bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combining Oncolytic HSV-1 with Immunogenic Cell Death-Inducing Drug Mitoxantrone Breaks Cancer Immune Tolerance and Improves Therapeutic Efficacy
Authors: Workenhe Samuel T. , Pol Jonathan G. , Lichty Brian D. , Cummings Derek T. , Mossman Karen L. 
Published: August 2013

Abstract
Although antitumor activity of herpes simplex virus 1 (HSV-1) ICP0 null oncolytic vectors has been validated in murine breast cancer models, oncolytic virus treatment alone is insufficient to break immune tolerance. Thus, we investigated enhancing efficacy through combination therapy with the immunogenic cell death–inducing chemotherapeutic drug, mitoxantrone. Despite a lack of enhanced cytotoxicity in vitro, HSV-1 ICP0 null oncolytic virus KM100 with 5 μmol/L mitoxantrone provided significant survival benefit to BALB/c mice bearing Her2/neu TUBO-derived tumors. This protection was mediated by increased intratumoral infiltration of neutrophils and tumor antigen-specific CD8+ T cells. Depletion studies verified that CD8-, CD4-, and Ly6G-expressing cells are essential for enhanced efficacy of the combination therapy. Moreover, the addition of mitoxantrone to KM100 oncolytic virus treatment broke immune tolerance in BALB-neuT mice bearing TUBO-derived tumors. This study suggests that oncolytic viruses in combination with immunogenic cell death–inducing chemotherapeutics enhance the immunogenicity of the tumor-associated antigens, breaking immunologic tolerance established toward these antigens. Cancer Immunol Res; 1(5); 309–19. ©2013 AACR.
CD4+ T Effectors Specific for the Tumor Antigen NY-ESO-1 Are Highly Enriched at Ovarian Cancer Sites and Coexist with, but Are Distinct from, Tumor-Associated Treg
Authors: Ayyoub Maha , Pignon Pascale , Classe Jean-Marc , Odunsi Kunle , Valmori Danila 
Published: August 2013

Abstract
Whereas tumor infiltration by T effectors is generally associated with a more favorable prognosis, the accumulation of CD4+ regulatory T cells (Treg) within tumors is instead often associated with poor disease outcome. Because approaches to improve antitumor immunity aim, on one hand, at expanding tumor antigen-specific T cells and, on the other, at eliminating or inactivating Treg, an outstanding question is whether, and to what extent, tumor antigen-specific CD4+ T effectors present at tumor sites overlap with tumor-associated Treg. Here, we used MHC class II/peptide tetramers incorporating an immunodominant peptide from the human tumor-specific antigen NY-ESO-1 to assess antigen-specific CD4+ T cells among conventional CD4+ T effectors and Treg at sites of ovarian cancer. We found that, in patients who spontaneously respond to the antigen, the frequency of NY-ESO-1 tetramer+ cells detected ex vivo was highly enriched in tumors as compared with the periphery. At tumor sites, NY-ESO-1 tetramer+ cells were detected concomitantly with high proportions of Treg but were distinct from the latter and displayed characteristics of TH1 effectors. Thus, even in the presence of high proportions of Treg, tumor antigen-specific CD4+ T cells can accumulate in ovarian tumors and maintain an effector phenotype. Cancer Immunol Res; 1(5); 303–8. ©2013 AACR.
Sinoatrial Node Reentry in a Canine Chronic Left Ventricular Infarct Model
Authors: Glukhov Alexey V. , Hage Lori T. , Hansen Brian J. , Pedraza-Toscano Adriana , Vargas-Pinto Pedro , Hamlin Robert L. , Weiss Raul , Carnes Cynthia A. , Billman George E. , Fedorov Vadim V. 
Published: August 2013

Background—
Reentrant arrhythmias involving the sinoatrial node (SAN), namely SAN reentry, remain one of the most intriguing enigmas of cardiac electrophysiology. The goal of the present study was to elucidate the mechanism of SAN micro-reentry in canine hearts with post–myocardial infarction (MI) structural remodeling.

Methods and Results—

In vivo, Holter monitoring revealed ventricular arrhythmias and SAN dysfunctions in post–left ventricular MI (6–15 weeks) dogs (n=5) compared with control dogs (n=4). In vitro, high-resolution near-infrared optical mapping of intramural SAN activation was performed in coronary perfused atrial preparations from MI (n=5) and controls (n=4). Both SAN macro- (slow-fast; 16–28 mm) and micro-reentry (1–3 mm) were observed in 60% of the MI preparations during moderate autonomic stimulation (acetylcholine [0.1 µmol/L] or isoproterenol [0.01–0.1 µmol/L]) after termination of atrial tachypacing (5–8 Hz), a finding not seen in controls. The autonomic stimulation induced heterogeneous changes in the SAN refractoriness; thus, competing atrial or SAN pacemaker waves could produce unidirectional blocks and initiate intranodal micro-reentry. The micro-reentry pivot waves were anchored to the longitudinal block region and produced both tachycardia and paradoxical bradycardia (due to exit block), despite an atrial ECG morphology identical to regular sinus rhythm. Intranodal longitudinal conduction blocks coincided with interstitial fibrosis strands that were exaggerated in the MI SAN pacemaker complex (fibrosis density: 37±7% MI versus 23±6% control;
P
<0.001).

Conclusions—
Both tachy- and brady-arrhythmias can result from SAN micro-reentry. Postinfarction remodeling, including increased intranodal fibrosis and heterogeneity of refractoriness, provides substrates for SAN reentry.
Transforming Growth Factor-β Signaling Promotes Pulmonary Hypertension Caused by
Schistosoma Mansoni
Authors: Graham Brian B. , Chabon Jacob , Gebreab Liya , Poole Jennifer , Debella Elias , Davis Laura , Tanaka Takeshi , Sanders Linda , Dropcho Nina , Bandeira Angela , Vandivier R. William , Champion Hunter C. , Butrous Ghazwan , Wang Xiao-Jing , Wynn Thomas A. , Tuder Rubin M. 
Published: August 2013

Background—
The pathogenic mechanisms underlying pulmonary arterial hypertension resulting from schistosomiasis, one of the most common causes of pulmonary hypertension worldwide, remain unknown. We hypothesized that transforming growth factor-β (TGF-β) signaling as a consequence of Th2 inflammation is critical for the pathogenesis of this disease.

Methods and Results—

Mice sensitized and subsequently challenged with
Schistosoma mansoni
eggs developed pulmonary hypertension associated with an increase in right ventricular systolic pressure, thickening of the pulmonary artery media, and right ventricular hypertrophy. Rho-kinase–dependent vasoconstriction accounted for ≈60% of the increase in right ventricular systolic pressure. The pulmonary vascular remodeling and pulmonary hypertension were dependent on increased TGF-β signaling, as pharmacological blockade of the TGF-β ligand and receptor, and mice lacking Smad3 were significantly protected from
Schistosoma
-induced pulmonary hypertension. Blockade of TGF-β signaling also led to a decrease in interleukin-4 and interleukin-13 concentrations, which drive the Th2 responses characteristic of schistosomiasis lung pathology. Lungs of patients with schistosomiasis-associated pulmonary arterial hypertension have evidence of TGF-β signaling in their remodeled pulmonary arteries.

Conclusion—

Experimental
S mansoni
–induced pulmonary vascular disease relies on canonical TGF-β signaling.
Myocardial Reloading After Extracorporeal Membrane Oxygenation Alters Substrate Metabolism While Promoting Protein Synthesis
Authors: Kajimoto Masaki , O'Kelly Priddy Colleen M. , Ledee Dolena R. , Xu Chun , Isern Nancy , Olson Aaron K. , Rosiers Christine Des , Portman Michael A. 
Published: August 2013

Background

Extracorporeal membrane oxygenation (
ECMO
) unloads the heart, providing a bridge to recovery in children after myocardial stunning.
ECMO
also induces stress which can adversely affect the ability to reload or wean the heart from the circuit. Metabolic impairments induced by altered loading and/or stress conditions may impact weaning. However, cardiac substrate and amino acid requirements upon weaning are unknown. We assessed the hypothesis that ventricular reloading with
ECMO
modulates both substrate entry into the citric acid cycle (
CAC
) and myocardial protein synthesis.

Methods and Results

Sixteen immature piglets (7.8 to 15.6 kg) were separated into 2 groups based on ventricular loading status: 8‐hour
ECMO
(
UNLOAD
) and postwean from
ECMO
(
RELOAD
). We infused into the coronary artery [2‐
13
C]‐pyruvate as an oxidative substrate and [
13
C
6
]‐L‐leucine as an indicator for amino acid oxidation and protein synthesis. Upon
RELOAD
, each functional parameter, which were decreased substantially by
ECMO
, recovered to near‐baseline level with the exclusion of minimum dP/dt. Accordingly, myocardial oxygen consumption was also increased, indicating that overall mitochondrial metabolism was reestablished. At the metabolic level, when compared to
UNLOAD
,
RELOAD
altered the contribution of various substrates/pathways to tissue pyruvate formation, favoring exogenous pyruvate versus glycolysis, and acetyl‐CoA formation, shifting away from pyruvate decarboxylation to endogenous substrate, presumably fatty acids. Furthermore, there was also a significant increase of tissue concentrations for all
CAC
intermediates (≈80%), suggesting enhanced anaplerosis, and of fractional protein synthesis rates (>70%).

Conclusions

RELOAD
alters both cytosolic and mitochondrial energy substrate metabolism, while favoring leucine incorporation into protein synthesis rather than oxidation in the
CAC
. Improved understanding of factors governing these metabolic perturbations may serve as a basis for interventions and thereby improve success rate from weaning from
ECMO
.
Hypertrophy of Neurons Within Cardiac Ganglia in Human, Canine, and Rat Heart Failure: The Potential Role of Nerve Growth Factor
Authors: Singh Sanjay , Sayers Scott , Walter James S. , Thomas Donald , Dieter Robert S. , Nee Lisa M. , Wurster Robert D. 
Published: August 2013

Background
Autonomic imbalances including parasympathetic withdrawal and sympathetic overactivity are cardinal features of heart failure regardless of etiology; however, mechanisms underlying these imbalances remain unknown. Animal model studies of heart and visceral organ hypertrophy predict that nerve growth factor levels should be elevated in heart failure; whether this is so in human heart failure, though, remains unclear. We tested the hypotheses that neurons in cardiac ganglia are hypertrophied in human, canine, and rat heart failure and that nerve growth factor, which we hypothesize is elevated in the failing heart, contributes to this neuronal hypertrophy.

Methods and Results

Somal morphology of neurons from human (579.54±14.34 versus 327.45±9.17 μm
2
;
P
<0.01) and canine hearts (767.80±18.37 versus 650.23±9.84 μm
2
;
P
<0.01) failing secondary to ischemia and neurons from spontaneously hypertensive rat hearts (327.98±3.15 versus 271.29±2.79 μm
2
;
P
<0.01) failing secondary to hypertension reveal significant hypertrophy of neurons in cardiac ganglia compared with controls. Western blot analysis shows that nerve growth factor levels in the explanted, failing human heart are 250% greater than levels in healthy donor hearts. Neurons from cardiac ganglia cultured with nerve growth factor are significantly larger and have greater dendritic arborization than neurons in control cultures.

Conclusions
Hypertrophied neurons are significantly less excitable than smaller ones; thus, hypertrophy of vagal postganglionic neurons in cardiac ganglia would help to explain the parasympathetic withdrawal that accompanies heart failure. Furthermore, our observations suggest that nerve growth factor, which is elevated in the failing human heart, causes hypertrophy of neurons in cardiac ganglia.
Concussion Symptoms and Neurocognitive Performance of High School and College Athletes Who Incur Multiple Concussions
Authors: Covassin Tracey , Moran Ryan , Wilhelm Kristyn 
Published: August 2013

Background: Multiple concussions have been associated with prolonged symptoms, recovery time, and risk for future concussions. However, very few studies have examined the effect of multiple concussions on neurocognitive performance and the recently revised symptom clusters using a large database. Purpose: To examine concussed athletes with a history of 0, 1, 2, or ≥3 concussions on neurocognitive performance and the recently revised symptom clusters. Study Design: Cohort study (prognosis); Level of evidence, 2. Methods: The independent variables were concussion group (0, 1, 2, and ≥3 concussions) and time (baseline, 3 days, and 8 days). The dependent variables were neurocognitive test scores as measured by the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) neurocognitive test battery (verbal and visual memory, processing speed, and reaction time) and 4 concussion symptom clusters (migraine-cognitive-fatigue, affective, somatic, and sleep). All concussed athletes (n = 596) were administered the ImPACT test at a mean 2.67 ± 1.98 and 7.95 ± 4.46 days after injury. A series of 4 (concussion group) × 3 (time) repeated-measures analyses of covariance (age = covariate) were performed on ImPACT composite scores and symptom clusters. Results: Concussed athletes with ≥3 concussions were still impaired 8 days after a concussion compared with baseline scores on verbal memory ( P < .001), reaction time ( P < .001), and migraine-cognitive-fatigue symptoms ( P < .001). There were no significant findings on the remaining dependent variables. Conclusion: Concussed athletes with a history of ≥3 concussions take longer to recover than athletes with 1 or no previous concussion. Future research should concentrate on validating the new symptom clusters on multiple concussed athletes, examining longer recovery times (ie, >8 days) among athletes with multiple concussions.
Q222R polymorphism in DNAse I gene is a risk factor for nephritis in South Indian SLE patients
Authors: Panneer D , Antony PT , Negi VS 
Published: August 2013

Objective Systemic lupus erythematosus (SLE) is a multisystem disorder in which defective apoptotic clearance is considered to be an important factor in pathogenesis. DNAse I is associated with disposal of apoptotic nuclear debris. The defective enzyme production due to +2373  A to G ( Q222R) in exon 8 is reported to be a genetic risk factor for SLE. SLE in Indians is reported to be severe. There are no genetic studies reported from India which have explored this aspect of DNAseI gene. This study aimed to analyze whether Q222R is a susceptibility factor for SLE and to study its influence on clinical manifestations and autoantibody production in South Indian Tamils. Method Three hundred SLE cases (based on ACR 1982 criteria) and 530 age, sex similar and ethnicity matched controls were recruited. All the cases and controls were genotyped for DNAse I Q222R polymorphism using PCR-RFLP method. Results DNAse I Q222R polymorphism is prevalent in our population. We observed higher frequency of Q/R in patients compared with controls (60% vs. 53%). This was found to be a genetic risk for SLE susceptibility ( p = 0.04, odds ratio 1.5, 95% confidence interval 1–2.1). It also conferred a significant risk for development of nephritis ( p = 0.007, odds ratio 1.93, 95% confidence interval 1.2–3.2). Conclusion DNAse I Q222R polymorphism is a potential genetic risk factor for SLE in South Indian Tamils. In addition, the mutant allele confers a significant risk for lupus nephritis.
Impaired sexual function in women with systemic lupus erythematosus: a cross-sectional study
Authors: Morales M García , Rubio JL Callejas , Peralta-Ramírez MI , Romero LJ Henares , Fernández R Ríos , García MT Camps , Navarrete N Navarrete , Centeno N Ortego 
Published: August 2013

Objective The objectives of this paper are to compare sexual function and distress in women with systemic lupus erythematosus (SLE) and in healthy controls; to determine the association between disease characteristics, quality of life, psychopathology and sexual function; and to compare sexual function and distress of women according to age (reproductive and nonreproductive-age women). Methods We conducted a cross-sectional study of 120 participants; 65 women had SLE (aged 18–65), and 55 were healthy, age-matched controls. The assessment included the Female Sexual Function Index (FSFI), Symptom Checklist-90-Revised (SCL-90-R), Short Form 36 health survey (SF-36), socio-demographic characteristics and the Systemic Lupus International Collaborating Clinics (SLICC) and SLE Disease Activity Index (SLEDAI) in SLE patients only. Results Of 65 eligible patients with SLE, 61 (94%) responded; of 55 control subjects, 53 (96%) responded. The FSFI total score and subscale scores for desire, arousal, lubrication, orgasm and pain were significantly lower in patients with SLE. More somatization, obsessive-compulsive symptoms, interpersonal sensitivity, depression, anxiety, hostility, phobia, paranoid ideation, psychoticism, the Positive Symptom Total (PST), Positive Score Discomfort Index (PSDI), the use of psychotropic drugs, general health, vitality, social function, emotional role and mental health were significantly associated with changes in the patient group’s sexuality. Multivariate analysis indicated that depression, PSDI and vitality were the variables significantly associated with low sexual function in patients with SLE. Conclusions Women with SLE reported significantly impaired sexual function compared with healthy controls. Impaired sexual function was associated with somatization, obsessive-compulsive behavior, interpersonal sensitivity, depression, hostility, paranoid ideation, psychoticism, PST, higher scores in the PSDI subscale, vitality, social functioning and mental health. These results indicate that, in daily practice, inquiring about sexuality and quality of life and screening for psychopathology are important for every patient with SLE, irrespective of their clinical characteristics.
The number of spanning trees of a graph
Authors: Das Kinkar C , Cevik Ahmet S , Cangul Ismail N 
Published: August 2013

Abstract
Let G be a simple connected graph of order n, m edges, maximum degree

Δ
1

and minimum degree δ. Li et al. (Appl. Math. Lett. 23:286-290, 2010) gave an upper bound on number of spanning trees of a graph in terms of n, m,

Δ
1

and δ:

t
(
G
)
≤
δ

(

2
m
−

Δ
1

−
δ
−
1

n
−
3

)

n
−
3

.

The equality holds if and only if

G
≅

K

1
,
n
−
1

,

G
≅

K
n

,

G
≅

K
1

∨
(

K
1

∪

K

n
−
2

)

or

G
≅

K
n

−
e

, where e is any edge of

K
n

. Unfortunately, this upper bound is erroneous. In particular, we show that this upper bound is not true for complete graph

K
n

.
In this paper we obtain some upper bounds on the number of spanning trees of graph G in terms of its structural parameters such as the number of vertices (n), the number of edges (m), maximum degree (

Δ
1

), second maximum degree (

Δ
2

), minimum degree (δ), independence number (α), clique number (ω). Moreover, we give the Nordhaus-Gaddum-type result for number of spanning trees.

MSC:05C50, 15A18.
Long term healthcare costs of infants who survived neonatal necrotizing enterocolitis: a retrospective longitudinal study among infants enrolled in Texas Medicaid
Authors: Ganapathy Vaidyanathan , Hay Joel W , Kim Jae H , Lee Martin L , Rechtman David J 
Published: August 2013

AbstractBackgroundInfants who survive advanced necrotizing enterocolitis (NEC) at the time of birth are at increased risk of having poor long term physiological and neurodevelopmental growth. The economic implications of the long term morbidity in these children have not been studied to date. This paper compares the long term healthcare costs beyond the initial hospitalization period incurred by medical and surgical NEC survivors with that of matched controls without a diagnosis of NEC during birth hospitalization.MethodsThe longitudinal healthcare utilization claim files of infants born between January 2002 and December 2003 and enrolled in the Texas Medicaid fee-for-service program were used for this research. Propensity scoring was used to match infants diagnosed with NEC during birth hospitalization to infants without a diagnosis of NEC on the basis of gender, race, prematurity, extremely low birth weight status and presence of any major birth defects. The Medicaid paid all-inclusive healthcare costs for the period from 6 months to 3 years of age among children in the medical NEC, surgical NEC and matched control groups were evaluated descriptively, and in a generalized linear regression framework in order to model the impact of NEC over time and by birth weight.ResultsTwo hundred fifty NEC survivors (73 with surgical NEC) and 2,909 matched controls were available for follow-up. Medical NEC infants incurred significantly higher healthcare costs than matched controls between 6–12 months of age (mean incremental cost = US$ 5,112 per infant). No significant difference in healthcare costs between medical NEC infants and matched controls was seen after 12 months. Surgical NEC survivors incurred healthcare costs that were consistently higher than that of matched controls through 36 months of age. The mean incremental healthcare costs of surgical NEC infants compared to matched controls between 6–12, 12–24 and 24–36 months of age were US$ 18,274, 14,067 (p < 0.01) and 8,501 (p = 0.06) per infant per six month period, respectively. These incremental costs were found to vary between sub-groups of infants born with birth weight < 1,000g versus ≥ 1,000g (p < 0.05).ConclusionsThe all-inclusive healthcare costs of surgical NEC survivors continued to be substantially higher than that of matched controls through the early childhood development period. These results can have important treatment and policy implications. Further research in this topic is needed.
Prevalence and patterns of multimorbidity among tuberculosis patients in Brazil: a cross-sectional study
Authors: Reis-Santos Bárbara , Gomes Teresa , Macedo Laylla R , Horta Bernardo L , Riley Lee W , Maciel Ethel L 
Published: August 2013

Abstract

Introduction
The number of subjects with tuberculosis (TB) presenting with co-occurrence of multiple chronic medical conditions, or multimorbidity (MM) is increasing in Brazil. This manuscript aimed to characterize subjects with TB, according to their MM status and to analyse factors associated with TB treatment outcomes.

Methods
This is a cross-sectional study that included 39,881 TB subjects reported in Brazil, in 2011. MM were defined as any (two or more) occurrence of chronic medical conditions in a TB patient (TB–MM). Data analysis was performed by hierarchical logistic regression models comparing TBMM with those with only TB.

Results
Of the reported TB cases in 2011, 454 (1.14%) had MM. The subjects in the age group 40–59 years (OR: 17.89; 95% CI, 5.71-56.03) and those ≥ 60 years (OR: 44.11; 95% CI, 14.09-138.06) were more likely to develop TB–MM. The TB–MM subjects were less likely to be male (OR: 0.63; 95% CI, 0.52-0.76), institutionalized (OR: 0.59; 95% CI, 0.23-0.80) and live in rural areas (OR: 0.63; 95% CI, 0.42-0.95). Death from causes other than TB was higher among TB–MM subjects (OR: 1.76; 95% CI, 1.36-2.28). Of 454 TB–MM subjects 302 (66.5%) were cured and 152 (33.5%) were not cured. The odds of not being cured was 1.55 (95% CI, 1.04-2.32) among males, 2.85 (95% CI, 1.12-7.28) among institutionalized subjects, and 3.93 (IC 95%, 1.86-8.30) among those who were infected with HIV. TB retreatment after previous abandonment (OR: 7.53; 95% CI, 2.58-21.97) and transfer from a treatment site (OR: 2.76; 95% CI, 1.20-6.38) were higher for subjects not cured compared to those who were cured.

Conclusions
While TB is well recognized to be a disease engendered by social inequity, we found that even among TB patients, those who have MM have greater inequity in terms of socioeconomic status and adverse clinical outcomes. Addressing the problem of TB and TB–MM requires a multisectorial approach that includes health and social service organizations.