overloads, elevated level of NHE-1, necrosis, hypertrophy, heart failure, and early death. Our results showed that 310-day pretreatment of 30-day-old HCMHs with EMD significantly prevented cardiac necrosis, cardiomyocyte hypertrophy, and reduced the heart to body mass ratio. This treatment significantly prevented Na+ and Ca2+ overloads and the increase in NHE-1 protein level observed in HCMHs. Importantly, this lifelong preventive treatment significantly decreased the levels of creatine kinase and prevented early death of HCMHs. Curative treatment of hypertrophic 275-day-old HCMHs for 85 days with EMD significantly prevented hypertrophy and early death of HCMHs. However, treatments with cilazapril did not have any significant effects on the cardiac parameters studied or on early death of HCMHs. Our results suggest that the increase in the NHE-1 level and the consequent Na+ and Ca2+ overloads are implicated in the pathological process leading to heart failure and early death in HCMHs, and treatment with the NHE-1 inhibitor is promising for preventing early death in hereditary cardiomyopathy.
M-Ary Alpha-Stable Noise Modulation in Spread-Spectrum Communication
Authors: Cek Mehmet Emre
Published: April 2015

In this paper, a spread-spectrum communication system based on a random carrier is proposed which transmits M-ary information. The random signal is considered as a single realization of a random process taken from prescribed symmetric α-stable (SαS) distribution that carries digital M-ary information to be transmitted. Considering the noise model in the channel as additive white Gaussian noise (AWGN), the transmitter sends the information carrying random signal from non-Gaussian density. Alpha-stable distribution is used to encode the M-ary message. Inspired by the chaos shift keying techniques, the proposed method is called M-ary symmetric alpha-stable differential shift keying (M-ary SαS-DSK).

The main purpose of preferring non-Gaussian noise instead of conventional pseudo-noise (PN) sequence is to overcome the drawback of self-repeating noise-like sequences which are detectable due to the periodic behavior of the autocorrelation function of PN sequences. Having infinite second order moment in α-stable random carrier offers secrecy of the information due to the non-constant autocorrelation behavior. The bit error rate (BER) performance of the proposed method is illustrated by Monte Carlo simulations with respect to various characteristic exponent values and different data length.
Addendum: "Chain equivalences for symplectic bases, quadratic forms and tensor products of quaternion algebras"
Authors: Chapman Adam
Published: April 2015

We show how the chain lemma for quaternion algebras over fields of F ≠ 2 and [Formula: see text] can be strengthened so that up to two slots are changed at a time.
Erratum: "Rational maps of ℙn with prescribed fixed points and the smooth conic case"
Authors: Vargas J. A. , Argáez A. S.
Published: April 2015

We correct the errors found in our work referred in the present title. In particular, we acknowledge that the extent of our results does not generalize a theorem of Castelnuovo, as we incorrectly stated previously.
Decreased melatonin secretion is associated with increased intestinal permeability and marker of endotoxemia in alcoholics
Authors: Swanson Garth R. , Gorenz Annika , Shaikh Maliha , Desai Vishal , Forsyth Christopher , Fogg Louis , Burgess Helen J. , Keshavarzian Ali
Published: April 2015

Chronic heavy alcohol use is known to cause gut leakiness and alcoholic liver disease (ALD), but only 30% of heavy drinkers develop increased intestinal permeability and ALD. The hypothesis of this study was that disruption of circadian rhythms is a potential risk factor in actively drinking alcoholics for gut leakiness and endotoxemia. We studied 20 subjects with alcohol use disorder (AD) and 17 healthy controls (HC, 6 day workers, 11 night workers). Subjects wore a wrist actiwatch for 7 days and underwent a 24-h dim light phase assessment and urine collection for intestinal permeability. The AD group had significantly less total sleep time and increased fragmentation of sleep ( P < 0.05). AD also had significantly lower plasma melatonin levels compared with the HC [mean area under the curve (AUC) 322.78 ± 228.21 vs. 568.75 ± 304.26 pg/ml, P = 0.03]. In the AD group, AUC of melatonin was inversely correlated with small bowel and colonic intestinal permeability (lactulose-to-mannitol ratio, r = −0.39, P = 0.03; urinary sucralose, r = −0.47, P = 0.01). Cosinor analysis of lipopolysaccharide-binding protein (marker of endotoxemia) and lipopolysaccharide every 4 h for 24 h in HC and AD subjects had a midline estimating statistic of rhythm of 5,026.15 ± 409.56 vs. 6,818.02 ± 628.78 ng/ml ( P < 0.01) and 0.09 ± 0.03 vs. 0.15 ± 0.19 EU/ml ( P < 0.05), respectively. We found plasma melatonin was significantly lower in the AD group, and lower melatonin levels correlated with increased intestinal permeability and a marker of endotoxemia. Our study suggests the suppression of melatonin in AD may promote gut leakiness and endotoxemia.
Partial deletion of ROCK2 protects mice from high-fat diet-induced cardiac insulin resistance and contractile dysfunction
Authors: Soliman Hesham , Nyamandi Vongai , Garcia-Patino Marysol , Varela Julia Nogueira , Bankar Girish , Lin Guorong , Jia Zhengping , MacLeod Kathleen M.
Published: April 2015

Obesity is associated with cardiac insulin resistance and contractile dysfunction, which contribute to the development of heart failure. The RhoA-Rho kinase (ROCK) pathway has been reported to modulate insulin resistance, but whether it is implicated in obesity-induced cardiac dysfunction is not known. To test this, wild-type (WT) and ROCK2+/− mice were fed normal chow or a high-fat diet (HFD) for 17 wk. Whole body insulin resistance, determined by an insulin tolerance test, was observed in HFD-WT, but not HFD-ROCK2+/−, mice. The echocardiographically determined myocardial performance index, a measure of global systolic and diastolic function, was significantly increased in HFD-WT mice, indicating a deterioration of cardiac function. However, no change in myocardial performance index was found in hearts from HFD-ROCK2+/− mice. Speckle-tracking-based strain echocardiography also revealed regional impairment in left ventricular wall motion in hearts from HFD-WT, but not HFD-ROCK2+/−, mice. Activity of ROCK1 and ROCK2 was significantly increased in hearts from HFD-WT mice, and GLUT4 expression was significantly reduced. Insulin-induced phosphorylation of insulin receptor substrate (IRS) Tyr612, Akt, and AS160 was also impaired in these hearts, while Ser307 phosphorylation of IRS was increased. In contrast, the increase in ROCK2, but not ROCK1, activity was prevented in hearts from HFD-ROCK2+/− mice, and cardiac levels of TNFα were reduced. This was associated with normalization of IRS phosphorylation, downstream insulin signaling, and GLUT4 expression. These data suggest that increased activation of ROCK2 contributes to obesity-induced cardiac dysfunction and insulin resistance and that inhibition of ROCK2 may constitute a novel approach to treat this condition.
G-CSF Promotes Neuroblastoma Tumorigenicity and Metastasis via STAT3-Dependent Cancer Stem Cell Activation
Authors: Agarwal Saurabh , Lakoma Anna , Chen Zaowen , Hicks John , Metelitsa Leonid S. , Kim Eugene S. , Shohet Jason M.
Published: April 2015

Increasing evidence suggests that inflammatory cytokines play a critical role in tumor initiation and progression. A cancer stem cell (CSC)-like subpopulation in neuroblastoma is known to be marked by expression of the G-CSF receptor (G-CSFR). Here, we report on the mechanistic contributions of the G-CSFR in neuroblastoma CSCs. Specifically, we demonstrate that the receptor ligand G-CSF selectively activates STAT3 within neuroblastoma CSC subpopulations, promoting their expansion in vitro and in vivo. Exogenous G-CSF enhances tumor growth and metastasis in human xenograft and murine neuroblastoma tumor models. In response to G-CSF, STAT3 acts in a feed-forward loop to transcriptionally activate the G-CSFR and sustain neuroblastoma CSCs. Blockade of this G-CSF–STAT3 signaling loop with either anti-G-CSF antibody or STAT3 inhibitor depleted the CSC subpopulation within tumors, driving correlated tumor growth inhibition, decreased metastasis, and increased chemosensitivity. Taken together, our results define G-CSF as a CSC-activating factor in neuroblastoma, suggest a comprehensive reevaluation of the clinical use of G-CSF in these patients to support white blood cell counts, and suggest that direct targeting of the G-CSF–STAT3 signaling represents a novel therapeutic approach for neuroblastoma. Cancer Res; 75(12); 2566–79. ©2015 AACR.
Boosting Cancer Immunotherapy with Anti-CD137 Antibody Therapy
Authors: Yonezawa Atsushi , Dutt Suparna , Chester Cariad , Kim Jeewon , Kohrt Holbrook E.
Published: April 2015

In the past 5 years, immunomodulatory antibodies have revolutionized cancer immunotherapy. CD137, a member of the tumor necrosis factor receptor superfamily, represents a promising target for enhancing antitumor immune responses. CD137 helps regulate the activation of many immune cells, including CD4+ T cells, CD8+ T cells, dendritic cells, and natural killer cells. Recent studies indicate that the antitumor efficacy of therapeutic tumor-targeting antibodies can be augmented by the addition of agonistic antibodies targeting CD137. As ligation of CD137 provides a costimulatory signal in multiple immune cell subsets, combination therapy of CD137 antibody with therapeutic antibodies and/or vaccination has the potential to improve cancer treatment. Recently, clinical trials of combination therapies with agonistic anti-CD137 mAbs have been launched. In this review, we discuss the recent advances and clinical promise of agonistic anti-CD137 monoclonal antibody therapy. Clin Cancer Res; 21(14); 3113–20. ©2015 AACR.
Effect of Vitamin D3 Supplementation in Combination with Weight Loss on Inflammatory Biomarkers in Postmenopausal Women: A Randomized Controlled Trial
Authors: Duggan Catherine , de Dieu Tapsoba Jean , Mason Caitlin , Imayama Ikuyo , Korde Larissa , Wang Ching-Yun , McTiernan Anne
Published: April 2015

Obesity and vitamin D deficiency are associated with risk for several cancers, possibly through inflammation and adipokine-related pathways. Two hundred and eighteen postmenopausal women with BMI > 25 kg/m2 and low serum 25-hydroxyvitamin D (25(OH)D; ≥10–<32 ng/mL), were randomized to 12 months of either (i) weight-loss intervention + 2000 IU/day oral vitamin D3 or (ii) weight-loss intervention + daily placebo. Serum adiponectin, leptin, TNFα, IL6, IL1β, IL8, and IL10, were measured by immunoassay, and a composite inflammatory biomarker score calculated. Using generalized estimating equations, mean changes in outcomes were compared between arms (intent-to-treat), adjusted for possible confounders. Analyses were also stratified by weight-loss (gained/no weight-loss; <5%; 5% to 10%; ≥10%). At 12 months, there were no significant differences in analyte changes between arms. In stratified analyses, participants randomized to vitamin D3 who lost 5% to 10% of baseline weight, versus participants who gained weight/had no weight-loss, had significantly greater decreases in levels of IL6 compared with those randomized to placebo: absolute change −0.75 pg/mL (−17.2%), placebo versus −1.77 pg/mL (−37.3%), vitamin D, P = 0.004. Similar but attenuated results were observed for participants who lost ≥10% of baseline weight: −0.41 pg/mL (−13.6%), placebo versus −0.67 pg/mL (−17.3%), vitamin D, P = 0.02. Effects of vitamin D3 supplementation on levels of IL1β were inconsistent when stratified by weight loss. There were no intervention effects on IL10, TNFα, IL8, the composite score, adiponectin, or leptin, when stratified by weight-loss. In conclusion, vitamin D3 supplementation in combination with weight-loss of at least 5% of baseline weight was associated with significant reductions in levels of IL6. Cancer Prev Res; 8(7); 628–35. ©2015 AACR.
Genetic Manipulation of Homologous Recombination In Vivo Attenuates Intestinal Tumorigenesis
Authors: McIlhatton Michael A. , Murnan Kevin , Carson Daniel , Boivin Gregory P. , Croce Carlo M. , Groden Joanna
Published: April 2015

Although disruption of DNA repair capacity is unquestionably associated with cancer susceptibility in humans and model organisms, it remains unclear if the inherent tumor phenotypes of DNA repair deficiency syndromes can be regulated by manipulating DNA repair pathways. Loss-of-function mutations in BLM, a member of the RecQ helicase family, cause Bloom's syndrome (BS), a rare, recessive genetic disorder that predisposes to many types of cancer. BLM functions in many aspects of DNA homeostasis, including the suppression of homologous recombination (HR) in somatic cells. We investigated whether BLM overexpression, in contrast with loss-of-function mutations, attenuated the intestinal tumor phenotypes of ApcMin/+ and ApcMin/+;Msh2−/− mice, animal models of familial adenomatous polyposis coli (FAP). We constructed a transgenic mouse line expressing human BLM (BLM-Tg) and crossed it onto both backgrounds. BLM-Tg decreased adenoma incidence in a dose-dependent manner in our ApcMin/+ model of FAP, although levels of GIN were unaffected and concomitantly increased animal survival over 50%. It did not reduce intestinal tumorigenesis in ApcMin/+;Msh2−/− mice. We used the pink-eyed unstable (pun) mouse model to demonstrate that increasing BLM dosage in vivo lowered endogenous levels of HR by 2-fold. Our data suggest that attenuation of the Min phenotype is achieved through a direct effect of BLM-Tg on the HR repair pathway. These findings demonstrate that HR can be manipulated in vivo to modulate tumor formation at the organismal level. Our data suggest that lowering HR frequencies may have positive therapeutic outcomes in the context of specific hereditary cancer predisposition syndromes, exemplified by FAP. Cancer Prev Res; 8(7); 650–6. ©2015 AACR.
Effect of Metformin, Rapamycin, and Their Combination on Growth and Progression of Prostate Tumors in HiMyc Mice
Authors: Saha Achinto , Blando Jorge , Tremmel Lisa , DiGiovanni John
Published: April 2015

In this study, we compared the effect of oral administration of metformin (MET) and rapamycin (RAPA) alone or in combination on prostate cancer development and progression in HiMyc mice. MET (250 mg/kg body weight in the drinking water), RAPA (2.24 mg/kg body weight microencapsulated in the diet), and the combination inhibited progression of prostatic intraepithelial neoplasia lesions to adenocarcinomas in the ventral prostate (VP). RAPA and the combination were more effective than MET at the doses used. Inhibition of prostate cancer progression in HiMyc mice by RAPA was associated with a significant reduction in mTORC1 signaling that was further potentiated by the combination of MET and RAPA. In contrast, treatment with MET alone enhanced AMPK activation, but had little or no effect on mTORC1 signaling pathways in the VP of HiMyc mice. Further analyses revealed a significant effect of all treatments on prostate tissue inflammation as assessed by analysis of the expression of cytokines, the presence of inflammatory cells and NFκB signaling. MET at the dose used appeared to reduce prostate cancer progression primarily by reducing tissue inflammation whereas RAPA and the combination appeared to inhibit prostate cancer progression in this mouse model via the combined effects on both mTORC1 signaling as well as on tissue inflammation. Overall, these data support the hypothesis that blocking mTORC1 signaling and/or tissue inflammation can effectively inhibit prostate cancer progression in a relevant mouse model of human prostate cancer. Furthermore, combinatorial approaches that target both pathways may be highly effective for prevention of prostate cancer progression in men. Cancer Prev Res; 8(7); 597–606. ©2015 AACR.
The Blockade of Transmembrane Cl- Flux Mitigates I/R-Induced Heart Injury via the Inhibition of Calpain Activity
Authors: Zhang Jian-Ying , Wu Feng , Gu Xiao-Ming , Jin Zhen-Xiao , Kong Ling-Heng , Zhang Yuan , Zhou Jing-Jun , Gao Feng
Published: April 2015

Aims: The aim of this study was to determine whether calpain is involved in Cl- -induced myocardial ischemia/reperfusion (I/R) injury. Methods: Isolated rat hearts were subjected to either 45 min of global no-flow ischemia followed by reperfusion or successive perfusion with Ca2+ -free KH solution for 3 min and normal KH solution for 30 min, also known as Ca2+ paradox. Results: The hearts in the I/R group exhibited increases in myocardial injury area, LDH release, caspase 3 activity and apoptotic indices and a marked decline in cardiac performance. As was the case regarding the effects of MDL 28170, an inhibitor of calpain, treatment with 5 µM NPPB, 5 µM DIDS and low Cl- significantly attenuated cardiac injury. Moreover, each of the treatments significantly protected against Ca2+ overload-induced injury in the setting of Ca2+ paradox. The Western blot and immunofluorescence data revealed that there was an increase in the percentages of calpain membrane-positive cells and the numbers of fragments resulting from the calpain-mediated proteolysis of α-fodrin in both the I/R and the Ca2+ paradox, indicating that the activation of calpain occurred. More importantly, these effects were mitigated by the blockade of transmembrane Cl- flux, as was accomplished via MDL 28170. Conclusion: Our results provide evidence that the blockade of transmembrane Cl- flux mitigates I/R-induced cardiac injury via the inhibition of calpain activity. They also indicate that intracellular Ca2+ overload regulates calpain activation in the setting of Cl- -induced injury.
Antitumor Enhancement by Irradiated Haploidentical Donor Lymphocyte Infusion of Mice with Melanoma
Authors: Zhu Yingjiao , Lai Xiaolan , Zhao Shen , Zheng Jianwei , Wang Xinli , Weng Xiaojiao , Li Jieyu , Ye Yubin , Chen Qiang , Lin Xiaoyan
Published: April 2015

Background: Previous researches have reported that donor lymphocyte infusion (DLI) provides a new approach for the treatment of hematological malignancies and some solid tumors. The present study was designed to discuss the antitumor effect on mice with melanoma and possible involvement of the mechanism of haploidentical DLI in CB6F1 mice→CC3HF1 mice (F1→F1) mouse model. Methods: An F1→F1 haploidentical infusion model was established. CB6F1 mice (H-2b/d) bearing melanoma were used as recipients. CC3HF1 mice (H-2d/k) were used as donors. Changes in tumor volume and mice survival, host-derived lymphocytes proliferation, cytotoxicity, donor cell survival in vivo, histopathological examination of important organs, and the secretion Th1/Th2 cytokines were analyzed. Results: Irradiated haploidentical DLI combined with low-dose cyclophosphamide (Cy) chemotherapy induced an antitumor effect on mice with melanoma using the F1→F1 infusion model. Graft-versus-host disease (GvHD) was not obvious in any DLI-treated groups. Donor lymphocytes disappeared within 5 days after infusion, while the antitumor effect continued to be observed. Moreover, the DLI-treated groups showed a significant increase in the secretion of Th1 cytokines, including IFN-γ and IL-2, and an enhanced proliferation of CD8+ T lymphocytes and NK cells. Conclusions: Irradiated haploidentical DLI without bone marrow transplantation offers a safe, feasible, and effective approach in the treatment of melanoma.
Angiotensin-Converting Enzyme 2 Inhibits Apoptosis of Pulmonary Endothelial Cells During Acute Lung Injury Through Suppressing SMAD2 Phosphorylation
Authors: Ji Yong , Gao Fengying , Sun Bo , Hao Jing , Liu Zhenwei
Published: April 2015

Background/Aims: Angiotensin converting enzyme 2 (ACE2) has an established role in suppressing the severity of acute lung injury (ALI), especially when it was applied together with transplantation of human umbilical cord mesenchymal stem cells (uMSCs). Although the effects of ACE2 in ALI are believed to mainly result from its role in hydrolyzing angiotensin II (AngII), which subsequently reduces the vascular tension and subsequent pulmonary accumulation of inflammatory cells, we and others have recently reported a possible role of ACE2 in suppressing the ALI-induced apoptosis of pulmonary endothelial cells. However, the underlying mechanisms remain undetermined. Methods: Here, we analyzed the alteration in lung injury severity in ALI after ACE2, by histology and inflammatory cytokine levels. We analyzed apoptosis-associated proteins in lung after ALI, as well as in cultured endothelial cells treated with nitric oxide (NO). We overexpressed SMAD7 to inhibit SMAD2 signaling in cultured endothelial cells and examined its effects on NO-induced cell apoptosis. Results: ACE2 alleviated severity of lung injury after ALI. ACE2 significantly decreased the ALI-induced apoptosis of pulmonary cells in vivo, and ACE2 protected endothelial cells against NO-induced apoptosis in vitro. NO induced phosphorylation of a key factor of transforming growth factor β (TGF β) receptor signaling, SMAD2, which could be dose-dependently inhibited by ACE2. Inhibition of SMAD2 phosphorylation through expression of its inhibitor SMAD7 significantly inhibited NO-induced cell apoptosis, without need for ACE2. Conclusion: Our data suggest that ACE2-mediated AngII degradation may inhibit AngII-mediated SMAD2-phophorylation, possibly through a TGFβ-independent manner, which subsequently suppresses the ALI-induced cell death. Our results thus reveal a novel molecular pathway that controls the pathogenesis of ALI.
IL-4 Modulates Macrophage Polarization in Ankylosing Spondylitis
Authors: Lin Shishui , Qiu Meiguang , Chen Jianting
Published: April 2015

Background/Aims: Osteoclasts (OC) originate from monocytes/macrophages and play a critical role in the development of ankylosing spondylitis (AS). Receptor activator of NF-kB ligand (RANKL) is critical for the differentiation and maturation of OC from monocytes/macrophages, the underlying mechanisms of which processes have not been completely elucidated. Interleukin 4 (IL-4) attenuates the pathogenesis of AS via ill-defined mechanisms. Methods: We used a proteoglycan-induced arthritis (PGIA) model in Balb/c mice to study AS in humans. We injected IL-4 into the articular cavity and evaluated its effects on PGIA by incidence of arthritis, clinical and pathological arthritis severity and PET tracer uptake. We isolated and analyzed the number and polarization of macrophages in the articular cavity before and after IL-4 treatment. We analyzed RANKL levels in macrophage subtypes. We then isolated bone-marrow derived macrophages and treated them with IL-4 in vitro, with or without histone deacetylase inhibitors trichostatin A (TSA), and then analyzed the polarization of cultured macrophages before and after IL-4 treatment and RANKL levels in macrophage subtypes. Results: IL-4 treatment decreased the incidence and severity of arthritis in a mouse AS model, and polarized macrophages from a classical M1 subtype to an M2 subtype in vivo and in vitro. RANKL was predominantly produced by M1, but not by M2 macrophages. IL-4-mediated inhibition of RANKL in macrophages was abolished by TSA. Conclusion: Our data suggest that the therapeutic effects of IL-4 on AS may result from a M1-to-M2 macrophage polarization and its inhibition of RANKL expression on macrophages, possibly through enhanced histone deacetylation.
Mice Lacking Free Fatty Acid Receptor 1 (GPR40/FFAR1) are Protected Against Conjugated Linoleic Acid-Induced Fatty Liver but Develop Inflammation and Insulin Resistance in the Brain
Authors: Sartorius Tina , Drescher Andrea , Panse Madhura , Lastovicka Petr , Peter Andreas , Weigert Cora , Kostenis Evi , Ullrich Susanne , Häring Hans-Ulrich
Published: April 2015

Background/Aims: Conjugated linoleic acids (CLAs) affect body fat distribution, induce insulin resistance and stimulate insulin secretion. The latter effect is mediated through the free fatty acid receptor-1 (GPR40/FFAR1). This study examines whether GPR40/FFAR1 interacts with tissue specific metabolic changes induced by CLAs. Methods and Results: After chronic application of CLAs C57BL/6J wild type (WT) and GPR40/FFAR1 (Ffar1-/-) knockout mice developed insulin resistance. Although CLAs accumulated in liver up to 46-fold genotype-independently, hepatic triglycerides augmented only in WT mice. This triglyceride deposition was not associated with increased inflammation. In contrast, in brain of CLA fed Ffar1-/- mice mRNA levels of TNF-α were 2-fold higher than in brain of WT mice although CLAs accumulated genotype-independently in brain up to 4-fold. Concomitantly, Ffar1-/- mice did not respond to intracerebroventricular (i.c.v.) insulin injection with an increase in cortical activity while WT mice reacted as assessed by radiotelemetric electrocorticography (ECoG) measurements. In vitro incubation of primary murine astrocytes confirmed that CLAs stimulate neuronal inflammation independent of GPR40/FFAR1. Conclusion: This study discloses that GPR40/FFAR1 indirectly modulates organ-specific effects of CLAs: the expression of functional GPR40/FFAR1 counteracts CLA-induced inflammation and insulin resistance in the brain, but favors the development of fatty liver.
Using Next-Generation Sequencing to Identify a Mutation in Human MCSU that is Responsible for Type II Xanthinuria
Authors: Zhou Yunan , Zhang Xueguang , Ding Rui , Li Zuoxiang , Hong Quan , Wang Yan , Zheng Wei , Geng Xiaodong , Fan Meng , Cai Guangyan , Chen Xiangmei , Wu Di
Published: April 2015

Background: Hypouricemia is caused by various diseases and disorders, such as hepatic failure, Fanconi renotubular syndrome, nutritional deficiencies and genetic defects. Genetic defects of the molybdoflavoprotein enzymes induce hypouricemia and xanthinuria. Here, we identified a patient whose plasma and urine uric acid levels were both extremely low and aimed to identify the pathogenic gene and verify its mechanism. Methods: Using next-generation sequencing (NGS), we detected a mutation in the human molybdenum cofactor sulfurase (MCSU) gene that may cause hypouricemia. We cultured L02 cells, knocked down MCSU with RNAi, and then detected the uric acid and MCSU concentrations, xanthine oxidase (XOD) and xanthine dehydrogenase (XDH) activity levels, and xanthine/hypoxanthine concentrations in cell lysates and culture supernatants. Results: The NGS results showed that the patient had a mutation in the human MCSU gene. The in vitro study showed that RNAi of MCSU caused the uric acid, human MCSU concentrations, the XOD and XDH activity levels among cellular proteins and culture supernatants to be extremely low relative to those of the control. However, the xanthine/hypoxanthine concentrations were much higher than those of the control. Conclusions: We strongly confirmed the pathogenicity of the human MCSU gene.
Effects of Synthetic Neural Adhesion Molecule Mimetic Peptides and Related Proteins on the Cardiomyogenic Differentiation of Mouse Embryonic Stem Cells
Authors: Xu Ruodan , Srinivasan Sureshkumar Perumal , Sureshkumar Poornima , Nembo Erastus Nembu , Schäfer Christoph , Semmler Judith , Matzkies Matthias , Albrechtsen Morten , Hescheler Jürgen , Nguemo Filomain
Published: April 2015

Background/Aims: Pluripotent stem cells differentiating into cardiomyocyte-like cells in an appropriate cellular environment have attracted significant attention, given the potential use of such cells for regenerative medicine. However, the precise mechanisms of lineage specification of pluripotent stem cells are still largely to be explored. Identifying the role of various small synthetic peptides involved in cardiomyogenesis may provide new insights into pathways promoting cardiomyogenesis. Methods: In the present study, using a transgenic murine embryonic stem (ES) cell lineage expressing enhanced green fluorescent protein (EGFP) under the control of α-myosin heavy chain (α-MHC) promoter (pαMHC-EGFP), we investigated the cardiomyogenic effects of 7 synthetic peptides (Betrofin3, FGLs, FGLL, hNgf_C2, EnkaminE, Plannexin and C3) on cardiac differentiation. The expression of several cardiac-specific markers was determined by RT-PCR whereas the structural and functional properties of derived cardiomyocytes were examined by immunofluorescence and electrophysiology, respectively. Results: The results revealed that Betrofin3, an agonist of brain derived neurotrophic factor (BDNF) peptide exerted the most striking pro-cardiomyogenic effect on ES cells. We found that BDNF receptor, TrkB expression was up-regulated during differentiation. Treatment of differentiating cells with Betrofin3 between days 3 and 5 enhanced the expression of cardiac-specific markers and improved cardiomyocyte differentiation and functionality as revealed by genes regulation, flow cytometry and patch clamp analysis. Thus Betrofin3 may exert its cardiomyogenic effects on ES cells via TrkB receptor. Conclusion: Taken together, the results suggest that Betrofin3 modulates BDNF signaling with positive cardiomyogenic effect in stage and dose-dependent manner providing an effective strategy to increase ES cell-based generation of cardiomyocytes and offer a novel therapeutic approach to cardiac pathologies where BDNF levels are impaired.
Resveratrol Attenuated Low Ambient Temperature-Induced Myocardial Hypertrophy via Inhibiting Cardiomyocyte Apoptosis
Authors: Yin Kun , Zhao Liang , Feng Dan , Ma Wenya , Liu Yu , Wang Yang , Liang Jing , Yang Fan , Bi Chongwei , Chen Hongyang , Li Xingda , Lu Yanjie , Cai Benzhi
Published: April 2015

Background/Aims: Low ambient temperature is an important risk factor for cardiovascular diseases, and has been shown to lead to cardiac hypertrophy. In this study, we aim to investigate if Resveratrol may inhibit cold exposure-induced cardiac hypertrophy in mice, and if so to clarify its molecular mechanism. Methods: Adult male mice were randomly assigned to Control group (kept at room temperature), Cold group (kept at low air temperature range from 3°C to 5°C) and Resveratrol treatment group (100mg/kg/day) for eight weeks. HE staining, Masson staining and Transmission electron microscopy were employed to detect cardiac structure, fibrosis and myocardial ultrastructure, respectively. Echocardiogram was used to measure myocardial functions. Western blot was used to detect the expression of MAPK pathway and apoptotic proteins. TUENL assay was performed to evaluate cardiomyocyte apoptosis. qRT-PCR was employed to measure the mRNA level. Results: Cold-treated mice showed a higher heart/body weight ratio and heart weight/tibia length ratio compared with control mice, and Resveratrol treatment may suppress these changes in cold-treated mice. Myocardial cross-section area and cardiac collagen volume were larger in cold group than control group, which also can be attenuated by Resveratrol treatment. Also, Resveratrol improved the ultrastructure damage of myocardium such as myofibril disarray in cold group. Echocardiogram measurement showed that EF and FS values in cold group declined apparently as compared to control group, and Resveratrol may improve the reduction of heart functions. The expression of p-JNK, p-p38 and p-ERK relative to total JNK, p38 and ERK in cold group was not altered in cold group and Resveratrol group as compared to control group. Cold-treated mouse hearts also showed the upregulation of hypertrophy-related miRNA-miR-328 but not miR-23a, and Resveratrol treatment can inhibit the increase of miR-328. Finally, Resveratrol treatment also may suppress apoptosis of myocardium in cold-treated mouse hearts via inhibiting Bax and caspase-3 activation. Conclusion: In summary, low ambient temperature can cause enlarged heart, ultrastructure damage of myocardium and weakened functions, and Resveratrol treatment effectively suppressed these changes at least partially via inhibiting cardiomyocyte apoptosis.
Activation in M1 but not M2 Macrophages Contributes to Cardiac Remodeling after Myocardial Infarction in Rats: a Critical Role of the Calcium Sensing Receptor/NRLP3 Inflammasome
Authors: Liu Wenxiu , Zhang Xin , Zhao Meng , Zhang Xiaohui , Chi Jinyu , Liu Yue , Lin Fang , Fu Yu , Ma Dandan , Yin Xinhua
Published: April 2015

Aims: Macrophage (MΦ) infiltration during myocardial infarction (MI) amplifies cardiac inflammation and remodeling. We investigated whether activation of the NRLP3 inflammasome by a calcium sensing receptor (CaSR) in MΦ subsets contributes to cardiac remodeling following MI. Methods and Results: Infiltrated MΦ exhibited biphasic activation after MI; M1MΦ peaked at MI 3d and decreased until MI 14d, whereas M2MΦ peaked at MI 7d and decreased at MI 14d as shown via immunohistochemistry. IL-1β co-infiltrated with both M1MΦ and M2MΦ; IL-1β exhibited the same infiltrating tendency as M1MΦ, which was detected by immunohistochemistry. Increasing ventricular fibrosis was confirmed by Masson staining. CaSR and NLRP3 inflammasome in the MI group were upregulated in MΦ subsets in myocardium and peritoneal MΦ (p-MΦ) compared with the sham groups which were detected by immunofluorescence and western blotting. CaSR-activated NLRP3 inflammasome played a role in M1MΦ via PLC-IP3 but did not play a role in M2MΦ which were polarized by the THP-1 as shown by western blotting and intracellular calcium measurement. CaSR/NLRP3 inflammasome activation in M1MΦ led to the following effects: upregulated α-sma, MMP-2 and MMP-9, and collagen secretion; and downregulated TIMP-2 in cardiac fibroblasts via IL-1β-IL-1RI, which was detected by coculturing M1MΦ and cardiac fibroblasts. Conclusions: We suggest that the CaSR/NLRP3 inflammasome plays an essential role via the PLC-IP3 pathway in M1MΦ to promote cardiac remodeling post-MI in rats, including accelerated cardiac fibroblast phenotypic transversion, increased collagen and extracellular matrix (ECM) secretion; however, the CaSR/NLRP3 inflammasome does not play a role in this process in M2MΦ.