bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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

Abstract
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.
Class IA Phosphatidylinositol 3-Kinase Isoform p110α Mediates Vascular Remodeling
Authors: Vantler Marius , Jesus Joana , Leppänen Olli , Scherner Maximilian , Berghausen Eva Maria , Mustafov Lenard , Chen Xin , Kramer Tilmann , Zierden Mario , Gerhardt Maximilian , ten Freyhaus Henrik , Blaschke Florian , Sterner-Kock Anja , Baldus Stephan , Zhao Jean J. , Rosenkranz Stephan 
Published: April 2015

Objective—
Neointima formation after vascular injury remains a significant problem in clinical cardiology, and current preventive strategies are suboptimal. Phosphatidylinositol 3′-kinase is a central downstream mediator of growth factor signaling, but the role of phosphatidylinositol 3′-kinase isoforms in vascular remodeling remains elusive. We sought to systematically characterize the precise role of catalytic class IA phosphatidylinositol 3′-kinase isoforms (p110α, p110β, p110δ), which signal downstream of receptor tyrosine kinases, for vascular remodeling in vivo.

Approach and Results—

Western blot analyses revealed that all 3 isoforms are abundantly expressed in smooth muscle cells. To analyze their significance for receptor tyrosine kinases–dependent cellular responses, we used targeted gene knockdown and isoform-specific small molecule inhibitors of p110α (PIK-75), p110β (TGX-221), and p110δ (IC-87114), respectively. We identified p110α to be crucial for receptor tyrosine kinases signaling, thus affecting proliferation, migration, and survival of rat, murine, and human smooth muscle cells, whereas p110β and p110δ activities were dispensable. Surprisingly, p110δ exerted noncatalytic functions in smooth muscle cell proliferation, but had no effect on migration. Based on these results, we generated a mouse model of smooth muscle cell–specific p110α deficiency (sm-p110α
−/−
). Targeted deletion of p110α in sm-p110α
−/−
mice blunted growth factor–induced cellular responses and abolished neointima formation after balloon injury of the carotid artery in mice. In contrast, p110δ deficiency did not affect vascular remodeling in vivo.

Conclusions—
Receptor tyrosine kinases–induced phosphatidylinositol 3′-kinase signaling via the p110α isoform plays a central role for vascular remodeling in vivo. Thus, p110α represents a selective target for the prevention of neointima formation after vascular injury, whereas p110β and p110δ expression and activity do not play a significant role.
Involvement of Interleukin-1 Receptor–Associated Kinase-1 in Vascular Smooth Muscle Cell Proliferation and Neointimal Formation After Rat Carotid Injury
Authors: Jain Manish , Singh Ankita , Singh Vishal , Barthwal Manoj Kumar 
Published: April 2015

Objective—
Reduced frequency of atherosclerotic plaques is observed in interleukin-1 receptor–associated kinase-1 (IRAK1)–deficient mice; however, the underlying mechanism is not clear. Therefore, this study investigate the role of IRAK1 in vascular smooth muscle cell proliferation and neointimal hyperplasia.

Approach and Results—
Stimulation of rat primary vascular smooth muscle cells with fetal bovine serum (10%) or platelet-derived growth factor-BB (20 ng/mL) for 15 minutes to 24 hours induced a time-dependent increase in IRAK1 and extracellular signal–regulated kinase (ERK) activation, proliferating cell nuclear antigen upregulation and p27Kip1 downregulation as assessed by Western blotting. Inhibitors of ERK pathway (U0126, 10 μmol/L), IRAK (IRAK1/4, 3 μmol/L), protein kinase C (PKC; Ro-31-8220, 1 μmol/L), siRNA of toll-like receptor-4 (200 nmol/L), and PKC-ε (200 nmol/L) significantly attenuated these changes. Platelet-derived growth factor induced endogenous IRAK–ERK–PKC-ε association in a toll-like receptor-4 and PKC-ε–dependent manner. A time-dependent increase in IRAK1 and ERK activation was observed after 15 minutes, 30 minutes, 1 hour, 6 hours, 12 hours, and 24 hours of carotid balloon injury in rats. Balloon injury induced endogenous IRAK–ERK–PKC-ε interaction. Perivascular application of IRAK1/4 inhibitor (100 μmol/L), U0126 (100 μmol/L), and IRAK1 siRNA (220 and 360 nmol/L) in pluronic gel abrogated balloon injury–induced ERK phosphorylation, activation, and p27Kip1 downregulation. Hematoxylin and eosin staining and immunohistochemistry of proliferating cell nuclear antigen and smooth muscle actin demonstrated that balloon injury–induced intimal thickening and neointimal vascular smooth muscle cell proliferation were significantly abrogated in the presence of IRAK1/4 inhibitor, IRAK1 siRNA, and U0126.

Conclusions—
IRAK1 mediates vascular smooth muscle cell proliferation and neointimal hyperplasia by regulating PKC-ε–IRAK1–ERK axis.
Novel Protein Glycan Side-Chain Biomarker and Risk of Incident Type 2 Diabetes Mellitus
Authors: Akinkuolie Akintunde O. , Pradhan Aruna D. , Buring Julie E. , Ridker Paul M , Mora Samia 
Published: April 2015

Objectives—

Enzymatically glycosylated proteins partake in multiple biological processes, including glucose transport and inflammation. We hypothesized that a novel biomarker (GlycA) of
N
-acetyl methyl groups originating mainly from
N
-acetylglucosamine moieties of acute-phase glycoproteins is related to incident type 2 diabetes mellitus and compared it with high-sensitivity C-reactive protein.

Approach and Results—

In 26 508 initially healthy women free of diabetes mellitus, baseline GlycA and high-sensitivity C-reactive protein were quantified by nuclear magnetic resonance spectroscopy and immunoturbidimetry, respectively. During median follow-up of 17.2 years, 2087 type 2 diabetes mellitus cases occurred. In Cox models with adjustment for age, race, smoking, alcohol, activity, menopausal status, hormone use, family history, and body mass index, quartile 4 versus 1 hazard ratios and 95% confidence intervals were 2.67 (2.26–3.14) for GlycA and 3.93 (3.24–4.77) for high-sensitivity C-reactive protein; both
P
trend <0.0001. Associations for GlycA and high-sensitivity C-reactive protein were attenuated after additionally adjusting for lipids: 1.65 (1.39–1.95) and 2.83 (2.32–3.44), respectively, both
P
trend <0.0001, and after mutual adjustment: 1.11 (0.93–1.33;
P
trend=0.10) and 2.57 (2.09–3.16;
P
trend<0.0001), respectively.

Conclusions—
Our finding of an association between a consensus glycan sequence common to a host of acute-phase reactants and incident type 2 diabetes mellitus provides further support for inflammation in the development of type 2 diabetes mellitus. Additional studies exploring the role of enzymatic glycosylation in the prevention of type 2 diabetes mellitus are warranted.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00000479.
Downregulation of Dynamin-Related Protein 1 Contributes to Impaired Autophagic Flux and Angiogenic Function in Senescent Endothelial Cells
Authors: Lin Jing-Rong , Shen Wei-Li , Yan Chen , Gao Ping-Jin 
Published: April 2015

Objective—
Recent studies have shown that altered mitochondrial dynamics impairs the function in senescent endothelial cells (ECs). However, the underlying molecular mechanism remains to be elucidated. Herein, we investigated the role and underlying mechanism of mitochondrial fission protein dynamin-related protein 1 (DRP1) in vascular aging.

Approach and Results—
We found that DRP1 expression is decreased in senescent ECs, accompanied with long interconnected mitochondria and impaired angiogenic function. In addition, there was marked increase of autophagosomes but not of autolysosomes (assessed as punctate dual fluorescent mCherry-GFP (green fluorescent protein) tandem-tagged light chain 3 expression) in senescent ECs, indicating impaired autophagic flux. DRP1 knockdown or pharmacological inhibition in young ECs resulted in elongated mitochondria, suppressed autophagic flux, premature senescence, and impaired angiogenic function. In contrast, adenoviral-mediated overexpression of DRP1 in senescent ECs restored autophagic flux and improved angiogenic function. EC senescence was associated with the increase of mitochondrial reactive oxygen species and antioxidant N-acetyl-cysteine restored autophagosome clearance and improved angiogenic function. Consistently, en face staining of old rat thoracic aorta revealed a decrease of DRP1 expression and increase of autophagosomes accumulation. Furthermore, in vivo knockdown of Drp1 in common carotid arteries significantly impaired the autophagosome clearance. Importantly, downregulation of Drp1 directly abrogated microvessels outgrowth from ex vivo aortic rings.

Conclusions—
These results suggest that loss of DRP1 during senescence exacerbates ECs dysfunction by increasing mitochondrial reactive oxygen species and subsequently inhibiting autophagic flux.
Focal Atrial Tachycardia Surrounding the Anterior Septum
Authors: Wang Zulu , Ouyang Jinge , Liang Yanchun , Jin Zhiqing , Yang Guitang , Liang Ming , Li Shibei , Yu Haibo , Han Yaling 
Published: April 2015

Background—
Focal atrial tachycardias (ATs) surrounding the anterior atrial septum (AAS) have been successfully ablated from the right atrial septum (RAS), the aortic cusps, and the aortic mitral junction. However, the strategy for mapping and ablation of AAS-ATs has not been well defined.

Methods and Results—
Of 227 consecutive patients with AT, 47 (20.7%; mean age, 56.3±11.6 years) with AAS-ATs were studied; among them, initial ablation was successful at RAS in only 5 of 14 patients and at noncoronary cusp (NCC) in 28 of 33 patients. In 45 of the 47 patients, the 46 of 48 AAS-ATs were eliminated at RAS in 8 patients, NCC in 35 patients (earliest activation time at NCC was later than that at RAS by 5–10 ms in 6 patients), and aortic mitral junction in 3 patients (all with negative P wave in lead aVL and positive P wave in the inferior leads), including 1 patient whose 2 ATs were eliminated separately from the NCC and the aortic mitral junction.

Conclusions—
Most of the ATs surrounding the AAS can be eliminated from within the NCC, which is usually the preferential ablation site. Ablation at the RAS and aortic mitral junction should be considered when supported by P-wave morphologies on surface ECG and results of activation mapping and ablation.
Efficacy of Long-Term β-Blocker Therapy for Secondary Prevention of Long-Term Outcomes After Coronary Artery Bypass Grafting Surgery
Authors: Zhang Heng , Yuan Xin , Zhang Haibo , Chen Sipeng , Zhao Yan , Hua Kun , Rao Chenfei , Wang Wei , Sun Hansong , Hu Shengshou , Zheng Zhe 
Published: April 2015

Background—
Conflicting results from recent observational studies have raised questions concerning the benefit of β-blockers for patients undergoing coronary artery bypass grafting (CABG). Furthermore, the efficacy of long-term β-blocker therapy in CABG patients after hospital discharge is uncertain.

Methods and Results—
The study included 5926 consecutive patients who underwent CABG and were discharged alive. The prevalence and consistency of β-blocker use were determined in patients with and without a history of myocardial infarction (MI). β-Blockers were always used in 1280 patients (50.9%) with and 1642 patients (48.1%) without previous MI after CABG. Compared with always users (n=2922, 49.3%), the risk of all-cause death was significantly higher among inconsistent β-blocker users (hazard ratio [HR], 1.96; 95% confidence interval [CI], 1.50–2.57), and never using β-blockers was associated with increased risk of both all-cause death (HR, 1.42; 95% CI, 1.01–2.00) and the composite of adverse cardiovascular events (HR, 1.29; 95% CI, 1.10–1.50). In the cohort without MI, the HR for all-cause death was 1.70 (95% CI, 1.17–2.48) in inconsistent users and 1.23 (95% CI, 0.76–1.99) in never users. In the MI cohort, mortality was higher for inconsistent users (HR, 2.14; 95% CI, 1.43–3.20) and for never users (HR, 1.59; 95% CI, 1.07–2.63). Consistent results were obtained in equivalent sensitivity analyses.

Conclusions—
In patients with or without previous MI undergoing CABG, the consistent use of β-blockers was associated with a lower risk of long-term mortality and adverse cardiovascular events. Strategies should be developed to understand and improve discharge prescription of β-blockers and long-term patient adherence.
Left Atrial Enlargement and Stroke Recurrence
Authors: Yaghi Shadi , Moon Yeseon P. , Mora-McLaughlin Consuelo , Willey Joshua Z. , Cheung Ken , Di Tullio Marco R. , Homma Shunichi , Kamel Hooman , Sacco Ralph L. , Elkind Mitchell S.V. 
Published: April 2015

Background and Purpose—
Although left atrial enlargement (LAE) increases incident stroke risk, the association with recurrent stroke is less clear. Our aim was to determine the association of LAE with recurrent stroke most likely related to embolism (cryptogenic and cardioembolic) and all ischemic stroke recurrences.

Methods—
We followed 655 first ischemic stroke patients in the Northern Manhattan Stroke Study for ≤5 years. LA size from 2D echocardiography was categorized as normal LAE (52.7%), mild LAE (31.6%), and moderate–severe LAE (15.7%). We used Cox proportional hazard models to calculate the hazard ratios and 95% confidence intervals for the association of LA size and LAE with recurrent cryptogenic/cardioembolic and total recurrent ischemic stroke.

Results—
LA size was available in 529 (81%) patients. Mean age at enrollment was 69±13 years; 45.8% were male, 54.0% Hispanic, and 18.5% had atrial fibrillation. Over a median of 4 years, there were 65 recurrent ischemic strokes (29 were cardioembolic or cryptogenic). In multivariable models adjusted for confounders, including atrial fibrillation and heart failure, moderate–severe LAE compared with normal LA size was associated with greater risk of recurrent cardioembolic/cryptogenic stroke (adjusted hazard ratio 2.83, 95% confidence interval 1.03–7.81), but not total ischemic stroke (adjusted hazard ratio 1.06, 95% confidence interval, 0.48–2.30). Mild LAE was not associated with recurrent stroke.

Conclusion—
Moderate to severe LAE was an independent marker of recurrent cardioembolic or cryptogenic stroke in a multiethnic cohort of ischemic stroke patients. Further research is needed to determine whether anticoagulant use may reduce risk of recurrence in ischemic stroke patients with moderate to severe LAE.
Short-Term Blood Pressure Variability in Acute Stroke
Authors: Manning Lisa S. , Mistri Amit K. , Potter John , Rothwell Peter M. , Robinson Thompson G. 
Published: April 2015

Background and Purpose—
Short-term blood pressure variability (BPV) may predict outcome in acute stroke. We undertook a post hoc analysis of data from 2 randomized controlled trials to determine the effect of short-term BPV on 2-week outcome.

Methods—
Controlling Hypertension and Hypotension Immediately Post Stroke (CHHIPS) was a trial of BP-lowering, enrolling 179 acute stroke patients (onset <36 hours). Continue or Stop Post-Stroke Antihypertensives Collaborative Study (COSSACS) compared a strategy of continuation versus temporarily stopping prestroke antihypertensive therapy in 763 acute stroke patients (onset <48 hours). BPV at baseline (defined as SD, coefficient of variation, variation independent of the mean, and average real variability) was derived from standardized casual cuff BP measures (6 readings <30 minutes). Adjusted logistic regression models were used to assess the relation between BPV and death and disability (modified Rankin scale>3) at 2 weeks.

Results—
Seven hundred six (92.5%) and 171 (95.5%) participants were included in the analysis for the COSSACS and CHHIPS data sets, respectively. Adjusted logistic regression analyses revealed no statistically significant associations between any of the included BPV parameters with 2-week death or disability in either study data set: COSSACS, odds ratio SD systolic BP 0.98 (0.78–1.23); CHHIPS, odds ratio SD systolic BP 0.97 (0.90–1.11).

Conclusions—
When derived from casual cuff BP measures, short-term BPV is not a useful predictor of early (2 weeks) outcome after acute stroke. Differing methodology may account for the discordance with previous studies indicating long-term (casual BPV) and short-term (beat-to-beat BPV) prognostic value.

Clinical Trial Registration—

COSSACS was registered on the International Standard Randomised Controlled Trial Register; URL:
http://www.isrctn.com
. Unique identifier: ISRCTN89712435. CHHIPS was registered on the National Research Register; URL:
http://public.ukcrn.org.uk
. Unique identifier: N0484128008.
The Linkage between the Eastern Pacific Teleconnection Pattern and Convective Heating over the Tropical Western Pacific
Authors: Tan Benkui , Yuan Jiacan , Dai Ying , Feldstein Steven B. , Lee Sukyoung 
Published: April 2015

Abstract
The eastern Pacific (EP) pattern is a recently detected atmospheric teleconnection pattern that frequently occurs during late winter. Through analysis of daily ERA-Interim data and outgoing longwave radiation data for the period of 1979–2011, it is shown here that the formation of the EP is preceded by an anomalous tropical convection dipole, with one extremum located over the eastern Indian Ocean–Maritime Continent and the other over the central Pacific. This is followed by the excitation of two quasi-stationary Rossby wave trains. Departing from the subtropics, north of the region of anomalous convection, one Rossby wave train propagates eastward along the East Asian jet from southern China toward the eastern Pacific. The second wave train propagates northward from east of Japan toward eastern Siberia and then turns southeastward to the Gulf of Alaska. Both wave trains are associated with wave activity flux convergence where the EP pattern develops. The results from an examination of the E vector suggest that the EP undergoes further growth with the aid of positive feedback from high-frequency transient eddies. The frequency of occurrence of the dipole convection anomaly increases significantly from early to late winter, a finding that suggests that it is the seasonal change in the convection anomaly that accounts for the EP being more dominant in late winter.
Tropical Cyclone–Induced Ocean Response: A Comparative Study of the South China Sea and Tropical Northwest Pacific*,+
Authors: Mei Wei , Lien Chun-Chi , Lin I.-I. , Xie Shang-Ping 
Published: April 2015

Abstract
The thermocline shoals in the South China Sea (SCS) relative to the tropical northwest Pacific Ocean (NWP), as required by geostrophic balance with the Kuroshio. The present study examines the effect of this difference in ocean state on the response of sea surface temperature (SST) and chlorophyll concentration to tropical cyclones (TCs), using both satellite-derived measurements and three-dimensional numerical simulations. In both regions, TC-produced SST cooling strongly depends on TC characteristics (including intensity as measured by the maximum surface wind speed, translation speed, and size). When subject to identical TC forcing, the SST cooling in the SCS is more than 1.5 times that in the NWP, which may partially explain weaker TC intensity on average observed in the SCS. Both a shallower mixed layer and stronger subsurface thermal stratification in the SCS contribute to this regional difference in SST cooling. The mixed layer effect dominates when TCs are weak, fast-moving, and/or small; and for strong and slow-moving TCs or strong and large TCs, both factors are equally important.
In both regions, TCs tend to elevate surface chlorophyll concentration. For identical TC forcing, the surface chlorophyll increase in the SCS is around 10 times that in the NWP, a difference much stronger than that in SST cooling. This large regional difference in the surface chlorophyll response is at least partially due to a shallower nutricline and stronger vertical nutrient gradient in the SCS. The effect of regional difference in upper-ocean density stratification on the surface nutrient response is negligible. The total annual primary production increase associated with the TC passage estimated using the vertically generalized production model in the SCS is nearly 3 times that in the NWP (i.e., 6.4 ± 0.4 × 1012 versus 2.2 ± 0.2 × 1012 g C), despite the weaker TC activity in the SCS.