bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dietary Pyridoxine Controls Efficacy of Vitamin B
6
-Auxotrophic Tuberculosis Vaccine Bacillus Calmette-Guérin Δ
ureC
::
hly
Δ
pdx1
in Mice
Authors: Gengenbacher Martin , Vogelzang Alexis , Schuerer Stefanie , Lazar Doris , Kaiser Peggy , Kaufmann Stefan H. E. 
Published: June 2014

ABSTRACT

The only tuberculosis (TB) vaccine in use today, bacillus Calmette-Guérin (BCG), provides insufficient protection and can cause adverse events in immunocompromised individuals, such as BCGosis in HIV
+
newborns. We previously reported improved preclinical efficacy and safety of the recombinant vaccine candidate BCG Δ
ureC
::
hly
, which secretes the pore-forming listeriolysin O of
Listeria monocytogenes
. Here, we evaluate a second-generation construct, BCG Δ
ureC
::
hly
Δ
pdx1
, which is deficient in pyridoxine synthase, an enzyme that is required for biosynthesis of the essential cofactor vitamin B
6
. This candidate was auxotrophic for vitamin B
6
in a concentration-dependent manner, as was its survival
in vivo
. BCG Δ
ureC
::
hly
Δ
pdx1
showed markedly restricted dissemination in subcutaneously vaccinated mice, which was ameliorated by dietary supplementation with vitamin B
6
. The construct was safer in severe combined immunodeficiency mice than the parental BCG Δ
ureC
::
hly
. A prompt innate immune response to vaccination, measured by secretion of interleukin-6, granulocyte colony-stimulating factor, keratinocyte cytokine, and macrophage inflammatory protein-1α, remained independent of vitamin B
6
administration, while acquired immunity, notably stimulation of antigen-specific CD4 T cells, B cells, and memory T cells, was contingent on vitamin B
6
administration. The early protection provided by BCG Δ
ureC
::
hly
Δ
pdx1
in a murine
Mycobacterium tuberculosis
aerosol challenge model consistently depended on vitamin B
6
supplementation. Prime-boost vaccination increased protection against the canonical
M. tuberculosis
H37Rv laboratory strain and a clinical isolate of the Beijing/W lineage. We demonstrate that the efficacy of a profoundly attenuated recombinant BCG vaccine construct can be modulated by external administration of a small molecule. This principle fosters the development of safer vaccines required for immunocompromised individuals, notably HIV
+
infants.

IMPORTANCE
Mycobacterium tuberculosis
can synthesize the essential cofactor vitamin B
6
, while humans depend on dietary supplementation. Unlike the lipophilic vitamins A, D, and E, water-soluble vitamin B
6
is well tolerated at high doses. We generated a vitamin B
6
auxotroph of the phase II clinical tuberculosis vaccine candidate bacillus Calmette-Guérin Δ
ureC
::
hly
. The next-generation candidate was profoundly attenuated compared to the parental strain. Adaptive immunity and protection in mice consistently depended on increased dietary vitamin B
6
above the daily required dose. Control of vaccine efficacy via food supplements such as vitamin B
6
could provide a fast track toward improved safety. Safer vaccines are urgently needed for HIV-infected individuals at high risk of adverse events in response to live vaccines.
Developmental trajectories of Body Mass Index from infancy to 18 years of age: prenatal determinants and health consequences
Authors: Ziyab Ali H , Karmaus Wilfried , Kurukulaaratchy Ramesh J , Zhang Hongmei , Arshad Syed Hasan 
Published: June 2014

BackgroundKnowledge on the long-term development of adiposity throughout childhood/adolescence and its prenatal determinants and health sequelae is lacking. We sought to (1) identify trajectories of Body Mass Index (BMI) from 1 to 18 years of age, (2) examine associations of maternal gestational smoking and early pregnancy overweight with offspring BMI trajectories and (3) determine whether BMI trajectories predict health outcomes: asthma, lung function parameters (forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) ratio), and blood pressure, at 18 years.MethodsThe Isle of Wight birth cohort, a population-based sample of 1456 infants born between January 1989 and February 1990, was prospectively assessed at ages 1, 2, 4, 10 and 18 years. Group-based trajectory modelling was applied to test for the presence of latent BMI trajectories. Associations were assessed using log-binomial and linear regression models.ResultsFour trajectories of BMI were identified: ‘normal’, ‘early persistent obesity’, ‘delayed overweight’, and ‘early transient overweight’. Risk factors for being in the early persistent obesity trajectory included maternal smoking during pregnancy (RR 2.16, 95% CI 1.02 to 4.68) and early pregnancy overweight (3.16, 1.52 to 6.58). When comparing the early persistent obesity to the normal trajectory, a 2.15-fold (1.33 to 3.49) increased risk of asthma, 3.2% (0.4% to 6.0%) deficit in FEV1/FVC ratio, and elevated systolic 11.3 mm Hg (7.1 to 15.4) and diastolic 12.0 mm Hg (8.9 to 15.1) blood pressure were observed at age 18 years.ConclusionsMaternal prenatal exposures show prolonged effects on offspring's propensity towards overweight-obesity. Distinct morbid BMI trajectories are evident during the first 18 years of life that are associated with higher risk of asthma, reduced FEV1/FVC ratio, and elevated blood pressure.
Upper gastrointestinal bleeding in hospital inpatients: the role of antithrombotic drugs
Authors: Taha Ali S , Kelly Claire , McCloskey Caroline , Craigen Theresa , Angerson Wilson J 
Published: June 2014

Abstract

Background
Critically ill patients are considered to be most at risk from developing non-variceal upper gastrointestinal bleeding (NVGIB) while in hospital. The increasing prescription of low-dose aspirin and other antithrombotic drugs for protection against thromboembolism to many patients admitted to hospital may increase the vulnerability of a wider group to NVGIB.

Objective
This study compares two groups of patients with NVGIB: group I, inpatients cared for outside the intensive care unit; and group II, patients admitted with this condition, while considering the use of antithrombotic drugs.

Methods
We identified all patients who developed NVGIB in the two calendar years between 2008 and 2009 and compared group I with group II while taking into account their clinical details including Rockall scores and drug usage.

Results
Compared with group II (n=274), group I (n=96) were older (median age of 77 years vs 68; p&lt;0.001), had fewer males (45.8% vs 60.6%; p=0.016), higher prevalence of cardiovascular disease (52.1% vs 29.2%; p&lt;0.001), more patients with complete Rockall score ≥3 (84.4% vs 66.7%; p=0.001) and more patients treated with aspirin or other antithrombotic drugs (64.6% vs 44.5%; p=0.001). After adjustment for age and sex, group I were still significantly more likely to be taking antithrombotic drugs than group II (OR (95% CIs), 2.15 (1.25 to 3.68); p=0.006). The endoscopic abnormalities in more than 80% of patients included erosive oesophagitis, gastric or duodenal ulcers or erosions.

Conclusions
Subjects who develop NVGIB as inpatients have higher Rockall scores are mainly older females with cardiovascular disease and using antithrombotic drugs. Secondary care clinicians should be mindful of this at-risk group of patients and consider giving them prophylactic antiulcer therapy.
Gamma-Ray Pulsar Revolution
Authors: Caraveo Patrizia A. 
Published: June 2014

Isolated neutron stars (INSs) were the first sources identified in the field of high-energy gamma-ray astronomy. In the 1970s, only two sources had been identified, the Crab and Vela pulsars. However, although few in number, these objects were crucial in establishing the very concept of a gamma-ray source. Moreover, they opened up significant discovery space in both the theoretical and phenomenological fronts. The need to explain the copious gamma-ray emission of these pulsars led to breakthrough developments in understanding the structure and physics of neutron star (NS) magnetospheres. In parallel, the 20-year-long chase to understand the nature of Geminga unveiled the existence of a radio-quiet, gamma-ray-emitting INS, adding a new dimension to the INS family. We are living through an extraordinary time of discovery. The current generation of gamma-ray detectors has vastly increased the population of known gamma-ray-emitting NSs. The 100 mark was crossed in 2011, and we are now over 150. The gamma-ray-emitting NS population exhibits roughly equal numbers of radio-loud and radio-quiet young INSs, plus an astonishing, and unexpected, group of isolated and binary millisecond pulsars (MSPs). The number of MSPs is growing so rapidly that they are on their way to becoming the most numerous members of the family of gamma-ray-emitting NSs. Even as these findings have set the stage for a revolution in our understanding of gamma-ray-emitting NSs, long-term monitoring of the gamma-ray sky has revealed evidence of flux variability in the Crab Nebula as well as in the pulsed emission from PSR J2021+4026, challenging a four-decades-old, constant-emission paradigm. Now we know that both pulsars and their nebulae can, indeed, display variable emission.
Germline Mutations in BAP1 Impair Its Function in DNA Double-Strand Break Repair
Authors: Ismail Ismail Hassan , Davidson Riley , Gagné Jean-Philippe , Xu Zhi Zhong , Poirier Guy G. , Hendzel Michael J. 
Published: June 2014

Abstract
The BRCA1-associated deubiquitylase BAP1 is mutated in several cancers, most notably mesothelioma and melanoma, where it is thought to promote oncogenesis. In this study, we present evidence that BAP1 functions as part of the DNA damage response (DDR). We found that BAP1 mediates rapid poly(ADP-ribose)-dependent recruitment of the polycomb deubiquitylase complex PR-DUB to sites of DNA damage. Furthermore, we identified BAP1 as a phosphorylation target for the DDR kinase ATM. Functionally, BAP1 promoted repair of DNA double-strand breaks, enhancing cell survival after DNA damage. Our results highlight the importance of ubiquitin turnover at sites of DNA damage, and they provide a mechanism to account for the tumor-suppressive function of BAP1. Cancer Res; 74(16); 4282–94. ©2014 AACR.
A RAS Renaissance: Emerging Targeted Therapies for KRAS-Mutated Non–Small Cell Lung Cancer
Authors: Vasan Neil , Boyer Julie L. , Herbst Roy S. 
Published: June 2014

Abstract
Of the numerous oncogenes implicated in human cancer, the most common and perhaps the most elusive to target pharmacologically is RAS. Since the discovery of RAS in the 1960s, numerous studies have elucidated the mechanism of activity, regulation, and intracellular trafficking of the RAS gene products, and of its regulatory pathways. These pathways yielded druggable targets, such as farnesyltransferase, during the 1980s to 1990s. Unfortunately, early clinical trials investigating farnesyltransferase inhibitors yielded disappointing results, and subsequent interest by pharmaceutical companies in targeting RAS waned. However, recent advances including the identification of novel regulatory enzymes (e.g., Rce1, Icmt, Pdeδ), siRNA-based synthetic lethality screens, and fragment-based small-molecule screens, have resulted in a “Ras renaissance,” signified by new Ras and Ras pathway–targeted therapies that have led to new clinical trials of patients with Ras-driven cancers. This review gives an overview of KRas signaling pathways with an emphasis on novel targets and targeted therapies, using non–small cell lung cancer as a case example. Clin Cancer Res; 20(15); 3921–30. ©2014 AACR.
An Unconventional KITENIN/ErbB4-Mediated Downstream Signal of EGF Upregulates c-Jun and the Invasiveness of Colorectal Cancer Cells
Authors: Bae Jeong A. , Yoon Somy , Park So-Yeon , Lee Jae Hyuk , Hwang Jun-Eul , Kim Hangun , Seo Young-Woo , Cha Yoon Jin , Hong Sung Pil , Kim Hoguen , Chung Ik Joo , Kim Kyung Keun 
Published: June 2014

AbstractPurpose: EGF-stimulated signaling via EGF receptor (EGFR) is important in colorectal tumorigenesis and drug targeting. However, anti-EGFR therapy is not effective in a subset of patients with colorectal cancer, suggesting that unidentified EGF-stimulated pathways might play roles in colorectal cancer. Previously, we identified KAI1 C-terminal interacting tetraspanin (KITENIN) as a metastasis-enhancing gene and found it to be highly expressed in sporadic colorectal cancer tissues. We recently found that EGF further increases KITENIN-induced elevated AP-1 activity. Here we attempted to clarify this novel EGF-stimulated molecular pathway and its roles in colorectal cancer.Experimental Design: We analyzed how EGF modulates the downstream signaling pathway of oncogenic KITENIN in colorectal cancer cells. Biological alterations following EGF treatment were identified in KITENIN-overexpressed colorectal cancer cells with or without alteration of EGFR activity.Results: We identified the KITENIN/ErbB4–Dvl2–c-Jun axis as a novel downstream signal of EGF that is switched on under elevated KITENIN conditions in an EGFR-independent manner. This unconventional EGF signal upregulates c-Jun and enhances invasion and anchorage-independent growth of colorectal cancer cells. In addition, tumor tissues from metastatic patients with colorectal cancer who showed initial poor responses to cetuximab/chemotherapy expressed higher levels of KITENIN than did responders to therapy.Conclusions: Our results highlight the role of an EGFR-independent EGF signal in mediating the invasiveness and tumorigenesis of colorectal cancer cells. This unconventional pathway might be related to the limited clinical efficacy of anti-EGFR agents in a subset of patients with colorectal cancer. Clin Cancer Res; 20(15); 4115–28. ©2014 AACR.
Molecular Pathways: Targeting NRAS in Melanoma and Acute Myelogenous Leukemia
Authors: Johnson Douglas B. , Smalley Keiran S.M. , Sosman Jeffrey A. 
Published: June 2014

Abstract
Successful targeting of specific oncogenic “driver” mutations with small-molecule inhibitors has represented a major advance in cancer therapeutics over the past 10 to 15 years. The most common activating oncogene in human malignancy, RAS (rat sarcoma), has proved to be an elusive target. Activating mutations in RAS induce mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase–AKT pathway signaling and drive malignant progression in up to 30% of cancers. Oncogenic NRAS mutations occur in several cancer types, notably melanoma, acute myelogenous leukemia (AML), and less commonly, colon adenocarcinoma, thyroid carcinoma, and other hematologic malignancies. Although NRAS-mutant tumors have been recalcitrant to targeted therapeutic strategies historically, newer agents targeting MAP/ERK kinase 1 (MEK1)/2 have recently shown signs of clinical efficacy as monotherapy. Combination strategies of MEK inhibitors with other targeted agents have strong preclinical support and are being evaluated in clinical trials. This review discusses the recent preclinical and clinical studies about the role of NRAS in cancer, with a focus on melanoma and AML. Clin Cancer Res; 20(16); 4186–92. ©2014 AACR.
Cotargeting of Epidermal Growth Factor Receptor and PI3K Overcomes PI3K–Akt Oncogenic Dependence in Pancreatic Ductal Adenocarcinoma
Authors: Wong Matthew H. , Xue Aiqun , Julovi Sohel M. , Pavlakis Nick , Samra Jaswinder S. , Hugh Thomas J. , Gill Anthony J. , Peters Lyndsay , Baxter Robert C. , Smith Ross C. 
Published: June 2014

Abstract
Purpose: PI3K–Akt is overexpressed in 50% to 70% of pancreatic ductal adenocarcinoma (PDAC). The hypothesis of this study is that PI3K and EGFR coinhibition may be effective in PDAC with upregulated PI3K–Akt signaling.
Experimental Design: Multiple inhibitors were tested on five PDAC cell lines. EGFR inhibitor (EGFRi)–resistant cell lines were found to have significantly overexpressed AKT2 gene, total Akt, and pAkt. In vitro erlotinib-resistant (ER) cell models (BxPC-ER and PANC-ER) with highly constitutively active PI3K–Akt were developed. These and their respective parent cell lines were tested for sensitivity to erlotinib, IGFIR inhibitor NVP-AEW541 (AEW), and PI3K-alpha inhibitor NVP-BYL719 (BYL), alone or in combination, by RTK-phosphoarray, Western blotting, immunofluorescence, qRT-PCR, cell proliferation, cell cycle, clonogenic, apoptosis, and migration assays. Erlotinib plus BYL was tested in vivo.
Results: Erlotinib acted synergistically with BYL in BxPC-ER (synergy index, SI = 1.71) and PANC-ER (SI = 1.44). Treatment of ER cell lines showing upregulated PI3K–Akt with erlotinib plus BYL caused significant G1 cell-cycle arrest (71%, P &lt; 0.001; 58%, P = 0.003), inhibition of colony formation (69% and 72%, both P &lt; 0.001), and necrosis and apoptosis (75% and 53%, both P &lt; 0.001), more so compared with parent cell lines. In primary patient-derived tumor subrenal capsule (n = 90) and subcutaneous (n = 22) xenografts, erlotinib plus BYL significantly reduced tumor volume (P = 0.005). Strong pEGFR and pAkt immunostaining (2+/3+) was correlated with high and low responses, respectively, to both erlotinib and erlotinib plus BYL.
Conclusion: PDAC with increased expression of the PI3K–Akt pathway was susceptible to PI3K–EGFR coinhibition, suggesting oncogenic dependence. Erlotinib plus BYL should be considered for a clinical study in PDAC; further evaluation of pEGFR and pAkt expression as potential positive and negative predictive biomarkers is warranted. Clin Cancer Res; 20(15); 4047–58. ©2014 AACR.
Neuroblastoma Killing Properties of Vδ2 and Vδ2-Negative γδT Cells Following Expansion by Artificial Antigen-Presenting Cells
Authors: Fisher Jonathan P.H. , Yan Mengyong , Heuijerjans Jennifer , Carter Lisa , Abolhassani Ayda , Frosch Jennifer , Wallace Rebecca , Flutter Barry , Capsomidis Anna , Hubank Mike , Klein Nigel , Callard Robin , Gustafsson Kenth , Anderson John 
Published: June 2014

Abstract
Purpose: The majority of circulating human γδT lymphocytes are of the Vγ9Vδ2 lineage, and have T-cell receptor (TCR) specificity for nonpeptide phosphoantigens. Previous attempts to stimulate and expand these cells have therefore focused on stimulation using ligands of the Vγ9Vδ2 receptor, whereas relatively little is known about variant blood γδT subsets and their potential role in cancer immunotherapy.
Experimental Design: To expand the full repertoire of γδT without bias toward specific TCRs, we made use of artificial antigen-presenting cells loaded with an anti γδTCR antibody that promoted unbiased expansion of the γδT repertoire. Expanded cells from adult blood donors were sorted into 3 populations expressing respectively Vδ2 TCR chains (Vδ2+), Vδ1 chains (Vδ1+), and TCR of other δ chain subtypes (Vδ1negVδ2neg).
Results: Both freshly isolated and expanded cells showed heterogeneity of differentiation markers, with a less differentiated phenotype in the Vδ1 and Vδ1negVδ2neg populations. Expanded cells were largely of an effector memory phenotype, although there were higher numbers of less differentiated cells in the Vδ1+ and Vδ1negVδ2neg populations. Using neuroblastoma tumor cells and the anti-GD2 therapeutic mAb ch14.18 as a model system, all three populations showed clinically relevant cytotoxicity. Although killing by expanded Vδ2 cells was predominantly antibody dependent and proportionate to upregulated CD16, Vδ1 cells killed by antibody-independent mechanisms.
Conclusions: In conclusion, we have demonstrated that polyclonal-expanded populations of γδT cells are capable of both antibody-dependent and -independent effector functions in neuroblastoma. Clin Cancer Res; 20(22); 5720–32. ©2014 AACR.
Toll-like Receptor Agonist Imiquimod Facilitates Antigen-Specific CD8+ T-cell Accumulation in the Genital Tract Leading to Tumor Control through IFNγ
Authors: Soong Ruey-Shyang , Song Liwen , Trieu Janson , Knoff Jayne , He Liangmei , Tsai Ya-Chea , Huh Warner , Chang Yung-Nien , Cheng Wen-Fang , Roden Richard B.S. , Wu T.-C. , Trimble Cornelia L. , Hung Chien-Fu 
Published: June 2014

Abstract
Purpose: Imiquimod is a Toll-like receptor 7 agonist used topically to treat external genital warts and basal cell carcinoma. We examined the combination of topical imiquimod with intramuscular administration of CRT/E7, a therapeutic human papillomavirus (HPV) vaccine comprised of a naked DNA vector expressing calreticulin fused to HPV16 E7.
Experimental Design: Using an orthotopic HPV16 E6/E7+ syngeneic tumor, TC-1, as a model of high-grade cervical/vaginal/vulvar intraepithelial neoplasia, we assessed if combining CRT/E7 vaccination with cervicovaginal deposition of imiquimod could result in synergistic activities promoting immune-mediated tumor clearance.
Results: Imiquimod induced cervicovaginal accumulation of activated E7-specific CD8+ T cells elicited by CRT/E7 vaccination. Recruitment was not dependent upon the specificity of the activated CD8+ T cells, but was significantly reduced in mice lacking the IFNγ receptor. Intravaginal imiquimod deposition induced upregulation of CXCL9 and CXCL10 mRNA expression in the genital tract, which are produced in response to IFNγ receptor signaling and attract cells expressing their ligand, CXCR3. The T cells attracted by imiquimod to the cervicovaginal tract expressed CXCR3 as well as CD49a, an integrin involved in homing and retention of CD8+ T cells at mucosal sites. Our results indicate that intramuscular CRT/E7 vaccination in conjunction with intravaginal imiquimod deposition recruits antigen-specific CXCR3+ CD8+ T cells to the genital tract.
Conclusions: Several therapeutic HPV vaccination clinical trials using a spectrum of DNA vaccines, including vaccination in concert with cervical imiquimod, are ongoing. Our study identifies a mechanism by which these strategies could provide therapeutic benefit. Our findings support accumulating evidence that manipulation of the tumor microenvironment can enhance the therapeutic efficacy of strategies that induce tumor-specific T cells. Clin Cancer Res; 20(21); 5456–67. ©2014 AACR.
Dihydromyricetin Activates AMP-Activated Protein Kinase and P38MAPK Exerting Antitumor Potential in Osteosarcoma
Authors: Zhao Zhiqiang , Yin Jun-qiang , Wu Man-si , Song Guohui , Xie Xian-biao , Zou Changye , Tang Qinglian , Wu Yuanzhong , Lu Jinchang , Wang Yongqian , Wang Jin , Kang Tiebang , Jia Qiang , Shen Jingnan 
Published: June 2014

Abstract
Numerous patients with osteosarcoma either are not sensitive to chemotherapy or develop drug resistance to current chemotherapy regimens. Therefore, it is necessary to develop several potentially useful therapeutic agents. Dihydromyricetin is the major flavonoid component derived from Ampelopsis grossedentata, which has a long history of use in food and medicine. The present study examined the antitumor activity both in vitro and in vivo without noticeable side effects and the underlying mechanism of action of dihydromyricetin in osteosarcoma cells. We found that dihydromyricetin induced increased p21 expression and G2–M cell-cycle arrest, caused DNA damage, activated ATM–CHK2–H2AX signaling pathways, and induced apoptosis in osteosarcoma cells as well as decreasing the sphere formation capability by downregulating Sox2 expression. Mechanistic analysis showed that the antitumor potential of dihydromyricetin may be due to the activation of AMPKα and p38MAPK, as the activating AMPKα led to the inactivation of GSK3β in osteosarcoma cells. Moreover, GSK3β deletion or GSK3β inhibition by LiCl treatment resulted in increased p21 expression and reduced Sox2 expression in osteosarcoma cells. Taken together, our results strongly indicate that the antitumor potential of dihydromyricetin is correlated with P38MAPK and the AMPKα–GSK3β–Sox2 signaling pathway. Finally, immunohistochemical analysis indicated that some patients had a lower p-AMPK expression after chemotherapy, which supports that the combination of dihydromyricetin and chemotherapy drug will be beneficial for patients with osteosarcoma. In conclusion, our results are the first to suggest that dihydromyricetin may be a therapeutic candidate for the treatment of osteosarcoma. Cancer Prev Res; 7(9); 927–38. ©2014 AACR.